Ss

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Marijuana and Health (1982)
Division of Health Sciences Policy; Institute of Medicine
Pages
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ISBN
0309032369
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Marijuana and Health

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Report of a Study
by
Committee of the
INSTITUfE OF MEDICINE
Division of Health Sciences Policy
NATIONAL ACADEMY PRESS
Washington, D.C.
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1982
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NOTICE The proj ect that is the subj ect of thi s repor t was approved
by the Governing Board of the Nat iona l Research Counc i l , whose
members are drawn from the Counc ils of the Nat ional Academy of
Sciences , the National Academy of Eng ineering , and the Inst itute of
Med ic ine . The member s of the ccmm i ttee responsible for the repor t
were chosen for the i r spec ial competence & and with r egard for
appropr iate balance .
Th i s r epor t has been reviewed by a g roup other than the authors
accord ing to procedures approved by a Repor t Review Comm i ttee
cons isting of members of the Nat ional Academy of Sc iences , the
Nat iona l Academy of Eng ineer ing , and the Inst itute of Med ic ine .
The Institute of Med icine was char tered in 1970 by the Nat ional
Academy of Sc iences to enl ist dist inguished members of the
appropr iate professions in the examinat ion of policy matters
In th is , the Inst itute act s
pertaining to the health of the publ ic .
under both the Academy ' s 1863 Cong ress ional charter respons ibil ity to
be an advi sor to the federal government , and its own initiative in
ident ifying i ssues of med ical care , research , and educat ion .
Th i s study was suppor ted by the Nat ional Inst itutes of Health ,
Contract No . NOl-oD-0-2114 .
Internat ional Standard Boo k NUmber 0-309-0 3236- 9

Library of Cong ress Catalog Card Number 8 1-86534
Avai lable from :

NAT:J:ONAL ACADEMY PRES S
2 101 Constitut ion Ave . , N . W .
ashing ton , D . C .
2 0 4 18
P r inted in the Un ited States of Amer ica

COMMI'l"l'EE '1'0 STUDY THE HEALTHRE LATED EFFECTS

OF CANNAB IS AND ITS DERIVATIVES
Arnold s. Relman , Cha i rman
Edito r
The New England Jou rnal of Medicin e
I rwin Fe inberg
Professor of Psychiatry
University of California ,
San Fra nc isco and
Vete rans Administration Medica l
Center , San Francisco
Konrad E . Bloch
Professor
Depa rtment of Chemistry
Harvard Univer sity
Bar ton Childs
Professor of Ped iatric s
and B iology
The Johns Hopkins Unive r sity
School of Med icine
Alfred P . Fishman
Professor of Med icine
Dir ector
Card iovascular Pulmonary Divis ion
Hospital of the Univer sity
of Pennsylvania
Michael I . Cohen
Chai rman and Professo r
Depar tment of Pediatr ics
Alber t Einste in Colleg e
of Med icine
Montefiore Hospital and
Med ical Center
Beat r ix Bamburg
Assoc iate Professor of Psychiatry
Department of Psych iatry and
Department of Social Med icine
and Health Pol icy
Harvard Med ical School
P . B . Dews
and Psychobiology
Laboratory of Psychobiology
Harvard Med ica l School
Edward F . Domino
Professor
Depar tment of Pharmacology
Unive r s ity of Michigan
B . Car l Baywood
Professor of Psychology
and Neurology
Director
The John F . Kennedy Center
for Research on Educat ion
and Ruman Development
Vanderbilt Univer sity
Robert B . Edgerton
Professor
Depar tments of Psychiatry
and Anthropology
University of Cal ifornia ,
Los Angeles
Reese T. Jones
Langley Porter Psych iatr ic
Inst i tute
University of California ,
San Franci sco
Daniel D. Federman
Dean for Students and Alumni
Harvard Medical School
Harold Kalant
Professor
Department of Pharmacology
University of TOronto
iii

Nor ton Ne lson

Professor of Env ironmental
Med ic i ne
New Yor k Un iver s i ty
Med ical Cente r
Den i se Kandel
P rofessor of Publ ic Health
Depa r tment of Psychiatry
Columbia Un ive r s i ty and
New Yor k State Psychiatr i c
I nstitute
Charles P . O ' Br ien

Professor of Psychiat r y
Unive r s i ty o f Pennsylvan ia
School of Medicine and
Philadelphia Veterans Adminis
tration Medical Center
Barbara M . Kor sc h
Professor of Ped i atr ics
and Head
D iv i s ion of General Ped iatr ics
Ch i ldren ' s Hospital of
Los Angeles
Unive r s i ty of Southern California
School of Med ic ine
S heldon J . Segal
Di r ector
Popu lat ion Sc iences Division
Rockefelle r Foundat ion
Rober t Y . Moo r e
Professor and Cha i rma n
Department of Neurology
State Unive r s ity of New Yor k
a t Stony Brook
Robe r t F. Mur r ay , Jr .
Professor of Ped iatr ics,
Med ic ine and Oncolog y
C h ief , Divis ion of Med ical Genet ics
Depa rtment of Pediatr ics and Ch ild
Health
College of Med ic ine
Howard Univers ity
Paul D . Stolley
Professor
Depar tment of Med ic ine
Unive r si ty of Pennsylvani a
School of Med ic ine
iv

INSTITUTE OF MEDIC INE

Frede r ick c . Robbins
Pres iden t
Study Staf f
Bnrlqueta c . Bond , Director , Divis ion of Health Sc iences Polley
Linda s . Duj ack , Study Director
Kathryn G. King , Research Assoc iate
caren M . Carney , Research Assoc iate
Allyn M. Mor t imer , Research Ass i stant
Roszel s . Thomsen I I , Research Ass istan t
Linda A . DePugh , Admini strat ive secretary
Constance
v.
Shuck , Administrat ive Secretary
With the collaborat ion of the Direc tor of the Divis ion of Mental
Health and Behavioral Med ic ine , Fred r ic Solomon , and the assistanc e
of Institute of Med ic ine staff members Bar bara Fllne r , Barbara
Mandula , and Rober t Field .
Consu ltant s
Henry D . Abraham , Harvard Univer s ity
Richa rd B . Belleville , Pr ivate Consultant
Kevin Fehr , Add ict ion Research FOundat ion
He rbert Moskowiz , Southern Cali fornia Research Inst itute
Wendy Nel son , Un ive r s ity of Pennsylvan ia
Oakley s . Ray , Veterans Admini strat ion Med ical Center
Br ian L . St rom, Univers ity of Pennsylvania

Study of the Halth-Related Effects of

Cannabis and I ta Derivatives
PANELS
cardiovascular and Respir atory Issue s
Alf red P . Fishman* , Chairman
Gerard M . Turlno
Professor of Medicine
Deprtment of Medicine
Columbia University College
of Physicians and Surgeons
Brian F. Hoffman
P rofessor and Chairman
Depar tment of Pharmacology
Columbia Univer sity College
Jerome I . K lelnerman
Chairman
Depar tment of Patholog y
Mount Sinal School o f Medicine
Neurobiological I ssues
I rwin Feinberg* , Chairman
Edward
F.
Domino*
A. Edward Maumenee
Professor of Ophthalmolog y
Wilmer Institute
Johns Hopkins Hospital
B. C raig Beller
Associate Professor of Biology
Depar tment of Biological Sciences
S tanford University
Robert Moo r e*
Reese T . Jone s*
Char les
p.
O ' Brien *
Harold K alant*
I rwin B . Krakof f
Director
Ve rmont Regional Cancer Center
* Commi ttee member .
vi

Behavioral , Psychosocia l , and Epidemiologic Issue s

Charles P . O ' Brien* and H . Carl Haywood* , co-chairmen
Michae l I . Cohen*
Denise Kandel*
Robert B . Edger ton*
Barbara M . Kor sch*
Beatrix Hamburg*
Pau l D . Stolley*
Reese T . Jones*
Reproductive and Fetal Issues

Danie l D. Fede rman* , Chairman
Nor ton Nelson*
F . Clarke Fraser
Director of Medical Genetic s
Montreal Child ren ' s Hospi tal
Sheldon Segal*
Genetic , Oncogenic , and Cytogenetic I ssue s

Bar ton Child s* , Chairman
Rober t F . Mu r r ay , Jr . *
Arthur D. Bloom
P rofessor of Pediat rics and of
Human Genetic s and Development
Direc tor , Clinical Genetics
Columbia Univer sity Colleg e
Norton Nelson*
Diet rich Hoffmann

Associate Director
Naylor Dana Institute fo r
Disease Prevention
Ce ll Biology , Pharmacology , and Immunological Issues

P . B . Dews* , Chairman
Konrad E . Bloch*
Peter B. Schur
Professor of Medicine
Ha rvard Univer sit y
B rig ham and women ' s Hospital
Reese T . Jones*
Louis Lembe rge r
Director o f Clinical
Pharmacology
Lilly Laboratory for
Clinical Research
*Committee membe r .
vii

ACKNOWLEDGMENTS
Many per sons outside the Institute of Medicine provided he lpfu l

sugg estions , timely observations , and data bearing on the complex
scientific , clinical , and societal issue s that we re being explored b,y
the commi ttee and staff . We wish especially to express ou r g ratitude
for contributions made by Monique Braude , Jacqueline Ludford , Robert
Peter sen , William Pollin , and Marvin Snyde r of the National Institute
on Drug Abuse r Edward Tocus and Stuart Nightingale of the Food and
Drug Administration , the Interagency Commi ttee to Monitor the
Marij uana S tudy r Car l Leventhal of the National Institutes of Health
and the chairman of the Interagency Commi ttee r and Joseph Perpich of
t he National Institutes of Health , our proj ect office r .
We wish also to acknowledge the many scientists and others who
r esponded to specific requests to review informally a por tion of the
draft repor t and those who , in general , gave their act ive assistance
and collaborationa
c. Wayne Bardin , Population Council

Neal Benowitz , Lang ley Porter Psychiatric Institute
Alber t Car lin , Univer sity of Wa shington
Sidney Cohen , Alcohol Research Center
El len Dempsey , McGill Unive r sity
Everett Ellinwood , Duke Univer sity Medical Center
Keith Green , Medica l College of Georgia
Daniel Both , National Cancer Institute
Lld Johnston , Institute for Social Researc h
Louise Lev , National Cancer Institute
Markku Linnoila , Nationa l Institute of Mental Healt h
Oriana Kalant and the Documentation Center of the Addiction
Research FOundation
Edward Khantzian , Cambridge Hospital
Kaye Kilburn , Univer sity of Southern California Schoo l of
Medicine
Warren Levinson , Unive rsity of California , San Francisco
Raphae l Mechoulam , School of Pharmacy , The Hebrew
University , I s rae l
John Mer ritt , Univer sity o f Nor th Carolina
ix

Akira Moriah tma , College of Physicians and Surgeons ,

Columbia University
Al Munson , Medical Col lege of Virgini a
Gabrie l Nahas , College of Physicians and Surgeons , Columbia
Univer sity
William Paton , Univer sity of Oxford
Bruce Petersen , Lilly Laboratory for Clinical Research
Steven Podaa , the Mount Sinai Medical Cente r
Lee Robina , Washington University Medical School
Har ris Rosenkrantz , EG&G Mason Research Institute
Donald Taahkin , University of California , Loa Angeles
David Taylor , Centers for Disease Control
Carlton Turner , Senior Policy Adviser for Drug Policy ,
Office of Policy Development
Ar thur Zimmerman , Unive rsity of Toronto

PREFACE
Thi s repor t i s the wor k of the many people ident if ied in the
preced ing pages , and to all of them I am very g rateful .
I
par t icularly wish to thank my d i stinguished colleagues on the study
comm i ttee , upon whose expert knowledge and c r i t ical j udgment this
report rests . They responded consc ient iou sly to all the demand s
placed on them , and they d id so with a promptness and grace that made
my tas k easy .
No study of this kind can be car r ied out without the help of a
s k i l led staff . We were fortunate to have had the ass istance of a
devoted and highly capable staff team led by Enr iqueta c. Bond and
Linda s . Duj ack . They coord inated the efforts of the comm i ttee , the
panel , the consultants , and the Inst itute of Med ic ine staff , and they
played the key role in keep ing everything on schedu le . Moreover ,
t hey carr ied out this formidable task with tact and common sense . On
behalf of the comm i ttee , I wish publ icly to acknowledge ou r
i ndebtedness to the IOM staf f , and I also wi sh to express my personal
thanks to Drs . Bond and Du j ack for the i r unfa i l ing support and
cooperat ion .
F inally , I w i sh to acknowledge my apprec iat ion of the ed itor ial
assi stance of Wallace K . Wate r fall , whose exper t touch is evident
t hroughout this document . Our aim was to wr ite a report in a clear
and inc i s ive form for the general public . Any success that we may
have achieved is due in no small measure to his efforts .
Arnold s . Re lman , M . D .
Cha i rma n
xi

CONTENTS
SUMMARY
IN'l'RODtx::T ION
CBBMIS'l'RY AND PHARMACOLOGY OF MARIJUANA

cannabis Ch i stry , 1 3
Pharmacology o f Cannabi s , 1 9
What i s a Large o r Small Cannabi s Dose?, 2 3
General icology , 24
Re levance of Nonhwaan Animal Models , 2 5
Cannabi s Contaminants , 2 5
Cellular !Ox ic i ty , 2 6
Tolerance and Dependence , 2 6
Drug I nteract ions , 2 7
Summa ry and Conclus ions , 2 8
Recommend at ions for Research , 2 8
References , 2 9
12
USE OF MARIJUANA IN 'l'BE UNI'l'ED STA'l'ES

Patterns and Trend s of Use of Mar i j uana , 3 5
Summa ry , 5 0
Recommendat ions for Research , 5 2
References , 5 3
34
EI'FEC'l'S OF MARIJUANA ON 'l'BE RESPIRA'l'ORY AND

CARD IOVASCULAR SYS'l'EMS
Respiratory Syst , 5 7
card iovascular Syst , 6 6
References , 73
EFFBC'l'S OF MARIJUANA ON '1'IIE BRAIN

Brain Morphology , 8 0
Neurophys iology , 8 2
Epi lepsy , 8 7
N eurochemi stry , 87
SUIIIa ry , 8 9
Recommendat ions for Research , 8 9
References , 9 0
xU i
57
80

94
EFFECTS OF MARIJUANA ON OTHER BIOLOGICAL SYSTHMS

Male Reproductive Function, 94
Female Reproductive Function, 97
Birth Defects and Teratogenicity, 99
Genetic Effects, 100
The Immune System, 103
Body Temperature, 104
Summary, 104
Recommendations for Research, lOS
References, 106
BEHAVIORAL AND PSYCHOSOCIAL EFFECTS OF MARIJUANA USE

Perceptual and Psychomotor Functions, 113
Clinical Syndromes, 121
Summary, 128
Recommendations for Research, 129
References, 130
112
THERAPEUTIC POTENTIAL AND MEDICAL USES OF MARIJUANA

Glaucoma, 140
Antiemetic Action, 142
Appetite Stimulant, 145
Anticonvulsant Action, 145
Muscle Relaxant Action, 147
Antiasthmatic Effect, 147
Antianxiety Effect, 148
Antidepressant Effect, 149
Analgesic Action, 149
Alcoholism, 149
Opiate Withdrawal, 149
Antitumor Action, 150
Summary, 150
Recommendations for Research, 150
References, 151
139
FEDERAL SUPPORT OF RESEARCH ON MARIJUANA

Present Sources and Amounts of Support, 156
Areas of Research Support, 160
Summary of Findings, 164
Recommendations, 167
References, 168
156
APPENDICES
169
A
B
C
D
WORK OF THE COMMITTEE

ACCESS TO ll-9-THC AND MARIJUANA FOR RESEARCH
AND TREATMENT
LONGITUDINAL STUDIES
PARAQUAT ISSUE
xiv
169
171
175
186

SUMMARY
The Inst itute of Med ic ine ( IOM) of the Nat ional Academy of Sciences
has conducted a 15-month study of the health-re lated effects of
mar i j uana , at the request of the Secretary of Health and Human
Services and the Director of the Nat ional Inst itutes of Health . Th e
IOM appointed a 2 2-member comm i ttee to :
analyze ex isting sc ient i f ic evidence bear ing on the possible

hazards to the health and safety of users of mar i j uana J
analyze data concerning the poss i ble therapeutic value and

health benefits of mar i j uana J
assess federal research prog rams in mar i j uana J
ident i fy promising new research d i rect ions , and make

sugggest ions to improve the qual i ty and usefulness of futur e
r e search r and
d raw conclus ions f rom this review that would accurately

assess the l imits of pre sent knowledge and thereb provide a factual ,
scient i f ic bas i s for the development of future government policy .
Th is a ssessment of knowledge of the health-re lated effects of
mar i j uana is important and t imely becau se mar i j uana is now the mos t
w idely u sed of all the illicit d rug s avai lable in the United States .
In 1 9 7 9 , more than 50 million per sons had tr ied it at least once .
There has been a steep r ise in its use dur i ng the past decade ,
part icular ly among adolescents and young adults, although there ha s
been a leveling-off in its overall use among high school seniors in
the past 2 or 3 years and a small dec l ine in the percentage of
senior s who use i t frequently . Although substant ially more high
school students have u sed alcohol than have eve r u sed mar i j uana , mor e
h igh school seniors use mar i j uana on a daily or near-daily bas is (9
percent ) than alcohol ( 6 percent ) . Much of the heavy use of
mar ij uana , unl ike alcohol , takes place in school , whe re effects on
behavior, cognit ion, and psychomotor per formance can be part icularly
d isturbing . Unl i ke alcohol, which is rapidly metabol ized and
eliminated from the body , the psychoact i ve component s of mar i j uan a
pe r s i st in the body for a long t ime . S imilar to alcohol , cont inued
use of mar i j uana may cause tole rance and dependence . FOr all these
r easons , i t i s imperat ive that we have reliable and detai led
1

information abou t the effects of marijuana use on health , both in the

long and short term .
What, then , did we learn f rom our review of the publi shed
sc ient i f ic literatu re? Numerou s acute effects have been descr ibed i n
a nimals , i n isolated cells and tissue s , and i n stud ies o f human
voluntee rs , clinical and ep idem iolog ical observat ions also have bee n
r epor ted . This informat ion is briefly summarized in the following
paragraphs .
EFFECTS ON
THE
NERVOUS SYSTEM AND ON BEHAVIOR
We can say with confidence that mar ijuana produces acute effects on
Its
the brain, including chemical and elec trophys iolog ical changes .
most clearly established acute ef fects are on mental funct ions and
behavior . With a seve r i ty directly related to dose, mar ijuana impa irs
moto r coord ination and affects t r ack ing ability and sensory and
perceptual functions important for safe driving and the operat ion of
other machines, it also impa i r s short-te rm memory and slows learn ing .
O ther acute e ffects include feel ing s of euphor ia and other mood
changes, but there also are d i stu rbing mental phenomena, such a s
b rief periods o f anxiety, confusion, o r psychosis .
There is not yet any conclus ive evidence as to whethe r prolonge d
u se o f marij uana cause s permanent changes in the nervou s system or
su stained impairment of brain funct ion and behavior in human being s .
I n a few unconf irmed stud ies in experimental an imals , impa irment of
lea rning and changes in electr ical brain-wave record ings have bee n
o bse rved several months after the ces sat ion of chronic administrat ion
of marij uana .
In the j udgment of the committee, widely c i ted stud ie s
purport ing to demonst rate that mar ij uana affects the g ross and
microscop ic structure of the human or monkey brain are not convinc ing ,
much more work i s needed to settle this important point .
Chronic relat ively heavy use of mar ijuana i s assoc iated wit h
behavioral dysfunct ion and mental d i sorder s in human be ing s, but
available evidence does not establish if mar i j uana use under the s e
c ircumstances is a cause or a result o f the mental cond ition . There
are s imilar problems in interpret ing the evidence link ing the use of
mar i j uana to subsequent use of other i llic it drugs, such as heroin or
coca ine . Assoc iat ion doe s not prove a causal relat ion , and the use
of mar i j uana may merely be symptomat ic of an underly ing dispos it ion
to u se psychoac t i ve drug s rather than a stepping stone to
i nvolvemet with more d angerous substances .
It is also d iff icult to
sor t out the re lationship between use of mar i j uana and the complex
symptoms known as the amotivat ional syndrome . Self-selection and
effects of the drug are probably both contributing to the
mot ivational problems seen in some chron ic use r s of marij uana .
Thus, the long-term ef fects of mar i j uana on the human brain and
on human behavior r emain to be def ined . Although we have no
convincing evidence thu s far of any effect s per s i st ing in huma n
being s after cessation of drug u se, there may well be subtle but
important physica l and psycholog ical consequences that have not bee n
r ecogni zed .

EFFECTS ON THE CARDIOVASCULAR AND RESPIRATORY SYSTEMS

There is good evidence that the smok ing of marij uana usually causes
acute change s in the heart and circulat ion that are character istic o f
stress, but there is no evidence t o ind icate that a permanently
deleteriou s effect on the normal cardiova scular system occu rs . The r e
i s good evidence t o show that mar ijuana increases the wo r k o f the
heart, usually by ra is ing heart rate and, in some persons, by raising
blood pressure . This rise in wor k load poses a threat to pat ients
with hyper tension, cerebrovascular d i sease , and coronary
a therosc lerosis .
Acute exposure to mar ijuana smoke generally elicits broncho
dilation , chronic heavy smok ing of mar i j uana causes inflamma t ion and
pre-neoplastic changes in the airways, similar to those produced by
smok ing of tobacco . Mar ijuana smoke is a complex mixture that not
only has many chemical components ( including carbon monox ide and
tar ) and biological effects similar to those of tobacco smoke , bu t
also some unique ingred ients . This suggests the strong possibility
that prolonged heavy smoking of mar i j uana , like tobacco, will lead to
cancer of the respiratory t ract and to ser iou s impa irment of lung
function . Althoug h there is evidence of impa ired lung funct ion i n
chron ic smokers, no d i rect conf i rmation o f the likelihood o f cancer
has yet been provided, poss ibly because mar i j uana has been widely
smoked in this country for only about 20 years , and data have not
been collected systemat ically in othe r countr ies with a much longe r
history of heavy marij uana u se .
EFFECTS ON THE REPRODUCTIVE SYSTEM AND ON CHROMOSOMES

A lthough stud ies in animals have shown that 6 -9-THC ( the maj or
psychoactive constituent of mar i j uana ) lowers the concentrat ion in
blood se rum of pituitary hormones (gonadotropins ) that control
r eproductive funct ions , it is not known if there is a d i rec t effect
on r eproductive t i ssues . Delta-9-THC appear s to have a modest
r ever sible suppressive e ffec t on sperm product ion in men, but there
is no proof that it has a deleter iou s effect on male fertility .
Effects on human female hormonal funct ion have been reported , but the
evidence is not convinc ing . However , there is convinc i ng evidence
t hat mar ij uana inte r feres with ovulat ion in female monkeys . No
sat isfac tory stud ie s of the relat ion between use of mar i j uana and
f emale fert i l i ty and chi ld-bear ing have been car r ied out . Although
6-9-THC is known to cross the placenta read ily and to cause birth
defects when administered in large doses to exper imental animals , no
adequate clinical stud ies have been car r ied out to determine i f
mar i j uana use can harm the human fetus . The re is no conclusive
evidence of teratogen ic ity in human offspr ing, but a slowly developing
or low-level effect might be undetected by the stud ies done so far .
The effects of mar i j uana on reproductive funct ion and on the fetu s
are unclear , they may prove to be negl ig ible , but fur ther research to
establish or rule out such effects would be of g reat importance .

Extracts from mar i j uana smoke part iculates ( tar ) have bee n
found to produce dose-related mutat ions in bacter ia J howeve r ,
9-TBC , by itself , i s not mutagenic . Mar ij uana and 6-9-TBC do
not appear to break chromosomes , but mar ijuana may affect chromosome
segregat ion dur ing cel l division , resulting in an abnormal numbe r of
c hromosomes in daughter cells . Although these results are of
conce rn , the i r clinical signif icance is unknown .
THE IMMUNE SYSTEM

S imila r l imitat ions ex ist in ou r under stand i ng of the effect s o f
FOr example , some stud ies of the
mar i j uana o n othe r body systems .
immu ne system demonstrate a m i ld, immunosuppressant effect on human
be ing s , but other studies show no effect .
THERAPEUTIC PO'l'EN'l' I AL
The comm ittee also has examined the evidence on the therapeut ic
effects of mar ij uana in a var iety of med ical d i sorde r s . Prel iminary
s tud ies suggest that mar i j uana and its der ivat ives or analogues might
be useful in the treatment of the rai sed intraocular pressure of
g laucoma , in the control of the seve re nausea and vomit ing caused by
cance r chemotherapy , and in the treatment of asthma . There also i s
some prel iminary evidence that a marij uana constituent ( cannabid iol )
might be helpfu l in the treatment of certain type s of epi lept ic
s e i zures , as well as for spast ic disorders and othe r ne rvou s system
d i seases . But , in these and all othe r condit ions , much more work i s
needed . Because mar i j uana and 6-9-THC often produce t roublesome
psychot ropic or cardiovascular s ide-effects that l imit their
therapeut ic usefulne ss , part icular ly in older pat ients , the greates t
t herapeut ic potent ial probably l ies in the use of synthet ic analogues
of mar i j uana der ivat ives with highe r rat ios of therapeutic to
undesirable effects .
THE NEED POR MORE RESEARCH ON MARIJUANA

The explanation for all of these unanswered que st ions i s insuff ic ien t
research . We need to know much more about the metabol ism of the
var iou s marij uana chemical compounds and the i r biolog ic effects .
Th is will require many more stud ies in an imals , with par t icular
emphasis on subhuman pr imates . Basic pharmacolog ic informat ion
obtained in animal exper iments will ult imately have to be tested in
clinical stud ie s on human beings .
Unt i l 10 or 15 years ago , there was virtually no systemat ic ,
rigorously controlled research on the human health-related ef fect s o f
marij uana and its maj or constituents . Even now, when standard i zed
mar i j uana and pure synthetic cannabinoids are available for
exper imental studies , and good qualitat ive methods ex ist for the

5
measurement of A-9-TBC and ita metabolites in body fluids, well
des igned stud ies on human be ing s are relat ively few . There are
d i f f icult ies in study ing the clinical effects of mar i j uana in huma n
be ing s, par t icularly the effects of long-term use . And yet, without
such stud ies the debate about the safety or hazard of mar i j uana wi l l
r ema in unresolved . Prospective cohort stud ies, as we l l as ret ro
spect ive case-control stud ies, would be usefu l in ident ifying long
term behavioral and b iolog ical consequences of mar i j uana use .
The federal investment in research on the health-related effect s
o f mar i j uana has been small, both in relat ion to the expend iture on
othe r i l li ci t d rug s and in absolute terms . The comm ittee cons ider s
t he research par t icular ly inadequate when viewed i n l ight of the
extent of mar ij uana use in thi s count ry, espec ially by young people .
We believe there should be a g reater investment in re search on
mar ijuana, and that invest igator-init iated research g rants should be
t he pr imary vehicle of support .
The comm i ttee considers all of the areas of research on mar i j uana
that are supported by the Nat iona l Inst itute on Drug Abuse to be
impor tant, but we d id not j udge the appropriateness of the allocat ion
of resource s among those areas, othe r than to conclude that the re
should be increased emphasis on stud ies in human be ing s and othe r
pr imates . Recomme ndat ions for future research are presented at the
e nd of Chapters 1-7 of this report .
CONCLUSIONS
The sc ient i f ic evidence publ i shed to date ind icates that mar i j uana
ha s a broad range of psycholog ical and biolog ical effects, some of
wh ich, at least under certain condit ions, are harmful to human
health . Unfortunately, the ava ilable informat ion does not tel l us how
ser ious this r i sk may be .
Ou r major conclus ion is that what little we know for certain
about the effects of mar i j uana on human health--and all that we have
r eason to suspect--just i f ies ser ious nat ional concern . Of no leas
concern i s the extent of ou r ignorance about many of the moat basic
and important questions about the drug . Our maj or recomme ndat ion is
that there be a g reatly intens i f ied and more comprehensive prog ram of
research into the e ffects of mar i j uana on the health of the Amer ican
people .

INTRODUCTION
The Inst itute of Med icine ( IOM) of the Nat iona l Academy of Sc iences
ha s undertaken this review and analysi s of the health-related effect s
o f mar i j uana* at the request of the Sec retary of the Department o f
Health and Human Services (DHHS ) and the Di rector of the Nat iona l
Inst itutes of Health (NIH ) .
S c ient i f ic controve rsy and publ ic confusion about mar i j uana
cont inue unabated and perhaps even are expand ing, notwithstand ing
numerous reports on the topic f rom author i tat ive agenc ies and
organi zat ions (Fifth, S ixth, Seventh, and Eighth Annual Reports from
t he Secretary of Health, Educat ion and Welfare to the Cong ress on
Mar ijuana and Health r Fehr, et al . , Cannabis : Adverse Effects on
Health, 1980ar Tink lenberg, Mar ij uana and Health Hazards and
Mar ijuana in the ' 8 0s, a report of the Counc i l on Sc ient i f ic Affa i r s,
t he Amer ican Med ical Assoc iat ion, 1980 ) . Increasing use of th i s
substance and g rowing concern about its poss ible long- and short-term
consequences for human health have added some urgency to the need for
reassessment of the ava i lable data . Interest has been further
h e ightened recent suggest ions that ma r i j uana may also have some
med ica l therapeutic value, wh ich only intens i f ies the debate abou t
what our publ ic pol icy towards mar i j uana ought to be .
With thi s as backg round, the Secretary of Hea lth, Educat ion, and
Welfare, Joseph A. Cal i fano, Jr . , in a press statement on Apr i l 1 8,
1979, announced the intent ion of h i s department to undertake a review
t hat would
assess the informat ion and sc ient i f ic work now
ava i lable on the effects of mar i j uana . He followed that with a
memorandum on May 16, 1979, to Donald s. Fred r ickson, Di rector of NIH
i n wh ich he further sta ted z
Th i s review must be undertaken by an independent sc ient i f ic

body that ha s not staked out a pos it ion in this h ighly
controversial f ie ld . Thi s review should be conducted by a
* The terms mar i j uana and cannabis will be used interchangeably in

thi s repor t . Str ictly spea ki ng, they are not synonymousr cannabi s i s
t he more general term .
( See Glossa ry, page 9 . )
6

g roup of d i st i ng u i shed biomed ical and clinica l sc ient i sts and

s hould involve thorough, systemat ic review and anay s i s of
the research literature
The report shou ld ident i fy th e
most urgently needed and promising l i nes of inqu i ry to bu i ld
a f i rme r base for dec i s ion-ma k i ng in yea r s to come . The
i nformat ion should be ava i lable in a c lear and inc i s ive form
for the general public .
Wh i le the Alcohol, Drug Abuse, and Mental Health
Admi ni stration ( ADAMHA) and its Nat ional Institute on Drug
Abuse ( NIDA) have provided leadership in research related to
biolog ical and hea lth effect s of marij uana, it i s most impor
tant that we have a review by an independent nongovernmental
body, such as the Inst itute of Med ic ine .
In order to avoid
e ven the appearance of a conflict of interest, inasmuch as
thi s review will cove r par t of the research plan of
ADAMHA-NIDA, I believe i t is important that the Nat ional
Inst itutes of Health se rve as the respons ible DRHS agency fo r
see ing that such a review i s conducted .
Following Mr . Cal ifano ' s res ignat ion, subsequent secreta r ie s have
c onf i rmed to the D irector of the NIH the i r des i re to see this review
car r ied forward . Accord ing ly, a contr act between the NIH and the IOM
was executed to provide for a study to commence September 3 0, 19 8 0,
and be completed by Decembe r 2 9, 1 9 8 1 .
THE COMM I 'l"l'EE 1 S TASK

Unde r thi s contract, the IOM ag reed to appoint a comm ittee to :
1 . analyze ex ist ing sc ient i f ic evidence bear ing on the possible
ha zards to the health and safety of use r s of ma r i j uana ,
2 . analyze data concerning the possible therapeut ic value and
health benef its of mar i j uana J
3 . assess federal research prog rams in this area ,
4.
ident ify promi sing new research d i rections, and mak e
s uggest ions to improve the qua lity and usefulness of future research ,
s. draw conclus ions f rom this review that would accurately
a ssess the l imits of present knowledge and the re provide a factual,
scient i f ic ba si s for the deve lopment of futu re government pol icy .
S uch an assessment also shou ld be helpful to pr ivate c it i zens who
want to make the i r own informed dec i s ions about this subj ect .
The comm i ttee ' s charge spec i f ically excluded the analys i s or
formulat ion of publ ic pol icy .
PROCEDURE FOR THE STUDY

Pr imary responsibil ity for the conduc t of the study was vested in a
s tee r ing comm i ttee of 2 2 biolog ists, behavioral sc ient i sts, and

8
clinic ians . Although they all were experts in relevant d i sc ipl ines,
only a few had previously been involved in the study of mar i j uana or
had taken publ ic pos it ions on the subj ect . The comm ittee was d ivided
i nto s ix panels, each concerned with maj or sc ient i f ic areas :
card iovascular and respiratory system effects J neurobiolog ica l
e ffects , epidemiolog ical, behavioral, and psychosoc ial effects ,
reproduct ive biology and ef fects on the fetus J pharmacology, cel l
b iology, a nd immunology , a nd gene t ic and oncogenic ef fects . Each
pane l was cha i red a membe r of the comm ittee and usually had one o r
more add it ional comm i ttee members and several expert consultants,
whose names appear in the front of thi s report . The comm ittee also
consu lted with many other expe rts in the cou rse of its work and
rece ived valuable help f rom many pe r sons and organ i zat ions .
The full comm i ttee met f ive t imes to coord inate and assess its
prog ress .
In the inte rvals between these meetings, the panels held
t he i r own independent sess ions and var ious ad hoc wor k ing g roups met
as necessary . The cha i rman and member s of the comm i ttee staff were
i nvited obse rvers at the Conference on Adverse Health and Behavioral
Consequences of Cannabi s Use, wh ich was sponsored by the Add ict ion
Research Foundat ion (ARF) of Ontar io and the World Health Organi zat ion
(WHO) and held in TOronto, Canada, from March 30 to Apr i l 3, 1981 .
Other members of our comm i ttee served as work ing members of that
conference . We were also fortunate in be i ng able to work closely
with members of the ARF/WHO conference staff and having access to all
the documents prepared for the Canad ian meet ing as well as the
r evi sed d raft of the summa ry report of the conference ( 19 8 1 ) .
The comm i ttee began by systemat ically reviewing all the
l iterature publ i shed s ince 1 975 on mar i j uana and related subj ects,
wh ich had been collected ou r staff through a Medl ine computer
search . Ear l ier l i terature was select ively examined, as were a
var iety of othe r documents, reviews, and monog raphs on the subj ect .
Our obj ect ive was not merely to compile and summa r i ze, but also to
evaluate the evidence c r i t ically and, with the aid of our consultants,
form some j udgment of the quality and reliabi l i ty of the work . Our
report i s an assessment of what i s and i s not known, based on ou r
best interpretat ions of the sc ient i f ic l i terature . We confined ou r
attent ion to publi shed sc ient i f ic a r t ic les as the pr imary sources of
i nformat ion, rely ing heav i ly on experts in each f ield to select the
re levant paper s and help us interpret the data .
To obtain add it iona l informat ion and opinions from the public and
f rom profess ional g roups on the health-related effect s of mar i j uana,
we sol ic ited wr itten responses in a not ice in the Federal Reg ister of
February 24, 1981 . Responses were rece ived and incorporated into the
r ecords of the comm i ttee .
( See Append ix A for a complete
descr ipt ion . )
The response s fel l into three categor ies :
1 . The dangers of mar ijuana . Letters in this category came from
mothers whose children were us ing or had used mar i j uana . These
parents be lieved that d rug use by the i r chi ldren led to a lack of
motivation and los s of interest in school and othe r act ivit ies .
Lette rs about the harmfulness of the use of mar i j uana were a lso
rece ived from phys ic ians and sc ient i st s .

9
2 . The therapeutic eotential of mar ij uana . Half of the
r esponses were f rom people who used mar i j uana illegally for var ious
med ical problems and who urged that it be made eas ily available to
pat ients . Several letters submitted by leg i slator s and doctor s
desc r i bed problems in obta ining ma r i j uana for the rapeut ic use ( se e
Append ix B ) . A g roup interested in the leg it imate medical use of
cannabis emphasi zed the need for cont inu ing investigat ion into the
numerous const ituents of the mar i j uana plant for therapeutic uses .
3 . Suppp r t of general use and legali zation of ma r ijuana .
Letters were rece ived f rom ind ividuals and g roups favor ing the use of
mar i j uana and actively promot i ng its legali zat ion .
Th i s report covers most of the concerns expressed by the public ,
except the question of legali zat ion . The var ious statements included
many opinions and much anecdotal evidence f rom laymen and
sc ient i sts . The comm i ttee took note of thi s mater ial , but has no t
c ited any of i t i n t h i s report unless i t was supported by publ i shed
data in the scient i f ic l i te rature .
THE ORGANI ZATION OF
THE
REPORT
Thi s report i s d i vided into e ight chapter s and a summa ry . The

summa ry includes the princ ipal f ind ings and conclu sions of the study ,
togethe r with suggest ions for future research .
The f ir st chapter reviews what i s known about the chemi stry and
pharmacology of mar i j uana . Chapte r 2 deals with the epidemiology and
demog raphy of the use of mar i j uana in the United States . The next
three chapter s d i scuss the effects of mar i j uana on cells , t i ssues ,
o rgans , and b iolog ical systems . Chapter 6 deals with behavioral and
psychsoc ial ef fects . Chapte r 7 discusse s the present status of
mar i j uana as a therapeut ic agent . Chapter 8 descr ibes and analyzes
the federal research prog ram on mar i j uana .
Th is report i s i ntended to be intellig ible to readers who are not
expe r t on the subj ects at hand . We have tr ied to use technical
language only where accuracy would be compromi sed by less prec ise
te rms , and to keep the d i scuss ions as br ief and as clearly stated a s
i s consi stent with our obligat ion to present a valid c r i t ique of the
state of knowledge in thi s f ield . Although we have surveyed the
l iterature as thoroughly as poss ible , our c itat ions a re select ive
rathe r than exhaustive , because they are intended to illustrate o r
document only the key points in the d iscuss ion . FO r comprehens ive
bibl iog raphies , see Walle r et al . , 1976 1 Abel , 1979 J and Kalant e t
al . , 1980 .
GLOSSARY OF TERMS FOR MARIJUANA-RELATED PRODUCTS

CANNAB IDIOL (CBD ) and CANNABINOL (CBN) are major cannabinoid s
g enerally present in cannabis ( see CANNAB I S and CANNAB I NOIDS ) .

10
CANNAB I NOIDS a r e a class o f 21-ca rbon compounds presen t i n
C annabis sat iva . The bas ic structure conta ins a s ix-membered
hydroaromat ic r i ng and a benzene r ing joined by a pyran moiety ( se e
F igure 1-1 i n Chapter 1 ) . Der ivat ives include a numbe r o f carboxylic
ac ids , the i r analogues , and t ransformat ion product s .
CANNAB I S i s a general term for any of the var ious preparat ions of
the plant Cannabi s sat iva and the cannab inoids obtai ned from it .
cannabinoid i s a gener ic term for a class of compounds . Cannab i s
sat i va , also called hemp , i s an herbaceou s annual plant that readily
g rows i n temperate climates . Depending on the geog raph ic reg ion , and
othe r conside rat ions , the var iou s natu ral preparat ions of cannab i s
possess d ifferent physical cha r acter i st ics and concentrat ions of
cannabinoids . Cannabi s preparat ions may conta in over 4 2 0 d i fferen t
compounds J of these , 61 have been ident i f ied as cannabinoids , many of
wh ich posses s some biolog ical act ivity . Ma r i j uana , hash i sh , and
tetrahydrocannabinol are examples of d if ferent forms or components of
cannabis .
HASHISH is a res i n , generally more potent than ma r i j uana , wh ich
is obta i ned from Cannab i s sat iva by shak ing , press ing , or scraping
t he leaves and flowe r s of the plant and usually conta ins some of the
latter .
MARIJUANA i s a general term for c rude preparat ions obtained from
the plant Cannabi s sat iva and i s a mixture of crushed leaves , twig s ,
In the United
seeds , and somet imes the flower s of this plant .
States , the term mar i j uana ha s often been used inte rchangeably wit h
c annabi s to refer to any part of the plant or extract therefrom or
any of the synthet ic cannabinoids that induce somatic and psychic
c hanges in man .
S INSEMILLA i s a seedless var iety of h igh-potency mari j uana ,
or ig i nally g rown in Cali fornia .
TETRAHYDROCANNAB I NOL (THC ) i s one of the maj or g roups of
cannabinoids . Delta-9-THC is the pr inc ipal act ive const ituent i n
natural cannabis preparat ions . Delta-9-THC i s also known as
A-1-TBC , by a different system of nomenclatu re .
( In the United
States , the A-9-THC content of mar i j uana ranges from unmeasurable
amounts to about 6 percent . )
Another active i some r , A-8-THC , i s
le ss often present i n mar i j uana and typ ically occu r s i n minute
amounts . Many de r ivat ive s of A-9-THC have been synthesi zed .
REFERENCES
Abel , E . L . A Comprehensive Gu ide to the Cannabi s Literatur e
Westport , Conn . : Greenwood Press , Inc . , 1 979 .
Amer ican Med ical Association . Mar ijuana in the ' 8 0s . Repor t of the
Counc il on Sc ient i f ic Affa i r s . Chicago Ill . : Amer ican Med ical
Assoc iation , 1 9 8 0 .
Fehr , K . o . , Kalant , O . J . , Kalant , H . , and S ingle , E . W . Cannabi s :
Adve r se Effects on Health . A statement prepa red by the
sc ient ists of the Add ict ion Research FOundat ion of Onta r io .
Toronto : Addict ion Research FOundat ion , 1980 .

11
Kalant , O . J . , Fehr , K . O . , and Ar ras , D . Cannabis : Health Ha zards :
A Comprehens ive Annotated B ibl iography . TOronto : Addict ion
Research Foundat ion , 1980 .
Repor t of Addict ion Research Foundation/World Health Organi zat ion
( ARF/WHO) . Conference on Adve r se Health and Behavioral
Consequences of Cannabi s Use . ARF/WBO , 1981 .
Tinklenberg , J . R . ( ed . ) Ma r ijuana and Health Ha zards : Methodolog ica l
I ssues in Cur rent Research . New Yorka Academ ic Press , Inc . ,
1975 .
u .s. Department of Health , Educat ion , and We lfare , Publ ic Health
Service . Mar ihuana and Health . Fi fth Annual Repor t to th e
Cong ress f rom the Secretary of Health , Educat ion , and Welfare ,
19 7 5 . DREW Publicat ion No . ( ADM) 76-314 . Wash ing ton , D . C . : u . s .
Government Pr int i ng Off ice , 1 9 7 6 .
u.s. Department of Health , Educat ion , and Welfare , Publ ic Healt h
Serv ice . Mar i huana and Health . S ix th Annual Report to the
Cong ress from the Secretary of Health , Educat ion , and Welfare ,
1 9 76 . DHEN Publicat ion No . ( ADM ) 77-4 4 3 . Wash ing ton , D . C . : u. s .
Gove rnment Pr int ing Of f ice , 1 9 7 7 .
u.s. Department of Health , Educat ion , and Welfare , Public Health
Serv ice . Ma r i huana and Health . Seventh Annual Repor t to the
Cong ress f rom the Secretary of Health Educat ion , and Welfare ,
1 9 7 7 . DREW Publ icat ion No . ( ADM) 79-7 0 0 . Wash ing ton , D . C . :
u . s . Government Pr int ing Off ice , 1979 .
u.s. Depa rtment of Health , Educat ion , and Welfare , Public Healt h
Service . Mar ijuana and Health . Eig hth Annual Report to the
Cong ress from the Secretary of Health , Educat ion , and Welfare ,
1 9 80 . DREW Publ icat ion No . ( ADM ) 809 4 5 . Washing ton , D . C . :
u . s . Gove rnment Pr int ing Off ice , 198 0 .
Walle r , c.w. , Johnson , J . J . , Buelke, J . , a nd Turner, c . E .
Mar ihuana : An Annotated B ibliographY New York : Macmilla n
Informat ion , 197 6 .

I
CHEMISTRY AND PHARMACOLOGY
OF MARIJUANA
The cannabis plant (Cannabis sat iva ) thr ives under a var iety of
g row ing cond i t ions .
I t has been cult ivated for centu r ies , mainly fo r
hemp f iber , but also for its psychoact ive and putat ive medic inal
properties (Abel , 1980 r Turne r et al . , 1 9 8 0 ) . Although the
behavioral and psycholog ical effects were well desc r i bed in
lite rature of the nineteenth century (Kalant and Kalant , 1 9 6 8 ) , the
complex chemistry and pharmacology of the cannabis plant di scouraged
extens ive invest igat ion until about 1 5 year s ago .
Th e most prominent effects o f cannabi s a re o n psycholog ical
phenomena and behavior . Psychopha rmacology and behavioral
pharmacology have developed a s divisions of sc ient i f ic inqu i ry only
ove r the past 2 5 years r therefore , the olde r cannabis literature , no
matter how valuable for observat ions on other matters , does not
prov ide a basis for quant itat ive pharmacolog ical analysi s and
e valuat ion .
E a rly pharmacolog ists could wor k only with crude extracts of the
plant . Althoug h the general structure of the cannabinoids ( Figure 1 )
was known by the turn o f the century , the par t icular cannabinoids
that were ident i f ied early and were available as pure substances wer e
largely devoid of the characte r i s t ic psychoact ive and other
pharmacolog ical effects of cannab i s . Synthetic cannabinoid s with
c annabislike act ivity became ava ilable in the 1930s .
It was not
until 196 4 that an active i ng red ient of cannabi s was ident i f ied a s
6- 9 -tetrahydrocannabinol (THC ) a nd synthes i zed ( Figure 1 ) ( Gaoni
and Mechoulam , l964 r Mechoulam and Gaoni , 1 96 5 , 1967 ) .
In the
mid-1960s , the i solation and synthe s i s of the mai n psychoact ive
component of cannabi s and related cannabinoids , together with a rapid
increase in the use of ma r i j uana by middle class North American
s tudents , stimulated sc ient i f ic act ivity (Waller et al . , 1976 r Waller
et al . , in press) . Thi s chapter , an overview of cannabis chemistry
and pharmacology , empha s i ze s d i f f icult ies in t he study of th is drug
( explored further in subsequent chapter s ) and in evaluat ing the
l i terature .
12

13
Cannabinol
.1-9-lliC
Cannabidiol
FIGURE 1
11-hydroxy-.1-9-lliC
Cannabinoid structures .
CANNAB I S CHEM I STRY

Chemistry of the Plan t
Cannabis , the crude mater ial f rom the plant Cannabi s sat iva , contains
hund rs of chemicals . Most of these are found in other plants , bu t
6 1 , termed cannabinoids , a re unique to the cannabis plant ( Table 1 ) .
Natural and most synthetic cannabinoids are relat ively insoluble i n
water , but d issolve in fats and fat solvents and are therefore called
lipid soluble .
A s ingle cannabinoid , A -9-THC , produces almost all the char
acter istic spec i f ic pharmacolog ical ef fects of the complex , crude
cannabi s mixtures . A numbe r of synthetic cannabinoid s have pharmaco
log ical effects s imilar to A -9-THC . Other cannabinoids in the
plant , for example , cannabinol ( Figure 1 ) , are almost inactive
pharmacolog ically or may interact with A-9-THC to modify its
actions . One cannabinoid , cannabid iol (CBD) , can influence the
metabolism of another , A-9-THC ( S iemens et al . , 1976 ) . A few
cannabinoids have effects qu ite different f rom A -9-THC . For
example , cannabid iol ( Figure 1 ) has relat ively little psychoactive
and ca rd iovascular e ffect but is an active ant iconvulsant (Karler and
Turkanis , 1981) .
I nvest igators have chemically altered the A -9-THC molecule in
an attempt to determine which of its structural elements are r equ i red
to produce behavioral or othe r effects ( Mechoulam et al . , 1 9 8 0 ) .
S tud ies of structure-activity relat ionships ind icate that , to produce

14
TABLE 1
Chemical Const ituents of Cannabis Prepa rat ion s
1 . Cannabinoid s :
61 known
Cannabiqerol (CBG) type :
6 known
a.
b.
Cannab ich romene ( CBC) type :
4 known
7 known
Cannab id iol (CBD ) type :
c.
d.
4-9-Tetrahyd rocannab inol ( 4-9-THC) type :
4 -8-Tetrahydrocannab inol ( 4-8-THC ) type :
e.
f.
Cannabicyclol (CBL ) type :
3 known
Cannab ielsoin (CBE ) type :
3 known
g.
Cannabinol (CBN ) type :
6 known
h.
Cannabinodiol (CBND) type :
i.
2 known
Cannab itr iol (CBT) type :
6 known
j.
Miscellaneous types :
9 known
k.
1.
Othe r cannabinoids :
4 known
2 . N it rogenou s compound s :
3. Amino ac ids :
20 known
1 8 known
4 . Prote ins , glycoprote in& , a nd enzymes :

3 4 known
s. Sugars and related compounds :
6 . Hydrocarbons :
so known
7 . S imple a lcohols :
7 known
a. S imple aldehydes :
9 . S imple ketones :
1 0 . S imple ac ids :
11 . Patty ac ids :
1 2 known
13 known
20 known
12 known
1 2 . Simple este r s and lactone& :
13. Steroids :
11 known
1 4 . Terpene&:
1 0 3 known
1 5. Noncannabinoid phenols :
16 . Flavanoid glycos ide& :
1 7 . Vitamins :
1 known
18 . Pigments :
2 known
SOURCE a
9 known
13 known
16 known
1 9 known
Adapted f rom Turner , 1980 .
9 k nown
2 known

15
effects on behavior, a pyran r ing must be part of the three-r ing
system , a f ree phenol ic hydroxyl on the aromat ic r ing at cl, and a
lipoph i l ic s ide cha i n (CsH ll ) at C- 3 ( Figure 1 ) . Unde rstanding
c hemical structu re-ef fect relat ionships i s impor tant to guide the
synthes i s of cannabinoids with d i f fer ing pharmacolog ical eff ects .
D i fferent e ffects of 6-9-THC activity by chemical design will
requ i re further syntheses and pharmacolog ical study of a large number
of cannabino ids .
Chem i stry of the Smoke

It i s impossible to unde r stand the ef fects of cannab i s withou t
quant itat ive control of the composit ion and the amount of the active
substances, that i s, control ove r the dose . Systematic pharmacology
must therefore be per formed using pure compounds .
In the Uni ted
States, cannab i s u sually is smoked, wh ich complicates the
pharmacology .
The BmQke f rom any bu rn ing plant conta ins hundreds of chemicals
that may have biolog ical ef fects . Th i s poses a d iemma for
r esearche r s , because consequences of smok ing cannabi s cannot be fully
dete rmined by studies only of the pure cannabinoids . Studies also
a re needed with doses of 6-9-TRC delivered , however imper fectly, by
smok ing .
The dose of 6 - 9-TRC obtained f rom smok ing cannabi s var ies
g reatly , depend ing on many factors ( Table 2 ) . First , the content of

6-9-THC depend s on the genetic backg round or phenotype of the
plant , the sex of the plant , cond itions of g rowth and storage , and
the plant preparat ion smoked . Second , much of the 6 -9-THC in fresh
leave s that can be detected Y g as-liquid chromatog raphy (GLC) is in
inac t ive carboxylated fora . Deca rbolat ion to the act ive 6 9-THC
occur s s lowly dur i ng storage and rapdly dur ing hea t i ng , such as
occu r s in smok ing or GLC analys i s . Thi rd , the way in wh ich a
c igarette i s smoked can g reatly affect how much of the 6 -9-THC
content i s absorbed by the smoker .
annabis smoke i s similar to tobacco smoke in that it i s a
m ixture of very small part icles ad a gas-vapor phase . Both the
part iculate and vapor phases conta in many ident i f ied and probably
some st ill unident i f ied const i tuents that , based on clinical
exper ience with tobacco smoke , must be assumed to be potent ially
harmful ( Leuchtenberger and Leuchtenberger , 1976 ) . The amounts of
some mater ials in tobacco c igarette and mar i j uana c igarette smoke a r e
compared in Table 3 . Toxic substances , such a carbon monox ide ,
hydrogen cyan ide , and nitrosamine& occu r in s imilar concentrat ions i n
'.
tobacco and mar i j uana smoke J so do the amounts o f the part iculate
mater ial known collectively as tars .
I t i s not easy to compare the tox ic i ty of a g iven number of
mar i j una c igarette s to a g iven number of tobacco c i garettes . Ther e
a re general s imila r i t ies in the compos it ion of the smoke , but the
var iat ions in compos ition of both tobacco and mar i j uana c igarette s
a nd d if ferences in smok ing technique s make s imple extrapolat ions of
r is k s of tobacco ver su s mar i j uana smok ing not val i d .

16
TABLE 2 Concentrat ions of 6-9-TBC in Different Var ieties o f
Mar i j uana
Percent 6 -9-'l'BC
( Percent by We igh t )
Nepal.2.
2 . 81
Mex icc
1 . 68
Pakistan
1 . 30
ColOIIb i a!.
Normali zed
Average a!
1 . 00
3 . 00-3 . 50
I nd iat
0 . 46
(g rown above 2 0 0 0 m )
1. 39
(grown below 2000 m )
J ama ica (Ganj a ) h
2 . 80 (Man)
United States
0 . 35
S insemilla ( f iber )
0.21
S insemilla
( intermed iate ) g
3. 58
S insemilla (drug ) g
6 . 28
3 . 00-11 . 00
Bashiah
( U . N . standard ) g
2 . 22 ( 7 . 4 0 )
1.90
NIDA ( c igarette l ) g
NIDA ( c igarette 2 ) g
C r ude mar ij uana
e xtrac t:Sl
I ll ic i t hash i sh o iX!
Research harvest
.0 . 8 4
1 . 8 6 ( 2 . 8 ) .i
20 . 0 0
10 . 00-30 . 00
( up to 6 0 ) .!.
20 . 00
0 . 90-2 . 8 0
SOURCES :
(!) Jones , 1980 J Q2) Braenden , 197 2 J ) Turner , 1974 J
Turner , 1 9 8 0 J (!) Turner , 1981 J (!,) Turne r et al . , 1979 J (51.)
Rosenkrant z , 1981 J (b) Marshman et al . , 1976 .
(g)

17
TABLE 3 Marijuana and Tobacco Reference Cigarette
Analysis of Mainstream Smoke
Marijuana
A.
Tobacco
Cigarette
(85 mm)
(85 mml
1115
10.3
14.7
0.88
10.7
1110
Cigarettes
Average weight, mg
Moisture, percent
Preaaure drop, cm
Static burning rate, mg/a
Puff number
B.
Cigarette
11.1
7.2
o.8o
11.1
Mainstream Bllloke
I. GaB !haae
Carbon monoxide, vol. percent
mg
Carbon dioxide, vol. percent
Aauaonia,
57.3
228
119
llg
HCN, llg
Cyanogen (CN) 2
Isoprene, llg
Acetaldehyde, llg
Acetone,
Acrolein, llg
Acetonitrile,
Benzene, 11g
Toluene,
3.99
17.6
8.27
532
19
83
1200
443
92
132
76
112
5.4
Vinyl chloride, nq!
4.58
20.2
9.38
65.0
199
498
20
310
980
578
85
123
67
108
12.4
Dimethylnitrosamine, n
75
84
Methylethylnitroaamine, ng.!
pH , third puff
27
30
fifth puff
seventh puff
ninth puff
tenth puff
II.
6.56
6.14
6.57
6.58
6.56
6.58
6.15
6.14
6.10
6.02
Particulate !haae
Total particulate matter, dry, mg

Phenol,
_2-Creaol, llg
!.- and .2-creaol,

Dimethylphenol,
119
Catechol,
Cannabidiol, 119
69-Tetrahydrocannabinol,
Cannabinol,
Nicotine,
22.7
76.8
17.9
54.4
6.8
188
190
llg
65
14.4
328
820
400
2850
!-Nitroaonornicotine, nq!
Naphthalene,
1-Methylnaphthalene,
2-Methylnaphthalene
Benz(a)anthracene, ng.!
Benzo(a)pyrene, ngl
39.0
138.5
24
390
3.0
6.1
3.6
75
31
1.2
3.65
1.4
43
21.1
.!Indicates known carcinogens.

SOURCESr
Hof_fmann et al., 1975, 19761 Brunnemann et al., 1976, 1977.

18
Othe r Preparat ion s
Bes ide s the c r ude plant leaf mate r ial for smok ing , usually called
ma r i j uana , res inou s mate r ia l f rom the plant , called hashish , and
solvent extrac t s of the plant , te rmed ha shish o i l , somet ime s appear
on the i l l ic i t ma r ket .
I n many pa r t s of the wo r ld , hash ish is mor e
commonly u sed t han mar i j uana . A s with a l l cannabis prepa rat ions , the
6-9-THC content of ha s h i sh va r ies enormous ly , but the uppe r l im i t s
o f - 9-THC content are u sua l ly much h igher than for ma r i j uana : 7
pe rcent or h ighe r and even h ighe r for hash ish o i l ( Table 2 ) .
Howeve r , even these gene r a l ly more potent forms of cannabis may
occas ional ly cont ain much less -9-THC .
The me re des ig nat ion of the nature of a cannabis prepa rat ion i s
The pract ical
an unrel iable pred ictor of its -9-THC content .
consequence of this for the c l i n ical researcher i s that the exposure
to cannabi s u se r s is not known .
What Potency of Ma r i j uana Is Ava i lable From Street Sample s?

Because of the many confound ing va r iables ment ioned above , i t i s
d i f f icult to know what potency of psychoact ive d rug i s i n ma r i j uana
sold i l l ic it ly .
The concentrat ion of -9-THC in a g iven sample
w i l l vary ( Ri t z l i n et a l . , 19 79 ) .
The content of -9 -THC from
va r iou s st reet samples ha s been assayed . Ma r i j uana f rom Drug
Enforcement Administrat ion con f i scated sample s 1 samples r eceived
throug h psychiatr i st s , pol ice depa r tments , and state cr ime
l aborator ies , and fug i t ive* sample s were quant i tative ly ana lyzed for
6-9-THC and othe r cannabino ids .
A phys ica l descr ipt ion of the
sample was made--e . g . , buds , s insemi lla .
The plants we re also
categor i zed by or ig in--where they were cultivated .
The analys i s
showed that tremendous var iabi l i ty ex i s t s i n the potency o f 6 -9-THC
on the st reet , normal i zed samples ranged f rom zero to 11 percent
-9-THC ( Turne r , 1 9 8 1 ) .
Analyt ic Methods
Detect ion and measu rement of cannab inoid s and the i r metabol ite s i n
body f luids i s far more d i f f icult than w ith s uch d rug s as alcohol .
The blood and t i ssue levels result ing from use of ord inary cannabi s
a r e very low--nanog ramst per m i l l i l iter o r lowe r .
In add i t ion ,
compounds l i ke steroids , occu r r ing normal ly in body f lu ids inte r fere
with the measurement of cannabinoid s in blood and can ma ke the test
much less sens i t ive t han if pure cannabinoids in an uncontaminated
* Samples rece ived , when no a r rests were made .

tone b i l lionth of a gram .

19
solut ion are be ing analyzed ( Ha r vey et al . , 1980 J Ha rvey and Paton ,
1 980) .
A combinat ion of gas-liqu id chromatography and mass spect rometry
is the most sensit ive d i rec t method of measu r i ng cannabinoids .
That ,
howeve r , requ i res s k i l led technic ians and expensive equ ipment not
Us ing mod i f icat ions of th i s expe r imental
read i ly ava i lable .
techn ique , one can measure a s l it t le as 5 p icog rams* of 6 -9-THC in
a m i l l i l i te r of plasma ( Harvey et a l . , 1 9 8 0 J Harvey and Paton ,
1 9 8 0 ) . Rad ioimmunoassay and enzyme immunoassay techn iques also ar e
a va i lable , the lowe r l imits of sens it ivity of these methods now are
not adequate for rel iable mea surements of 6-9-THC in human blood
more t han a few hou r s a fter d rug admin istrat ion .
A read i ly ava i lable
enzyme immunoassay w i l l detec t cannabi s metabol ite s in the ur ine fo r
a s long as a wee k after the smok ing of a s i ng le ma r i j uana c igarette .
Thu s , a posit ive u r ine test by th i s method i s not necessar i ly
i nd icat ive of u se within the previous few hou r s and does not provide
ev idence of recent intox icat ion as a breath test does for alcohol .
Assays for cannabinoids a re l i kely to rema in far more compl icated
than fo r alcohol and many othe r d r ug s .
PHARMACOLOGY OF CANNAB I S
Impl ic it i n a d i scuss ion of t h e ef fects of any d r ug i s som e
determinat ion of dose .
The i ntens i ty and durat ion of ef fects in
relat ion to drug dose must be determined or infer red f rom adequate
pha rmacolog ic study .
The intens ity and durat ion of a drug ef fect
depends on at least three maj or factor s :
1 . The concentrat ion of the d rug at the s ites of act ion in the
body .
Th i s i s determined by the dose , what the d r ug is d i ssolved i n
o r mixed with , the rou te of admi n i strat ion , and the pharmacok inet ics
of the drug .
The sensit ivity of the cells the drug acts upon .
2.
3 . The phys iolog ica l state of the bod i ly systems be ing
a f fected .
Th i s , in turn , depends on interactions with othe r systems
and , espec ially for drug s with behavioral and psycholog ical e ffects ,
a s wel l as envi ronmental and exper ient ial factor s , inc lud ing the
presence of other drug s .
W ith cannabi s , many or even most of the se factor s are not always
measurable or unde r the control of an invest igator .
* 1 pg
l o 1 2 g r ams .
-

20
Potency and Pharmacok inetic Cons iderat ion s
Pharmacok i netic stud ies of the absorpt ion , d istr ibut ion , metabol i sm ,
and e l imination of A-9-THC determine how long A-9-THC and its
metabol ites remain i n the body .
Pharmacok ine t ics vary with the route
of drug admini stration and such factor s as l ipid solubi l i ty J
A- 9 -THC tends to rema i n for long per iods of t ime i n fatty t issue .
When smoked , 6 - 9-THC i s rap id ly absorbed by the blood in the
lung .
I f taken orally , 6-9-THC is not absorbed into the blood as
rapidly .
The r ate of d isappearance of A -9-THC from the blood
var ies with t ime ( Lembe rge r et al . , 1 9 7 la , b , 1 9 7 2 J Ohlsson et al . ,
1 98 0 ) .
H igh blood levels fall rap idly for the f irst 3 0 minutes , as
the A-9-THC d i st r ibute s to t i ssue s with h ig h blood f low .
After the
init ial d i str ibut ion , the blood leve l falls much more slowly with a
hal f-l ife* of 1 9 hou r s or more (Bunt and Jones , 1 9 8 0 ) . Metabol ite st
of 6 - 9-THC have the i r own i ndependent rates of e l iminat ion .
Typically , metabol ites are e l iminated more slowly , having a half- l i f e
o f approx imately S O hours ( Hunt and Jones , 1 9 8 0 ) .
Afte r an inj ect ion of a s i ng le dose of A-9-TBC , approx imatel y
2 5-30 percent of the compound and its metabolites rema in in the body
at 1 wee k ( Lemberge r et a l . , 197lb r Hunt and Jones , 1 9 8 0 ) .
E s sent ially complete e l iminat ion of a s i ng le dose may take 30 days or
longe r (Jones , 198 0 ) .
Thus , repeated admini strat ion of even smal l
doses may lead t o an accumulat ion of drug h igher than levels reached
at any t ime after a s i ng le dose .
Ab so rpt ion
Inha l ing smoke from a cannabi s c igarette or p ipe i s pha rmaco
k inet ically d i f ferent from ingesting cannabis .
Smok i ng is a far more
eff icient way of del iver ing cannabinoid s to the b r a i n than ingest ion
becau se of the large sur face area of the lung s .
Inhaled , the
cannabinoids i n the smoke go rapidly f rom the lung s into the blood t o
the left s ide of the heart and are carr ied in seconds t o the brain
and othe r organs before passing through the l iver . When smoked , a
d rug reaches the bra i n with relat ively l i ttle t ime for metabolism or
d i lution .
Many substance s with h igh l ip id solubi l i ty such as
c annabinoids go qu ickly from blood into t issue s , includ ing brain
t i ssues .
Psycholog ica l and card iovascular effect s of cannabi s a r e
It
* The half-l ife i s a measure o f how rapidly a drug i s e l iminated .
i s the t ime requ i red for t h e leve l of a drug t o b e r educed by
one-half .
I f start i ng levels a re ten units and the half- l i fe i s 2 4
hou r s , then 1 day after admin i strat ion , the level w i l l be 5 units , 2
d ays after admini strat ion 2 . 5 units , etc .
tTbere are more than 4 5 metabol ite s of major cannabinoid s ident if ied
in d i f ferent spec ies , at least one of which , 1 1-QH-A-9-THC , i s
psychoact ive .

21
Peak effects occu r abou t
evident within a few second s o f inhalat ion .
t he t ime smok ing i s completed .
When taken by mouth , cannabinoids usually are in solut ions or
su spens ions . The mate r ia l they are mixed w ith affects the rate of
a bsorpt ion . Por example , blood levels of 6 -9-THC were h ighe r and
lasted longer when g iven in an o i ly solut ion than in an ethyl alcohol
solu t ion ( Perez-Reye s et a l . , 197 3 ) . Th i s suggests that cannabis
e aten i n food mixtures conta ining fat i s better absorbed .
An important di fference between smok i ng and ingest ion i s tha t
when cannabinoida are absorbed from the gut , the blood containing
them f i r st goe s d i rectly through the liver . The l ive r rapidly clear s
t he 6 -9-THC f rom the blood and enzymat ically changes much of the
6 -9-TBC to other metabolites before it reaches the bra in ( Bunt and
Jones , 1 9 8 0 ) . A large amount i s metaboli zed to 11-hydroxy-6-9-THC
( P igure 1 ) .
I t i s unknown if the spectrum of effects of this
metabol ite i s ident ica l to that of 6-9-THC . When taken by mouth ,
in contrast to when smoked , two o r three t imes more 6-9-T.RC i s
requ i red t o obtai n equ ivalent acute psycholog ical and phys iolog ica l
e ffects . After oral doses the effects develop more slowly , last
longer , are more var iable , and cannot be controlled by the rec ipien t
once the cannabi s has been swallowed .
In contrast , the smoker feels
the effec t s qu ic k ly and can mod i fy inhalat ion at any t ime , althoug h
overdosage i s still poss ible . Unpleasant reac t ions to overdose are
more commo n following ingest ion than inha lat ion .
A var iety of other routes of admini strat ion have been used
exper imentally in humans and in animals , includ ing intravenou s ,
i nt raper i toneal , subcutaneous , intramuscular , topical (on the ak in ) ,
and into the conj unc t ival sac ( eye ) . These var iou s routes inf luence
t he t ime to onset of effect , durat ion and peak intens ity , and the
rate with which the effect d i sappears . Di rect compar i son of f ind i ng s
i n stud ies using d i ffer ing admini stration routes i s d i ff icult and
must take these factor s into cons iderat ion .
Ruman use r s of cannabi s vary in the i r prefer red routes of use .
I n some countr ies and cultures cannabi s i s ma inly taken by ingestion
( for example , India) and in others by inhalat ion ( for example , the
Uni ted States) . Because of the effects of route of admin i stration on
pharmacology , i t i s reasonable to expect d i f ferent health consequences
of the d i fferent route s of admini stration ' therefore , compa r i sons of
health stat ist ics among countr ies must be made with care .
Although smoking avoids many of the absorpt ion problems d i scussed
a bove , a host of other var iables affecting dose are i ntroduced , such
as the s i ze and pack ing of the cannabi s c igarettes , the way the smoke
i s i nhaled , the number of puffs and the interval between puffs , the
temperature produced in the burning c igarette , and whether a c igarett e
i s shared . Because of the prog ressive concentrat ion of cannabis
const i tuent s in the c igarette butt , the last few puf f s y ield con
s ide rably more 6-9-THC and par t iculate matter than do the ear l ier
puf f s . All these and other fac tor s affect the dose rece ived , and
only rarely have they been measured . Only some of these factor s a r e
under the consc ious control o f the cannabis smoker . About half of
the 6-9-THC or ig inally in a cannabi s c igarette i s lost by

22
combust ion , by butt ent rapment , i n smoke not inhaled , and i n smok e
exhaled ( Fehr and K a lant , 1 9 7 2 1 Rosenk rant z , 1 9 8 1 ) .
I t ha s been repor ted that , l i ke nonsmoker s of tobacco , ind i v idual s
i n a poor ly vent i lated room whe re cannabi s i s smoked may pass ive ly
inhale ac t ive components ( Ze idenbe rg et al . , 1 9 7 7 ) .
Because only
t race amounts of cannabinoid metabol i tes are present in u r ine of
these passive inhale r s , i t i s unl i kely that the low levels of the
a bsorbed cannabino ids f rom the ambient a i r account for the so-ca l led
contact h igh . Expe r ienc ing subj ect ive cannabi s e f fect s in the
presence of cannabi s smoke r s cou ld .be expla ined by psycholog ic
factor s in add it ion to any pharmacolog ic ones .
But , because stud ie s
have shown that c h i ldren of parents who smoke tobacco a re more l i kely
to have respiratory infec t ions dur ing the f i r s t yea r of l i fe--wh ich
may be due to t he i r be ing exposed to c igarette smoke in the atmosphe re
( U . S . Depa r tment of Health , Educat ion , and We lfare , 1 9 7 9 ) --the i ssue
of pass ive inha lat ion of mar i j uana smoke i s worth fu rthe r study .
D i s t r ibut ion
The l ipid solubi l ity of A-9-THC and othe r cannabinoid s , inc lud ing
those with h ighest pharmacolog ic act i v i ty , fac i l itates d istr ibut ion
read i ly i nto t i ssue s and ce lls throughou t the body so blood level s
d rop r ap id ly .
I n i t ially , cannabinoid concentrat ions a re h ighest in
such t i ssue s as lung , l iver , and k idney that have a h ig h blood flow
( Agurell et a l . , 1 9 6 9 , 1 9 7 0 1 K lausne r and Dinge ll , 1 9 7 1 ) .
Delta-9-THC
crosses the placenta and ente r s the fetus of expe r imenta l animals
( Kennedy and Waddell , 1 9 7 2 ) .
Cannabinoid levels in the human fetus
have not been stud ied .
Small amounts are also found i n the milk o f
exper imental animals and can be t ransfer red t o progeny (Jakubovic e t
al . , 1 9 7 3 1 Chao e t a l . , 19 7 6 ) .
Afte r i n i t ia l d i st r ibut ion ,
concentrat ions of cannabinoids in t issue s , cells , and subcellular
compar tments are h ighly nonuniform , determined no doubt by solubi l i t y
a nd other phys icochemical characte r i s t ics .
The refore , blood
concentrat ions do not reflect concentrat ions at pharmacolog ically
active s i tes , as they do with alcohol .
Metabol i sm and El iminat ion

E l iminat ion of drug s and the i r metabolites is mostly through
excret ion by the k idney into the ur ine or by the gall bladder via the
b i le i nto the i ntest i ne and out with the feces . Cannabinoids do not
pass ou t of the blood into the lung s and do not appear in breath i n
apprec iable quant i t ies .
Some cannabinoids going into the intest ine
with bile are reabsorbed . Some also d i ffuse bac k th rough the k idney
t ubu les dur ing the process of u r ine format ion , so the amounts f inally
excreted per unit of t ime are sma ll .
The net result of th i s
r ecyc l i ng i s that the cannabinoids are only slowly el iminated from
the body .

23
Stud ie s of the d i sappea rance o f 6-9-THC f rom human plasma hav e
led to repor t s of values of half-l ives that ranged f rom 1 9 hou r s in
expe r ienced u se r s ( Hunt and Jones , 1 9 8 0 ) to 5 7 hou r s in na ive u se r s
( Lembe rger e t a l . , 1 9 7lb) . Whether t h i s d i fference in half-life i s
due to the expe r ience o f the use r has not been establ i shed .
Because
o f the i r h igh l ip id/water pa r t i t ion coef f ic ients , 6 -9-THC and some
of its metaboli tes can be sequeste red in fatty t issue s .
FOl low ing
the intravenou s administrat ion of rad ioact ive A-9-THC to human
volunteers , howeve r , 6 7 percent of the rad ioact ivity was excreted in
1 week , 2 2 percent i n the u r ine and 4 5 percent i n feces ( Lembe rge r e t
Almost no 6 -9-THC i tse lf was excreted in the u r i ne .
a l . , 197la) .
There may be f a i r ly r ap id and complete metabol i sm of f ree 6- 9-THC
followed by slow re lease and metabol i sm of seque ste red 6 -9-THC and
retained metabolites .
Because no d i rect measurements of cannabinoid
levels have been made in t i ssue sample s from human cannabi s use r s and
t he data are l imited in exper imenta l animals , one can only infer from
blood levels what metabolite s are accumu lat ing and where .
In rats , afte r i nhalat ion or intravenous administrat ion of
rad ioact ive 6-9-THC , rad ioac t ivity pe r s i sted in the brain for a t
least 7 days , mostly as metabol i tes ( Ho et al . , 1 9 7 0 ) . When g iven
subcutaneously in rat s , even at i nterval s as g reat as a day or two
apar t , A - 9-THC w i l l accumu late as metabol ites ( K reuz and Axelrod ,
197 3 ) .
Accumulat ion of some cannabinoids with even less frequent
intake appear s l i ke ly .
Although most metabol ites are concent rated i n
f atty t i ssues , they will slowly pass into plasma and c ircu late though
all par t s of the body , par t icula r ly inc lud ing such organs as the
brain , and generally all membranes .
The health consequences of the
cont i nued presence of such fore ign molecu les are not known .
The
mar ked per s istence of the cannabinoids i s qu ite unl i ke other widely
consumed agents , such a s alcohol , n icot ine , and caffe ine , that a r e
r apidly metabol i zed and leave no trace a few hour s after moderate
intake .
WHAT I S A LARGE OR SMALL CANNAB IS DOSE?

Large and frequent dose s of any d r ug are more l i kely to produc e
adve r se health e f fects than small infrequent doses of the drug .
Thus , j udgment s of health consequences of the use of cannabi s ca n
o nly b e made w i th impl ic it or expl ic i t knowledge about dose .
r the
reasons d i scussed above , the range of cannabinoid doses consumed
var ies widely .
Invest igators u sually repor t dose in terms of
mar i j uana c igarettes pe r unit of t ime , or they g ive some est imate o f
t he concentrat ion of 6- 9-THC u sed for oral applicat ion .
Th i s i s
not an adequate way t o quant i fy the amount o f cannabinoids actually
ente r i ng the body .
Only one epidemiolog ic study provide s a breakdown
of vary i ng dose levels in excess of one cannabi s c igarette da i ly
( Bachman et al . , 1 9 8 1 ) .
Epidemiolog ic surveys have not quant ified
6- 9 -THC levels . When repor t i ng less frequent use patterns than one
c igarette per day , invest igators u se measu res that make it d i f f icult
to compar e stud ies .
I n th i s repor t , any general or average dose
e st imates a re approximat ions .

24
I t i s generally ag reed that smok i ng f ive or six 1-gram cannabi s

c igarettes daily i s a large dose ( Dornbush e t al . , 1 971 J Rosenkrantz ,
1 9 8 1 ) . Because of the var iabi l i ty of 6-9-TBC content of cannabis
avai lable from street samples , i t wou ld be more appropr iate to
cons ider this heavy use . The def inition of a low dose i s mor e
controve r sial . Some consider one mar i j uana c igarette a day to be a
large dose . Othe r s thin k even one c igarette a week i s regular ,
f requent , and a h igh dose .
W ith tobacco and alcohol , for which dose i s easier to quant i fy ,
i t took many year s to establ ish what a small or large dose might be
i n terms of spec i fying doses that s ign i f icantly increased the r i sk of
var iou s behavioral and hea lth consequences . Even with those drug s ,
t here i s still d isag reement as to prec isely what a small and safe
dose might be . There will be even more problems i n spec i fying
typical cannabi s doses and pred ict ing the i r l i kely health
consequences .
In controlled laboratory cond i t ions , ingested doses of more than
20 mg of 6-9-TBC generally are cons idered by both invest ig ator s and
cannabi s users to be large doses . Doses of less than 10 mg are
cons idered small . Ma r i j uana c igarettes containing more than 2 0 mg o f
6- 9-TBC seem t o be a large dose , and those with 1 0 mg produce
ef fects generally cons idered t he result of a small dose . When
volunteer s were allowed to select the i r own self-dete rmined smoke d
doses in controlled exper iments , some smoked only one or two 2 0-mg
c igarettes da i ly , whi le other s imi lar volunteer s smoked s ix to ten o r
more c igarettes per day . var i abi l i ty in smok ing patterns is g reat
and not eas i ly quant i f ied , only broad range estimates of dose ar e
poss ible .
GENERAL TOX ICOLOGY
. Delta-9-TBC and related cannabinoids have very low lethal tox ic i ty .

That i s , a ve ry h igh s ing le acute dose of 6 -9-T.HC i s requ i red to
k i ll hal f of a popu lat ion of exper imental animals . Th i s lethal dose
for s o percent of the animals is called the LD s o The lack of
well-authent icated cases of human deaths from acute 6 -9-TBC or
cannabis overdose is consistent with the exper imental animal data .
The lethal dose inc reases as the phylogenet ic tree i s ascended . The
r at has an LDs o of 4 0 mg/kg intravenously , in contrast to a 1 2 5
mg/kg in the monkey ( Rosenk rantz , 1981 ) . Death i s usually due to
card iac dysfunct ion . Delta-9-T.HC appear s to be the most tox ic of the
c annabinoids .
S tud ies of chronic cannabi s admini strat ion to animals have
demonstrated delayed letha l i ty . Animals d i e after several days of a
r epeated h igh dose ( Rosenkrantz , 1981 ) . The reason for th i s patte rn
is unclear .
I t cou ld be related to accumu lat ion of 6-9-TBC or
metabol i tes in t issues .
A 1-year chron ic t reatment of rats w ith lowe r doses of
cannabinoids produced a pattern of tox ic ity consist ing of we igh t
loss , pulmonary pathology when the drug i s inhaled , and slowly

25
developing behavioral toxicity character i zed by hyperact ivi ty ,
vert ical j umping , f ighting , and se i zures ( Rosenk rantz , 1 9 8 1 ) .
RELEVA!CE OF NOHBUMAN ANIMAL MODELS

Much of what i s known about cannabi s comes f rom exper iments in
animals . Some aspects of the pharmacology of any drug can only b e
s tudied in animals other than human be ing s . Find i ng s f rom animal
exper iments have been cr itici zed because of what were thought to be
u nreasonably h igh doses of cannabis g iven to the animals as compared
with dose s common ly used by human be ing s . Although extrapolat ion of
human e ffects from animal data must be done with caut ion beCause of
spec ies d if ferences i n metabolic pathways and d i f fer ing sens itivity
a nd phys iology , a blanket c r i t ic i sm of an ima l stud ies beCause of high
dose s i s i nappropr iate . When an effect of a drug occurs consi stently
in several spec ies , it is l i kely to occur in human be ing s . Compari
sons of 6-9-TBC blood levels in human beings and in several spec ie s
suggest rough ly similar i ntens i ty o f effects a t s imilar blood levels
i n the var iou s species ( Rosenk rant z and Fle i shman , 1 9 79 ) .
CANNAB I S CONTAMINANTS
On occas ion cannabi s has been reported not only to contain the
herbic ide paraquat , but also salmonella bacteria and asperg i llus
fungus . De l iberate add it ion of such drug s as lyserg ic ac i d
d iethylamide ( LSD) , heroin , and phencyc l id ine ( PCP ) has been
c la imed . A plant mate r ial such as cannabi s is not always handled i n
the most sanitary way , and a var iety of contaminants are possible .
Paraquat
The re is no quest ion that large doses of paraquat by mouth or by
aerosol can cause pulmonary f ibrosis , but no cases in human being s
have yet been proved to result from paraquat-contaminated cannabis .
Few cannabi s smoker s are expected to be exposed to the large amounts
of paraquat known to cause severe lung damage . Thi s i s not to say
that no lung damage wi l l occu r from such exposu re . A more extensive
d i scuss ion of paraquat i s in Append ix D .
Bacte r i a and Fung i

A few outbreaks of salmonellosis epidemiolog ically l inked to
mar i j uana use were repor ted f rom Ohio and Mich igan ( Schrader et al . ,
1 9 8 1 ) . Mar i j uana was found to be contaminated with the same type of
salmonella that wa s obta ined from the 6 2 patients expe r iencing
d iar rhea , fever , and abdominal pai n .

26
Asperg i llus , a fungus , i s a common contaminant of some cannab i s
The spor es pass
( Llewellyn and O ' Rea r , 1977 r Llamas e t a l . , 19 7 8 ) .
eas i ly th roug h contaminated mar i j uana c igarettes and when smO ked a r e
p resumed to enter the body .
CELLULAR TOXIC ITY

A var ie ty of effects on cellular processes have been reported ,
usually based on stud ies of in vitro systems .
The low wate r
solub i l i ty of the cannab inoids and the need to add solvents and
emuls i f ie r s , along with a commo n tendency to use h igher in vitro
concentrat ions than occurs in l iving animals , makes interpretat ion of
such exper iments d if f icult .
In related stud ies , 4-9-THC a lte r s the act ions of a number of
int r acellular enzyme systems .
The biolog ical relevance of these
drug/enzyme inte ract ions is s t i l l unc lear at th i s t ime , but , togethe r
w i th the cytotox ic ity , i t suggests that 4 -9-TBC is produc ing mar ked
e ffects on cel l membrane s and intracellular processes .
Almost nothing i s known of the molecular mechan i sms by wh ic h
c annabinoids produce the i r e f fects in cells .
TOLERA!CE AND DEPENDENCE

Repeated admini strat ion of most psychoactive d rug s leads to the
deve lopment of tole rance .
Thi s state of increased drug resi stanc e
r esults f rom two general mechani sms (Kalant et al . , 1 9 7 1 ) :
D i sposit ional tolerance resulting from lowe r d rug

concentrat ions at s i tes of action , usually because of increased rates
of drug metabo l i sm or e l iminat ion
Funct ional tole rance a r i s ing from decreased sens i t ivity of

the target cells .
Tole rance to most cannabinoid ef fects has been demonstrated both
in animals and human be i ng s. (Jones , 1 9 8 1 )
Tolerance can develop
r apid ly after only a few small doses .
It d isappear s at an equally
rapid r ate for many effects , although after large doses in
exper imental animals some tole rance may pe r s i st for long per iods
(Jones , 1 9 8 1 ) .
Systematic stud ie s of tolerance loss have rarely been
done .
Many character i s t ics of tolerance to 4 -9-TBC , part icularly
i t s pattern of rap id acqu i s i t ion and loss , are s im i lar to that
occur r ing with opiates , n icot ine , and coca ine (Jones , 1 9 8 1 ) .
Mos t
evidence suggests func t ional rather than d i sposit iona l means of
acqu i r i ng tolerance .
The development of such tolerance to cannabis does not
However , i f tolerance shou ld
necessar i ly have health impl icat ions .
l ead to h igher or more f requent doses , adve r se consequences , e . g . ,
resp i ratory effect s , assoc i ated with h igher usage could result .

27
Phys ical dependence , man i fested by wi thdrawal s igns and symptoms ,
c an develop rap idly in animals and in human be i ng s (Jones , 1981 ) .
I t i s s imila r i n
The wi thdrawal syndrome i s not l i fe threaten ing .
many respects t o the m i ld dependence produced by low doses o f othe r
sedatives . Withd rawal symptoms can inc lude re stlessness ,
i r r i tabi l i ty , mild ag itat ion , insomn ia , and sleep EEG d i stu rbance .
Cannab i s dependence does not mean the same th ing as cannabi s
a dd ict ion . Dependence means only that a withdrawa l synd rome can
occu r when drug tak ing is stopped . Add ict ion impl ies compuls ive
behavior to acqu i re the d rug . The relat ionsh ip between dependence
and increased drug seek ing or drug u s ing i s more theoret ica l tha n
well documented , par t icula r ly in expe r iments with human be ing s .
Given the appearance o f tole rance and dependence with almost any
p sychoact i ve d rug , it would be unusual not to f ind tole rance and
dependence with the r ight dose and dosage schedule of cannabi s . Goo d
s tud ies of the relat ionsh ip of dependence , i f any , to per s i stent drug
use are important .
DRUG INTERACTIONS
Because cannabi s often i s consumed with othe r drug s , interaction s
can be expected . Other i llicit drug s , tobacco , caffe ine , alcohol , and
over-the-counte r or presc r ibed med icat ions shou ld be stud ied in
combinat ion with cannabi s , because 6 -9-THC and its f i r st metabolite
are strong ly bound to prote ins in the plasma ( Ga r rett and Runt , 1974 )
and may i nterac t with other drug s similarly bound . Cannabis and many
other d rug s share d i spos i t ion by the hepat ic metabolic enzyme systems ,
and there are possible inte ract ions at the d rug metabol i sm level . Pb r
example , drug s such a s alcohol or pentobarbital can inhibit metabolism
of 6-9-THC by enzyme substrate compet it ion . Or , i f afte r a pe r iod
of inhibit ion one drug i s removed , the enzyme activity can increase
so that faste r than expected metabol ism follows .
If g i ven
s imultaneously with other d r ug s , 6 -9-THC can slow metabol i sm of
d rug s such as theophyllin , ant ipyr ine , ethanol , and pentoba rbital
(Benowitz and Jones , 1 9 7 7 r Jusko , 1 9 7 9 ) . Cannabid iol can also
inhibit the metabol ism of a var iety of drug s normally metaboli zed by
the shared hepatic enzyme systems .
Drug interact ions also can occur by means of funct ional
mechani sms . These can be add it ive , result ing in enhancement o r
p rolongat ion o f behavioral and psycholog ical e f fects by cannabi s when
combined with othe r central ne rvous system depressant drugs , such a s
a lcohol and barbiturates . Animals less tolerant to cannabis will
also be less sen s i t ive to other central ne rvous system depressants .
Th i s phenomenon i s known as c ross-tolerance . Drug interact ions will
be mentioned in subsequent chapter s .

28
SUMMARY AND CONCLUS IONS
Cannabi s i s not a s ing le drug , but a complex preparat ion conta ining
many biolog ically act ive chemicals . The psycholog ica l and
physiolog ical e f fects produced by A -9-TRC probably result f rom
actions at s i tes within the central ne rvous system and elsewhe re in
the body , lead ing to the l i kelihood of compl icated effects depend ing
on dose , durat ion of use , and many other considerat ions .
The intens ity of ef fect an i ndividual exper ience s var ie s
c onsiderably according to the cannabis preparat ion and the amount
taken , route of administrat ion , frequency of use , and probably othe r
not-well-recognized biolog ical cons iderat ions . Dose var iabi l i ty must
be cons ide red both in conducting and in interpreting any stud ies of
t he e ffects of cannabi s , par t icula r ly when try ing to pred ict health
consequences .
In research the use of pure A-9-TRC avoids some problems of
dose control but cannot provide a complete picture of cannabis
effects , because the effects of A-9-TRC in crude preparat ions of
the plant may be influenced by othe r components . Other consequences
of cannabi s use , for example , exposure to harmfu l components in i t s
smoke , will have deleter ious health consequences in add it ion to
anything produced by the A-9-THC .
The long persi stence of cannabinoid metabolites in the body may
have delayed effect s or health impl icat ions not yet recogn i zed ,
because , even with relat ive ly infrequent use , there i s chronic
In th i s respect ,
exposure to biolog ically unknown mater ials .
c annabis d iffers fundamentally f rom such drug s as alcohol , n icot ine ,
and caf fe ine , which are rap idly metabol ized and eliminated from the
e nt i re body .
C annabinoid effec ts can be mod i f ied by many events , inc lud ing
inte ract ion with othe r drug s and the deve lopment of tolerance . Bot h
tolerance and dependence develop to many effects of the drug . The
health s ignif icance of tolerance and dependence , par t icular ly the i r
impor tance i n drug-see k i ng a nd d rug-using behavior , has not been
stud ied properly .
I t i s unl ikely that adequate epidemiolog ic data will be ava i lable
( soon ) to enable good est imat ion of the health consequences of var iou s
u sage levels .
A pre requ i s i te is that adequate chemical analytical methods be
appl ied on a large-scale bas i s to mon itor actual exposures . COnt inued
s tud ies in exper imental animals will play an essential role in the
assessment of the health r i sks of cannabi s .
POr example , the
b iolog ical act ivities of A-9-TRC metabolites can be assessed in
exper imental animals , but these tests a re techn ically more d i f f icult
to do in human beings .
RECOMMENDATIONS FOR RESEARCH

Seve ral research pr ior i t ies are ident i f ied by the preced ing
d iscuss ion :

29
Cannabinoids and the i r metabol ite s per s ist for relat ively
long per iod s in the body . More informat ion is needed on the
biolog ica l s ignif icance of that pe r s i stence in human beings . As a
f irst step , the tox icolog ical effects of the var ious metabolites need
to be determined .
Drug interactions alte r the act ions of cannab i s . Cannabis

use alters other drug effects . More informat ion is necessary to make
the combined effects of cannabis and othe r l ic i t and i l l ic i t d r ug s
more pred ictable , espec ially with respect to behavioral impa irment
and tox ic ity to lungs , liver , and othe r organa .
S tud ies of the mechan i sm of act ion of cannabis should

cont inue . Knowledge of mechanism i s l i kely to provide powerful
ins ights into the potent ial health effects .
Improved chemical analyt ical methods are necessary .

Epidemiolog ic appraisal of the health effects of cannabinoids
requ i re s method s suitable for wide-scale assay s of exposures .
Pharmacolog ical ve r i f icat ion of the self-reported extent of use will
make exper imenta l and clinical results much eas ie r to inte rpret . A
c hemical marker of the frequent user would be useful . Screening
techniques for the purpose of identifying and d i scou r ag ing
c annabis-impa i red d r iving would also be valuable .
Characte r i zat ion of the tox icolog ical s ignif icance of commo n
cannabi s contaminants such as paraquat and other chemicals , fung i ,
and bacte r ia should be cont inued .
The development of tolerance is a factor that potent ially

mod i f ies the express ion of all psychoactive drug effects . Add it ional
stud ies on the rate s of acqu i s i t ion and loss of tolerance and the
r e lat ionship of these phenomena to dependence are necessary . The
biolog ical s ignif icance of the changes that under l ie the developmen t
o f tolerance should be establ ished . e relat ionship , i f any ,
betwen tolerance and dependence and drug-seek ing behavior should be
e stabl ished .
C annabis products a re var iable and complex . More

informat ion on the amount , nature , and potency of the var ious
prepa rat ions used around the world would fac i l itate calcu lat ions o f
exposures to its constituents . Por example , what i s the biolog ical
and tox icolog ical s ign i f icance of the minor components of cannabi s
smoke?
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A note on the
Mar e hman , J . A . , Popham , R . E . , and Yawney , c . D .
cannabinoid content of Jama ican ganj a . Bull . Narcot ic 26 : 63-68 ,
1976 .

32
Mechoulam , R . and Gaon i , Y .
A total aynthes i s o f
6 -1-tetrahydrocannabinol , the act ive constituent o f haeh ish .
J . Am . Chem . Soc . 8 7 1 3 2 7 3- 3 2 7 5 , 1 96 5 .
Mechoulam , R . and Gaoni , Y .
The absolute conf igurat ion o f
6 -1-tet rahydrocannabinol , the maj or act ive conet ituent of
haehiah .
Tetrahedron Lett . 1 2 : 110 9-1111 , 196 7 .
Mechoulam , R . , Lander , N . , Va r kony , T . B . , et al .
Stereochem ica l
requ i rement for cannabinoid activi ty . J . Med . Chem .
2 3 1 1 0 6 8-10 7 2 , 198 0 .
O hleeon , A . , L indgren , J . E . , Wahlen , A . , et al .
Plasma
de lta-9-tetrahydrocannabinol concentrat ions and c l i n ical effect s
a fter oral and intravenoua admin istrat ion and smok ing . Clin .
Pharmacol . Ther . 2 8 1 4 0 9-416 , 198 0 .
Perez-Reyee , M . , L ipton , M . A . , T immons , M . C . , et al .
Pharmacology of
orally admini stered delta-9-tetrahydrocannabinol .
Clin .
Pharmacal . Ther . 14 : 48-55 , 1 9 7 3 .
Ritzlin , R . s . , Gupta , R . c . , and Lundbe rg , G . D . De lta-9 tetrahydrocannabinol leve ls in street aamplee of mar i j uana and
haeh i sh 1 Cor relat ion to u se r reac t ions . Clin . x icol .
1 5 : 45-53 , 1 9 7 9 .
Roaenk rantz , B .
The Immune reeponee and marihuana , pp . 441-4 56 .
In
Nahaa , G . G . , Paton , w . D . M . , and Idanpaan-Be i k k i la , J . E . ( eda . )
Mar ihuana : Chemistry, B iochemietry , and Cellular Effects .
New
York : Spr inger-Ve r lag , 1 9 7 6 .
Roeenk rantz , B .
In Report of an Add ict ion Research POundat ionJ!or ld
Health Organi zat ion (ARF/WBO) Sc ient i f ic Meet ing on Adverse
ARF/WHO ,
Health of Behavioral Consequence of Ma r i j uana Use .
ronto , 1 981 .
Rosenkrant z , B . and Fle iechman , R . W .
Effects of cannabis on lunge ,
pp . 279-299 .
In Nahae , G . G . and Paton , W . D . M . ( ed s . ) Mar ihuana :
B iolog ical Effecta .
Analy s i s , Metabol i sm , Cellula r Reeponses ,
Reproduct ion and Brain Oxford 1 Pergamon Preas , 1 9 79 .
Schrader , J . , Ste r ie , c . , Halpin , T . et al .
Salmonel loe i e t raced t o
mar i j uana--ohio , Michigan . MMNR 30 : 77-7 9 , 1 9 8 1 .
S iemene , A . J . , Kalant , H . , and deNie , J . C . Metabol ic interact ion s
between 6 -9-tetrahydracannabinol and other cannabinoide in
rate , pp . 7 7-9 3 .
In Braude , M . C . and Szara , s. ( eds . )
Pharmacology of Mar ihuana .
New York : Raven Press , 1 9 7 6 .
Turne r , C . E . Act ive substances in mar i j uana . Arch . I nveat . Med .
Suppl . 5 1 13 5-14 0 , 19 7 4 .
Turne r , C . E . , Cheng , P . C . , Lewi s , G . S . , et al . Const i tuents of
cannabi e eat iva .
xv .
Botanical and chemical prof ile of India n
var iants .
Planta Med . 3 7 & 2 1 7 -2 2 5 , 1 9 7 9 .
Turner , C . E . Chemistry and metaboli sm , pp . 81-9 7 .
In Pete r sen , R . C .
( ed . ) Marij uana Reeearch F ind ings :
1980 .
NIDA Research
Monog raph 31 . DHHS Publ icat ion Ho. (ADM) S0-1001 . Waeh ington ,
D . C . 1 u . s . Government Pr inting Off ice , 1 9 8 0 .
Turner , C . E .
Director , Reeearch Inst itute of Pharmaceut ica l Sc ience ,
Unive r e i ty of Miss i se ippi , Oxford , Mississippi .
Personal
commu nicat ion , 1 981 .

33
Turner , C . E . , Elaohly , M . A. , and Boeren , E . G . constituents o f
Cannabie sat iva L . XVI I . A review of the natural constituents .
J . Natural P r od . 4 3 z l69-234 , 1 9 8 0 .
u . s . Department of Health , Educat ion and Welfare . Smok ing and
DREW Publ icat ion No .
Bealth a A RePO r t of the Surgeon General .
( PBS ) 79-50 0 6 6 . Washing ton , D . C . a u . s . Gove rnment Pr int ing
O f f ice , 1979 .
Waller , C . W . , Johnson , J . J . , Bue l ke , J . , and Turne r , C . E .
Mar ihuana a
An Annotated Bibliography .
New York a Macmillan
Informat ion , 19 7 6 .
Walle r , c .w . , Nair , R . S . , McAlliete r , A . P . , e t a l . Ma r i huana a An
Annotated Bibli og r aphy .
Voluae 2 New York a Macmillan
Informat ion ( in prees ) .
Z e idenberg , P . , Bourdon , R . , and Nahas , G . G . Mar i j uana intox icat ion
by paes ive inhalat ion z
Documentat ion by detect ion of ur inary
metabol itea .
Am. J . P!Ych iatrY 134 a 76-78 , 1977 .

2
USE OF MARIJUANA
IN THE UNITED STATE S
Epidemiolog ic stud ies provide informat ion on the use of drug s in

var iou s subg roups of the popu lat ion and on the changes in patterns o f
u se over t tme . The epidemiolog ic approach i s part icu lar ly useful in
def i n ing patterns of use of mar i j uana in Ame r ican soc iety and in
d esc r ibing and analyzing the behavioral and psychosoc ial antecedents
and consequence s of that use . One of the r e d i f f icult quest ion s i s
whether par t icular behavior o r e ffects that are assoc iated with use
of a drug are the consequence s of that use , or whether att itudes ,
values , and behavior deve lop about the use of drug s to const i tute
fac tor s that may actually lead to the use of drug s . One o f the r e
u seful epidemiolog ic study des igns i s a cohort study that follows the
same ind i v idual with repeated obse rvat ion s at f&gula r inte rvals ove r
t ime . Such long itud inal stud ies have the potent ial for obta ining the
at compe lling evidence on the antecedents of known patterns of use
o f mar ij uana , as well a s possible long-te rm psychosoc ial and
biolog ical outcome s for these ind i v idual s .
The comm i ttee , with the help of consultants , sought answers in
the epidemi o log ic l i te rature to the following f ive quest ions :
1 . What a re impor tant patterns of use of mar i j uana in the
Amer ican popu lat ion includ ing spec ial groups ?
2 . What are the general character i s t ics of users of mar i j uana?
3 . What i s the prof ile o f a use r of ma r i j uana on a da i ly
basi s ?
4 . What is known about the antecedents o f use o f mar i j uana?
s.
Bow i s use of ma r i j uana re lated to the use o othe r drug s ?
The epidemiolog ic and survey l i terature have been extens ively
reviewed and the major long itud inal studies are s umma r i zed in a tabl e
i n Append ix c . Much of our recent knowledge der ive s f rom two
well-de s igned major , continu ing nationwide nitor ing effort s
*When placed in quotat ion mar k s , daily i s used as def ined by

Johnston et al . ( 1 9 8 0b) , i . e . , thoe ind ividuals us ing ma r i j uana 2 0
o r more t imes in the preced ing 3 0 days .
34

35
sponsored by the Nat ional Inst itute on Drug Abuse . One i s ba se d on
g ene ral hou sehold populat ion sample s , the Nat ional Household
Surveys . The second i s based on populat ions of high school sen ior s
a nd i s called Mon itor ing the Future .
The Nat ional Hou sehold Survey s of the general populat ion a r e
c onducted on an annual or biannual ba s i s by Response Analy s i s
Corporat ion and The George Washington Un ive r s i ty ( Fi shbu rne et al . ,
1 98 0 ) . There have been s ix c ross-sect ional stud ies s ince 1971 . The
latest one was in the winte r of 1979-19 8 0 , and the next one will be
i ni t i ated in 1 9 8 2 . The subj ec ts a re c las s i f ied as youth ( 1 2-1 7 ) ,
young adults ( 18-2 5 ) , and olde r adults ( 2 6 and olde r ) . The quest ion s
relate to mar i j uana and other psychoactive drug s , includ ing
inhalants , hal luc inogens , coca ine , heroin , st imulants , sedatives , and
analges ic s . Samples vary f rom about 3 , 0 0 0 to more than 7 1 2 0 0 new
re spondents at each su rvey . These are sample s that document pattern s
of use of d rug s in the spec if ied popu lat ions at a g iven t ime .
Mon itor ing the Future (Johnston et al . , 1 9 8 0b ) u ses a
c ohort-sequent ial long itud inal desig n , in wh ich a new cohort of high
school sen ior s is surveyed each year , and a representative panel
se lected f rom that sen ior c lass is also followed over t ime in
succe ss ive annua l or biannual testing s . The earl iest pane l has now
been re inte rviewed s ix t imes . Th i s survey design makes i t possible
to d i sentang le antecedents from consequences of u se as wel l as to
d i stingu i sh changes due to inc reased age from changes due to cohort
peculiar it ies or h i stor ica l c i rcumstances .
Initiated in 1975 by the
S urvey Research Cente r of the University of Michigan , and d irected by
Lloyd Johnston and Jerald Bachman , the su rvey involves a quest ion
n a i re self-admin istered each year by more than 1 6 , 0 0 0 h igh school
sen ior s in 130 publ ic and pr ivate schools throughout the United
S tates , and long i tud inal mai l follow-ups of about 2 , 0 0 0 former
students d rawn , as panels , from each of the previously par t ic ipating
sen ior c lasses ( Johnston et a l . , 1 979a , b r 1 9 8 0a , b) .
Because the Nat ional Household Surveys and Mon itor ing the Futur e
a re surveys of per sons in households or in h igh school , they exclude
pe r sons most l i kely to be using drug s--the trans ients , those withou t
r egular addresses , the schoOl absentees or d rop-outs , or those l iving
in institutions or g roup quar te r s . These pe r sons const itute a smal l
p ropor t ion o f the general populat ion , a nd the i r exclus ion does not
s ign if icantly bias the ep idemiolog ic est imates reported for the tota l
popu lat ion (Kande l , 1 9 7 5a ) . Howeve r , data on the very heavy use of
drug s may be unde r represented .
PATTERNS AND TRENDS OF USE OF MARIJUANA

Gene ral Popu lat ion
The Nat ional Household Surveys found that mar i j uana was the most
common ly used of all the nonlegal psychoact ive drug s invest igated ,
i nc lud ing inhalants , halluc inogens , coca ine , he roin , s t imulants ,
sedat ives , tranqu i l i ze r s , and analgesic s ( Fi shburne et al . , 1 9 8 0 ) .

36
In 1 9 7 9 more than 50 mill ion pe r sons had tr ied mar i j uana at leas t
once in the i r l ives a 6 8 . 2 percent of young adults ( 1 8-2 5 ) , or about
21 million r 30 . 9 percent of youth ( 1 2-17 ) , or more than 7 mill ion r
a nd 1 9 . 6 percent of older adults ( 26 and older ) , or 2 5 million . The
young adult age-g roup ( 18-2 5 yea r s ) has consistently bowed the
h ighe st rates of current use ( used in past month ) and ever ue
( l ifetime prevalence ) , and the olde r adult g roup ( 2 6 and older ) had
the lowest user rate Male use r s outnumbered females in all age
groups . Between 1977 and 1 979 , s ignif icant increase s in cur rent us e
and ever use of mar i j uana were obse rved among the young adult and
In 1 9 7 9 , in the young adu lt cohor t ,
olde r adult cohorts ( Figure 2 ) .
the most B igni f icant increases in use in the past month were found in
males , wh ites , h ig h school nong r aduates , people in the southe rn
United S tates , and those l iving in nonmetropolitan areas .
In the
olde r adult g roup , the most B ign i f icant recent increae i n cur ren t
u se of mar ij uana was obe rved in males , white , college g raduates ,
and people living in the souther n states (Miller and C i s in , 1 9 8 0 ) .
In the early 1960s , illic it drug use in the Un i ted States was
ch iefly a phenomenon of large coastal c it ies . Bu t since then , rate s
i n other reg ions of the country and in c it ies of all s i zes have
rapidly increased unt i l patte rns of ue are becoming increasing ly
comparable for all sector s in the Uni ted States . At cur rent levels
of u se , some exper ience with mar i j uana in adole scence i s becoming the
norm r ather than the except ion throughout the United S tates . Other
major urvey stud ies have con f i rmed the f i nd i ng s of the Nat iona l
Bouehold Survey for comparable cohort populat ions (Gallup Opin ion
Index , 1976 J O ' Donnell et a l . , 1 976 ) .
Mil itary Pe rsonne l

Much attent ion has recently been focused on what appear to be h ig h
r ates o f use o f i ll ic i t d rug s among military pe r sonnel . Stud ies of
drug use among male a rmy vete rans of the Vietnam War in 197 2 showed
t hat mar ij uana was the most common ly used illic i t drug before and
afte r the wa r ( Robins , 197 4 ) . A random sample of 4 7 0 men wa selected
f rom the 1 3 , 760 enli sted me who returned to the u. s . in September
1971 . Of the 4 51 men who were inte rviewed , 69 pe rcent had ued
mar i j uana wh ile in Vietnam , with 28 percent stating this was the ir
f i rst ue of the drug . The l ifet ime prevalence of use of mar i j uana
was 41 pe rcent pr ior to Vietnam r 4 5 percent of the veterans reported
us ing mar ij uana in the 1 0 months following return to the United
S tates . Among this g roup the prevalence of weekly use doubled from
12 percent pr ior to Vietnam to 25 percent fol lowing the wa r .
A wor ldwide survey of nonmed ical use of d rug s and alcohol among
u.s. act ive duty military per sonne l was conducted in 1980 unde r the
sponsor ship of the u.s. Depar tment of Defense ( Bur t et al . , 1 9 8 0 ) .
I n an anonymous , se lf-admini stered quest ionna i r e g iven to a repre
sentative ample of more than 1 6 , 0 0 0 per sons , mar i j uana was found to
be the most common ly used i ll ic i t drug . Twenty-s ix pe rcent admitted
to having used ma r i j uana/hash i sh within the past 30 days and 3 5

37
1 00
80
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c::
60
8
...
&
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1 960
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'76 ' 1 7
1 979
'76 '17
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YEAR
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:::J
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C)
z
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40
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0
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1 967
1 972
YEAR
FIGURE 2 Ma r i j uana z t rends in l ifetime exper ience , youth , and young

adults . Adapted from J . D . Mi ller and I . B . C i s i n . H ighl ights from
the Nat ional Survey on Drug Abuse z 1979 . Washington , D . C . z u. s .
Government Pr int ing Off ice , 1 9 8 0 . Youth 1 2 to 1 7 years old J young
adults 18 to 2 5 years old .

38
percent to having used i t i n the past 1 2 months . Five percent of the
sample repor ted use of mar i j uana daily .
When u sers of drug s were i temi zed accord ing to m i l i tary pay
clas s i f icat ions , the largest percentage of cur rent use of mar i j uan a
was i n t he lowest ranks of the m i l i tary .
Adolescents and Young Adu lts

Patterns and Trend s
One of the compelling reasons to focus on adolescence in study ing
mar i j uana i s the pervas ive and increasing use by t h i s age g roup . As
was ment ioned ear l ier , in 1 9 8 0 all g eog r aphical reg ions of the Uni ted
States and all soc ioeconomic classes had h ig h and increas ing ly
comparable i nvolvement in u se of mar i j uana .
The yea r 19 6 0 has been taken as a base l ine yea r that represent s
t he s table level of overall u se of mar i j uana that had character i zed
the Uni ted States for most of its h i story . Figure 2 shows the t rend s
for u se of mar i j uana f rom 1960 through 1979 , revealing the sharp
upward cl imb of use of mar i j uana star t ing in 1 9 6 7 . The dramat i c r i s e
i n u se of mar i j uana by adolescents has recently slowed , and the
l i fe t ime prevalence rates (eve r use ) of mar i j uana have rema ined a t
approx imately 6 0 percent o f all h ig h school seniors for the years
1979 and 1980 ( Figure 3 ) . To put it anothe r way , in 1979 over 2 . 5
m i ll ion h igh school senior s had t r ied or were user s of mar i j uana .
( Th i s f igure i s de r ived from calculat ions based on 1 9 7 9 Census Burea u
data t hat g ive a f igure of 4 , 2 7 6 , 0 0 0 for number of 18-year-olds in
the populat ion . The comm i ttee is aware that all 1 8-year-olds are not
h ig h school sen iors and that such a calculat ion may under repor t the
number s of use r s of mar i j uana , par t icularly heavy use r s who have bee n
s hown to be more l i kely to have dropped out of school . S imilar
calculat ions have been attempted throug hout th i s chapter . )
The use of other types of d rug s by young people also increased
beg inning in 1 9 6 7 (Mille r and C i s in , 1980 ) . Figure 4 g ives the mos t
r ecent nat ionwide f igures for use of 1 1 types of drug s among Amer ican
h ig h school senior s ( average age 18 year s ) . With the except ion of
neg l ig ible use of heroin , the f igures for use of all other drugs are
substan t ial .
Increase s i n patte rns of use have not been as dramat ic
for other d rug s ( except for r ecent coca ine increases ) as they have
been for mar i j uana . Use of mar i j uana , tobacco , and alcoho l far
outstr ips t hat of all other d rug s .
I n 1980 the l i fet ime prevalence
(eve r use ) for these substance s by h ig h school sen ior s wa s
mar i j uana--60 percent , tobacco--71 percent , and alcohol-- 9 3 percent .
Of even g reate r interest are the percentages of h igh school
s en iors who use the 11 types of d rug s da i ly . In 19 8 0 mar i j uana was
used da i ly by 9 . 1 percent ( about 390 , 0 0 0 ) , alcohol by 6 . 0 percent
( about 2 56 , 00 0 ) , and tobacco c igarettes by 2 1 . 3 percent ( about
9 0 0 , 0 0 0 ) of h ig h school sen ior s (Johnston et al . , 1 9 8 0 a ) . No othe r
s ubstance was u sed that frequently by as many as 1 percent of the

39
f::::: :::::J
70
60
Percent ever used

Percent who used in last 1 2 months
Percent who used i n last 30 days
Percent who used dai ly in last 30 days
60. 3
60.4
59 .2
56.4
5 2.8
(I)
a:
0
z
w
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40
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20
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O ass
1 975
of
Cl ass
1 976
of
Class
1 977
of
Cl ass
1 978
of
Cl ass
of
1 979
Cl ass
of
1 980
FIGURE 3 Trend s i n prevalence of mar i j uana use by h ig h school

seniors , 1 9 7 5-19 8 0 ( in school ) . Adapted f rom L . D . Johnson , J . G .
Bachman , and P . M . O ' Mal ley , H ig hl ig hts from Student Drug Use i n
Amer ica , 1 9 7 5-1980 . DHHS Publ icat ion No . (ADM) 81-1 0 6 6 . Washington ,
D . C . & u . s . Government Pr int i ng Off ice , 1 9 8 0 a .

40
1 00
93'16
KEY
Used Drug, but Not
w
u
0
80
in Pat VNr,
w
u
ww
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- c
ti
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.J A.
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(30 Dey PI'8VII I enc:el
60
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NOT E : The bracket nr the top of e bar ind icet the lower e nd upper l imits of the
95'lft confidence i ntei'VII I .
FIGURE 4 Prevalence and recency of use . Eleven types o f drug s ,

c lass of 1 980 . SOURCE Johnson , L . D . , Bachman , J . G r , and O ' Malley ,
P . M . H ighl ights f rom Student Drug Use in Amer ica , 1 9 7 5-1980 . DBHS
Publicat ion No. (ADM) 8 1-10 6 6 . Wash ing ton , D . c u. s . Government
Pr i nt i ng Off ice , 19 80a .
These f igures show that legal ( for adult s ) drugs are used
s tudents .
much more frequently than i llegal ones . Reports of i l legal use of
d rug s show that exper imentat ion with mar ij uana has , by far , the
h ighest prevalence .
It should be noted , also , that daily use o f
ma r i j uana ( 9 percent ) among h ig h school senior s is now more prevalent
than da i ly dr ink ing ( 6 pe rcent ) of alcoholic beve r ages .
In 1 9 8 0 , for the f irst t ime s ince 1 9 7 5 , when the Mon itor ing the
Futu re data collect ion began among h igh school seniors , the percentag e
o f daily users of mar i j uana among seniors in h ig h school decl ined
s ig n i f icantly from 1 0 . 3 percent i n 1 9 7 9 to 9 . 1 percent in 1 9 8 0
( Figure 3 ) , a nd there was a leveling o f l i fet ime prevalence a t
approx imately 6 0 pe rcent . Fur the rmore , the propor t ion of curren t
u se r s among those who ever u sed mar i j uana also showed a stat ist ically
s ignif icant decl ine in 1 9 8 0 as compared to 1979 , f rom 6 0 percent to
5 6 percent . However , dai ly user s may be increas i ng ly underrepre-

41
sented i n recent senior h igh school classes due to absentee i sm and
d rop-out assoc iated with increas ingly ear l ier and extens ive
involvement in use of mar i j uana . The extent to wh ich long-term
da i ly users have d ropped out of school by the senior year of high
school cannot be ascertained from monitor ing the future . Kandel
( 1975a) found that absentees d iffered from students attend ing school
regularly . Fifty-six percent of absentees reported use of mar i j uana
a s compared to 3 8 percent of in-class students . Stud ies that document
the patte rns of mar i j uana use in school drop-outs are needed .
Correlates of Use
Overall levels of use of mar i j uana have been s hown to cor relate with
patterns of use of the drug .
1.
Increased prevalance i s assoc iated with younger age of
initiation into use of mar i j uana . As success ive cohorts of h ig h
school senior s have shown increas ingly h igher levels of exper ience
with mar i j uana from 197 5 through 1980 , these cohorts also repor t
i ncreas ingly earlier ages at f irst use of mar i j uana . For example , in
the senior clas s of 1980 , wh ich had a l ifetime prevalence of 60
percent by senior year , 25 percent of those using mar i j uana had begun
in the e ighth g r ade ( average age 14 ) or below . In 1 9 7 5 when l i fetime
p revalence was 47 percent , 1 5 . 3 percent of mar i j uana users had begun
It i s of some interest to compare reported
in e ighth g r ade or below .
age of use of mar i j uana by g rade for the sen ior class of 1980
( l i fetime prevalence 6 0 percent ) and alcohol ( l i fet ime prevalenc e
9 3 . 2 percent ) . The more prevalent drug , alcohol , is used at earlier
age s than mar i j uana . Th i r ty-three rcent of alcohol use r s had
s tarted at e ighth g rade as compared to 21 . 5 percent of mar i j uana
use r s ( Johnston et a l . , 1980a ) .
2.
Ear lier onset of use of any drug is assoc iated with g reater
involvement in use of all othe r drugs . The ear l ier the introduct ion
to legal ( for adults ) drug s , the g reate r the probability that the
adolescent wi ll also exper iment with i l l ic it drug s . FOr example ,
among young adults 18-25 years of age surveyed from the general
popu lation in 1979-1980 , the proport ion who had exper imented with any
i llic it drug other than mar i j uana ranged from 87 percent among those
who reported having f i r s t tr ied alcohol or mar i j uana at ages 13 or
1 4 , to 4 7 percent among those who f irst tr ied these drug s at ages
15-17 , and 5 percent among those who f i rst exper imented at age 1 8 o r
over ( Rittenhouse , 1 9 80 ) . The f ind ing that the ear lier the
exper imentat ion with mar i j uana , the greater the intens ity of
i nvolvement and the g reater the l i kel ihood of using more ser ious
drugs has been confi rmed in many stud ies ( e . g . , Miller and Cisin ,
1980 1 Johnston et a l . , 1980a , Kandel et al . , 1981) .
3.
Greate r overall prevalence of use of mar i j uana i s associated
w ith g reater persi stence of use of mar i j uana into later years of
adult l i fe . The current prevalence rates for use of mar i j uana by
persons in the i r mid-3 0 s are increasing (Cisin et al . , 1978 ) . Many

42
stud ies have not sampled th i s popu lat ion in the belief that use o f
mar i j uana d rops o f f sharply in the mid-20 s . Among males , the
prevalence rate for use of mar i j uana in the past month for
over-2 6-year olds went f rom 4 percent in 1977 to 9 percent in 1979 .
I t will be exceed ingly impor tant to monitor the trend s in all olde r
adult age g roups .
Mar i j uana and the Use of Other Drug s

One of the key quest ions asked ove r the year s i s , doe s mar i j uana lead
to the use of other d rug s . In any populat ion , the use of var ious
drug s appear s inter related and use r s of any type of drug , whethe r
legal or i llegal , are much more l i kely to use othe r types of drug s
than nonuse r s . POr example , young people who smoke tobacco are also
much more l i kely to have used alcohol or mar i j uana than nonsmokers
( Fishburne et al . , 1980 ) . S imilarly , there i s a strong assoc iation
between the use of mar i j uana and of other i ll ic it drug s . Young
people who use mar i j uana are more l i kely to be consuming othe r
substances , such as alcohol and tobacco , as well as other i ll ic it
drug s ( Johnston et al . , 1980b) . The associat ion increases with
ex tent of mar i j uana involvement and i s espec ially str i k ing among
those young people who use mar i j uana on a daily bas i s , as wil l be
d i scussed below .
Results from the Nat ional Household Surveys and f rom samples of
h ig h school senior s had ind icated that the ratio of rates of use o f
i llicit drugs other than mar i j uana to use of mar i j uana declined
throug h 1979 (Kandel , 1980 r Mi lle r and Cisln , 1980 ) . In 1980 ,
however , the ratio started to r i se aga i n . Thus , in 1 9 8 0 , 6 5 percent
of mar i j uana use r s among the h ig h school seniors had also u sed othe r
i l licit drugs as compared to 61 percent in 1979 (Johnston et al . ,
l980a) .
naily Use r s i n High School

Because any health r isks result ing from the use of ma r ij uana would be
moat l i kely to appear f irst in chronic users of the drug , the young
persons who are chronic and heavy user s are of spec ial interest . The
comm i ttee reports in some deta i l the f ind ing s on this g roup . The
rank s of daily users are large . In 1980 they represented more tha n
9 pe rcent of h igh school senior s or ove r 390 , 0 0 0 18-year-olds in the
Uni ted States . One out of 11 senior s f itted the def i n i t ion of
da i ly u sers ( 20 or more occas ions of repor ted use within the
preced ing 3 0 days ) . Collection of systemat ic data on such user s
began in 1 9 7 5 with the annual monitor ing of in-school h igh school
senior s . There are many gaps in our knowledge about th i s g roup , bu t
suff ic ient data have been accumu lated that it i s now poss ible to
desc r ibe many of the behavioral attr ibutes of the da l ly u ser s .
Most of these data come f rom Mon itoring the Future . Some of the
f i nd i ng s recently repor ted by Johnston ( 1980 , 1981 ) and Bachman e t
a l . ( 1981) are a s follows a

43
Demog raph ic Find ing s

Rates of daily use d o not vary among reg ions o f the country , but
da i ly use shows a strong posit ive relat ionship to the s i ze of the
commu nity and is more prevalent in urban areas . Males are dai ly
user s a t almost double the rate o f females ( 1 3 percent ve r sus 7
percent ) . Dai ly use among white students i s double that for blacks
( 11 percent ver sus 5 percent ) . Da i ly use is spread evenly across
soc ioeconomic levels as def ined in terms of parents ' educat ion .
Da i ly use i s only sl ightly h igher among those from homes in wh ic h
one or both parents a re absent .
Academic Per formance and Goal s

Da i ly use i s assoc iated with poor schoo l ach ievement . Among
non-college-bound sen ior s the rate of da i ly use i s almost doubl e
t hat found among the college-bound ( 13 percent versus 7 percent ) .
There are strong and pos it ive cor re lat ions of da i ly use and cutting
c lasses , school absences , and truancy .
Much of da i ly use take s place within the school sett ing . A
s tatewide study of seventh through twelfth grade pup i ls in New Yor k ,
conducted i n 1 9 7 8 by the New Yor k State Drug Abuse Comm i ssion , found
that SO percent of those using mar i j uana within the last 6 months had
been intox icated one or more t imes whi le in class (Johnson and Uppal ,
1 9 80 ) . I n contrast , alcohol tends to be used most frequently after
school and on weekends .
Rel ig ious Comm i tment

A comm i tment to relig ion and self-rat ings of strong be lief in
law-abid ing behavior are assoc i ated with lowe r than average rates o f
da i ly use .
Dat ing and Soc ial Life

Dating and soc ial
mar i j uana . Those
o f daily use of
n ights a wee k and
da i ly ma r i j uana
l i fe show strong relat ionsh ips with da i ly use of

who spend more t ime on dates have the h ig hest rates
mar i j uana . Among those students who go out 6 or 7
are pract ically neve r at home , 3 4 percent are
u sers .
Use of Othe r Drug s

Daily mar ij uana users are much more likely than the i r peers to be
extens ive users of other drug s . Thus , of seniors in the class of
1 9 7 9 , 2 7 percent of da i ly users of mar i j uana d rank alcohol as
frequently , ve rsus 7 percent for the age-group as a whole J and 5 9

44
percent of daily use r s o f mar i j uana smoked c igarettes as frequently
versus 25 percent for the g roup as a whole ( Johnston et al . , 1980b) .
With respect to use of othe r i ll ic i t drug s , the rates for da ily
u sers o f mar ij uana generally run f ive to seven t imes the average for
the age g roup as a whole r 47 percent of daily use r s are cur rent*
u sers of amphetamines , 3 1 percent of coca ine r and the i r cur rent usage
f igures run from 1 5 to 17 percent for barbiturates , for lyserg ic ac id
d iethylamide ( LSD) , for phencyc lid ine ( PCP ) , for methaqualone , and
for tranqu i l i zers . S i nce nearly two-thi rds of daily mar i j uana user s
( 6 4 percent ) are cur rent users of hashish , they have substant ial
exposure to a h igh-potency form of mar i j uana .
We also know from data on age at f irst use that many of these
daily mar i j uana users began the i r use of c igarettes , alcohol , and
var ious other i llic i t drug s at quite an early age . To i llustrate , by
the end of e ighth grade 4 0 percent of them had smoked c igarettes
daily and SO percent had taken the i r f irst dr ink . Just about half
of them ( 4 8 percent ) f i rst tr ied mar i j uana by the e ighth grade , and
most of the remainder ( another 30 percent ) started in n inth grade .
These are very ear ly ages of initiation for all three drug s .
S imilarly , these youngsters tend to take up the other i ll ic i t d rugs
at an ear lier than average age--though most of that use st ill i s
i nit iated after n inth g rade . Da i ly use tends to per s ist longer
into adult life than ant ic ipated . In 1979 , 4 year s after graduat ion
f rom h igh school , 51 percent of mar i j uana users of the senior class
of 1 9 7 5 were still da ily users and an add it ional 34 percent we r e
cur rent although not daily users ( Johnston , 1980 ) .
Daily Users After H igh School

U s ing a nat ional sample of 1 9- to 2 2-year-olds der ived from the
follow-up surveys of Mon itor ing the Future , Johnston ( 19 8 1 ) reported
on da i ly use of mar i j uana after h igh school .
( These f i nd ings are
reproduced near ly verbatim below . )
College S tudent Status

S tudent status after h igh school cor relates negatively with dai ly
use r that is , full-t ime college students have the lowest rate ( 8
percent) , part-t ime students the next lowest ( 10 percent ) , and
nonstudents the h ighest rate ( 1 3 percent ) . However , althoug h
f ull-t ime students have a lower than average rate of da i ly u se ,
they showed the greatest increase after h igh school ( up from 4 . 5 to
8 . 3 percent ) : they s imply star ted from a very low level and in a
sense were catching up .
*A cur rent user i s one who has u sed the d rug in the th i r ty days
preced ing the surveys .

45
Living Status
Young people who are l iving away from home have a h ig her proport ion
of daily use than those still living with the i r parents ( 1 2 percent
versus 10 percent ) , probably reflecting the result of reduced soc ial
control by parents . Those who remained l iving with the i r parents
( nearly half ) showed relat ively l ittle increase in use ( up 1 . 3
percent) , wh ile those who moved out increased the i r daily use rate
substant ially ( up 3 . 9 percent ) .
Mar ital Statu s

Those who are single are almost twice as l ikely to be daily users
as those who are mar r ied ( 11 . 4 percent ve rsus 6 . 6 percent ) , and those
without children are somewhat more likely to use mar i j uana than those
with children ( 11 percent ver sus 8 percent ) . I t appear s that these
role respons ibilities have a dampening effect on use .
In the face of
an overall 2 . 6 percent increase i n da i ly prevalence after h igh
school for the whole sample , those who were marr ied showed virtually
no increase ( up 0 . 2 percent ) and those with ch i ldren actually had a
d ecline i n u se ( down 1 . 5 percent ) .
Type of dwelling
oaily use i s h ighest for those l iving in a rented room ( 14 percent )

or apar tment ( 1 2 percent ) , and lowest for those l iving in a college
dorm ( 8 percent ) . Obviously one ' s dwelling arrangement is highly
cor related with h i s or her major act ivi y after h ig h schoo l , as these
d i fferences reflect .
Employment
Employment status i s unrelated to daily use . ror those in military
service , daily use dropped sl ightly after h igh school ( from 13 . 4
percent to 1 2 . 4 percent ) . The act ivity g roup with by far the lowest
da i ly use rate are the full-t ime homemake r s (4 percent ) , wh ich
certaily occurs , in part , because they near ly all are female ,
mar r ied , and i n many cases have young childre n .
Reasons for Using o r Abstaining

Reasons for oaily Use of Mar i j uana
What reasons do daily users g ive for their use of mar i j uana? They
tend to use mar i j uana to produce an intox icated feeli ng , to cope
psycholog ically with feel ings of d i stress , to augment the effects of
othe r drug s , and to part ic ipate in drug-using fr iendsh ips . On a

46
checklist o f 1 3 poss i ble reasons , nearly all o f the senior s who wer e
da i ly users chec ked to feel g ood o r get hig h ( 94 percent ) and to
have a good time with my fr iend s ( 79 percent ) . Two-thi rds said they
u sed it to relax ( 6 7 percent ) and nearly half said they u sed it to
relieve boredom ( 4 5 percent ) . Roughly a quar ter of the da i ly user s
c hecked each of the following : to get away from my problems ( 2 7
percent ) , because of anger or frustrat ion ( 2 3 percent ) , and to ge t
through the day ( 2 2 percent ) . These psycholog ical coping motives in
par t icula r seem to d i st inguish the daily users from the less
f requent use rs . A fa i r ly h igh propor t ion ( 30 percent ) also said that
they used mar ij uana to increase the effects of othe r drug s , whi le
only 10 percent of the othe r cur rent users gave this reason . Only 11
percent of the da i ly users , or 1 percent of the total sample ,
s tated that they used it because they felt hoo k ed or had to have
it . All of these responses for senior s were close ly repl icated among
the da i ly users in the 19- to 22-year-old sample (Johnston , 1981 ) .
Nea r ly all da i ly use r s (over 8 5 percent ) , whether in h igh
schoo l or past high school , say (1) that most or all of the ir fr iends
smoke mar i j uana , ( 2 ) that most or all of the i r fr iends d r ink alcohol ,
( 3 ) that more than a few of the i r fr iends get drunk every week , ( 4 )
tha t more than a few o f the i r fr iends smoke c igarettes , and ( 5 ) that
at least a few of the i r f r iend s use a number of other i ll ic i t drug s .
Thi s deg ree o f immersion in a drug-using fr iendship c i rcle contrast s
sharply to what we obse rve for the i r peer s , even those who are
cur rent but less frequent u se r s of mar i j uana . Clear ly the soc ia l
s uppor ts and the soc ial pressu res are there , both dur ing and after
h igh school , for the da i ly use r to continue his or her habit .
Reasons for Qu itting and Absta ining

A number of use r s of mar i j uana stop using the d rug ( Johnston , 1981)
Among students ( in the c lasses of 1978 through 1980 combined ) , those
who have used mar ij uana 40 or more t imes but have stopped by the i r
senior year g ive as the i r most commonly ment ioned reason o n a
comprehens ive list of 17 reasons that they don ' t feel like getting
h ig h ( 5 6 percent ment ioned) . Also frequently ment ioned , however ,
are concerns about possible phys ica l effects ( 4 1 percent ) J concer n
about possible psycholog ical e ffects ( 38 percent ) J and , more
spec i f ically , concer n about loss of energy or ambition ( 4 1 percent ) .
These reasons also ranked h igh among those young people who smoked
less than 40 t imes before they stopped , as d id two addit ional
r easons--concern about parental d isapproval and f ind ing that use of
mar i j uana was not intr ins ically enj Ofable .
Concern about poss ible health effects appear s to play a role in
young people ' s g iving up the drug and i s ment ioned cons iderably more
often among qu itters now than in 1976 . Conce rn about physical health
increased substant ially between 1976 and 1980 among all h igh schoo l
senior s , from 3 5 percent to 57 percent , whi le concern about
psycholog ical damage went f rom 34 percent to 53 percent . A s imila r
analysis of the reasons g iven for abstaining by the minor ity ( about

47
4 0 percent ) o f seniors who have neve r tr ied mar i j uana reveals concern
abou t phys ica l ( 7 1 percent ) and psycholog ical ( 6 8 percent )
consequences , which are ment ioned far more often than any othe r type
of reason . Soc ial or ideolog ica l constra ints or d i s i nterest in
g ett ing h igh are infrequently ment ioned . There also has been a
signif icant increase in health conce rns among the absta ining segment
s ince 1976 , though not as large as among quitter s .
I n summary , many daily u se r s themselves see some negative
consequences of the i r habit , and there perhaps are some consequences
of wh ich they are unaware . The fact that the da ily smok ing of
mar i j uana is proving to be more endur i ng and stable than many may
have thought inc reases the probabi lity of cumu lative , long-term
e ffects . The fact that so many young people are becoming dai ly
use r s now puts a substantial numbe r o f people at r i sk of whateve r th e
long-term consequences may prove to be .
Sequence of Drug Use

Regardless of the age of onset , there i s a pred ictable sequence in
the patterns of initiation into the use of avai lable drug s .
Independent long itud inal stud ies have confirmed and ident i f ied a
stable sequence of drug use ( Hamburg et a l . , 197 5 1 Kandel , 1 9 7 5b J
K andel and Faust , 1 97 5 ) . The legal drug s for adults , such as alcohol
and tobacco , are an early , integ ral , and cruc ial par t of the
sequence . The i r u se precedes the use of all i ll ic i t d rug s . t least
fou r d i st inct successive stages of adolescent involvement with drug s
c an be ident i f ied :
( 1 ) use o f beer or wine , ( 2 ) use o f tobacco
c igarette s or hard l iquor , ( 3 ) use of mar i j uana , and ( 4 ) use of othe r
i llic it d rugs (Kandel , 1 9 7 5b) . A f i fth stage , problem dr inking , may
take place between mar i j uana and other illicit drug s ( Jessor et al . ,
1 980 ) . Adolescents rarely proceed from beer and wine to illicit
drug s without use of e ithe r hard liquor or tobacco c igarettes as an
i ntermed iate step . Furthe rmore , there i s an add it ive effect such
that the h ighest proport ion of adolescents who move to mar i j uana ar e
those who have experience with both hard liquor and tobacco . r
example , among 12- to 17-year-olds in the general popu lat ion , the
proport ion who have ever exper imented with mar i j uana is 81 percent
among cur rent tobacco c igarette smoke r s as compared to 24 percent
among nonsmokers ( Fi shburne et al . , 1980 ) . However , pos it ion on a
part icular point in the sequence does not ind icate that the young
person will necessar i ly progress to othe r drug s h ighe r up in the
sequence . Par t ic ipat ion in each stage is a necessary but not
suffic ient cond it ion for par tic ipat ion in a later stag e . There i s no
evidence to support the be l ief that the use of one drug will
i nevitably lead to use of any other drug . In othe r words , persons at
the top of the ladde r of use of drug s typically will have used all
substances at lower levels , includ ing mar i j uana . However , those at
lowe r rungs may stay the r e and not move to highe r rung s of the ladde r .
For example , data f rom the Nat iona l Household Surveys ( Fishbu rne
et a l . , 1980 ) ind icate that of those 18-25 years old who have t r ied

48
mar i j uana , almost a l l a r e users of tobacco o r alcohol J however , only
s l ightly more than one-four th of this 18- to 25-year-old populat ion
repor t having gone on to try any illegal drug other thn mar i j uana .
O f those who try other i llegal drug s , only a very small percentage
report be ing current use r s (Fishbu rne et al . , 198 0 ) .
Although i t i s of g reat interest , relatively l ittle i s known
about the factor s that determine wh ich persons will choose to go
t hrough the sequence of drug use or the rapid i ty with which they wi ll
do so . Ex i st ing research g ives u s some clues that user s of i l l ic i t
d rug s possess some d istingu ishing features .
There are fou r clusters of var iables--parental influences , pee r
i nfluences , adolescent involvement in deviant behavior s , and
adolescent beliefs and values--that assume d i f ferent ial importanc e
for predicting involvement at each stage of drug behavior (Kandel et
al . , 1978a , b) .
Involvement with d rugs legal for adu lts i s the ear l iest level of
drug use . Adolescents who star t to dr ink are exposed to peer s and
parents who d r ink , suggesting that these youths learn d r ink ing
patterns f rom the i r parents . Adolescents who have engaged i n a
n umbe r of delinquent or deviant activi t ies , and who seek h igh levels
of soc iabi l i ty with the i r peer s are likely to become involved with
a lcohol . S imilar patterns are found with tobacco smoking , also one
of the ear liest drug s to be tr ied .
The use of mar i j uana follows that of alcohol and tobacco .
It is
preceded by acceptance of a cluste r of beliefs and values that ofte n
r eflect d isavowal of many standards uphe ld by adults . Involvement in
a mar i j uana-using pee r envi ronment strongly pred i sposes to ita use
and i s the best pred ictor ( Becker , 1953 1 Good e , 1 9 7 0 ) . Part ic ipat ion
in minor forms of deviant behavior s , such as those that also preced e
t he use of hard l iquor , i s also an important precursor .
Antecedents of Adolescent Use of Ma r i j uana

When use of mar i j uana f irst came under research scrut iny in the late
1960s , very few youths had exper imented with illic i t drugs . Much was
made of the deviant status of use of mar i j uana and of the counter
cultural and rebelliou s meaning that came to be attached to using the
d rug ( Suchman , 1 9 6 8 ) . Yet even today , when over 60 percent of all
hig h school senior s have used ma r i j uana , those youths who use
mar i j uana are qu ite d ifferent from nonusers . The mar i j uana users in
1979 show the same patterns of d i saffection from major institution s
t hat characte r i zed the users in 1967 . The most recent data show that
mar i j uana user s per form more poo r ly in school , are less relig ious ,
have per formed more delinquent acts , are in trouble with the law,
have more traff ic acc idents , and use more illicit drugs than nonusers .
Those persons who also use several i llic it drug s show the h ighest
involvement in deviant behaviors . There is a linear relationsh ip
w i th deg ree of involvement with i llicit drug s , such that persons
using mar i j uana exclusively are only quant itat ively d i fferent from
those who have also used harder drug s ( Johnston et al . , 1980b) .

49
I n two cross-sect ional nat ional samples o f h igh school students ,
surveyed i n 1974 and 1978 , Jeasor e t al . have found that not only are
t he patterns of assoc iat ion between use of mar i j uana and deviant
character i st ics atmilar in both surveys , but also that the streng t h
o f the assoc iat ions , aa reflected in the s i zes o f the cor relat ion
coeff ic ients , are almost ident ical . The very same conclus ions der ive
f rom analyses baaed on f ive successive cohor ts of high schoo l sen ior s ,
sampled a t year ly intervals i n Moni tor ing the Future (Bachman et al . ,
1 981) .
Long i tud inal stud ies of students aged 12-21 have done much to
extend ou r under stand ing of the precu r sor s of using var ious forma o f
d r ug s . Stud ies have been reviewed i n deta i l by Kandel ( 1978a , b r
1980a J also see Appe nd ix C ) and document that many of the factors
found to be assoc iated with use of drug s at one point in t tme , such
aa low academic per formance , cr ime , low self-esteem , depressive mood ,
rebell iousness , and other per sonality characte r i st ics , precede the
use of drug s ( see in par t icular Mell inger et al . , 1 976 J Jeasor and
Jeasor , 1977 J Johnston et al . , 1978 J Kandel , 1978a J Kandel et al . ,
1978b , c J Kaplan and Pokorny , 1978 J Smith and FOgg , 1978 J Wingard et
a l . , 19 7 9 J Kaplan , 1980 ) . Some of the pred ict ive factors can be
identif ied in chi ldhood , such aa agg ressiveness with or withou t
a ssoc iat ion with shyness (Kellam et a l . , 1980 , in press) and
rebell iousness ( Smith and Fogg , 1 9 7 8 ) .
Other long itud inal stud ies also document that many of the factors
found to be associated with use of drug s at one point in t ime , such
a a low academic per formance , del inquency , low self-esteem , and
depress ive mood actually precede the use of drug s (O ' Malley , 197 5 J
Mellinger et a l . , 1 9 7 6 J Jeasor and Jeasor , 197 7 J Johnston et al . ,
1978 J Kande l et al . , 1978a J Kaplan and Pokorny , 1978 J Wingard et al . ,
1 979 J K aplan , 1 9 8 0 ) .
O ne study shows not only that cer tain behaviors pred ict use of
mar i j uana , but also that drug s may aggravate or exagge rate certain
behavior s . A cohor t of h igh schoo l students was followed at annual
intervals throughout the four year s of h igh schoo l (Jeasor and Jeasor ,
1 97 7 ) . Dur ing this t ime annual scores for var ious attr ibutes were
char ted i n four g roups of students d i stinguished by d iffer ing d rug
h i ator iea a veteran user s , who used d rug s pre-h igh achool J ear ly
in itiates , who began relat ively early in the i r h igh schoo l career ,
i . e . , between the f i rst and second year of teat ing J late init iates ,
who began relatively late , i . e . , between the second and the thi rd
year J and nonusers , who had not started to use mar i j uana at the last
testing in the sen ior year of h ig h school (Jeasor and Jeasor , 1977 ,
1978) .
These four g roups of students d iffered on measures , such as
general deviant behavior ( a 12-item scale measur ing frequency of
i nvolvement in stealing , f ighting , property destruct ion , truancy , or
othe r del i nquent act ivities in the last year ) or value on academic
ach ievement ( a f ive-item scale , measur ing the value placed on the
attainment of success in school wor k ) , at the beg inn ing of the study .
Scores pred icted if and when students init iated use of mar i j uana .
Those students already involved i n use of drug s before h ig h schoo l
scored h ighest on deviance and lowest on achievement mot ivat ion at

50
i ni t ial test ing and throughout subsequent retests . The scores of all
groups of user s converged over t ime so that all three g roups
i ncreased in deviance scores and decreased in the i r ach ievement
or ientat ion over the four yea r s . The sharpest change s in score s
occurred in the year preced ing the drug use .
Peer Influence s
The most consistent and reproduc ible f ind ing in drug research i s the
strong relat ionship between an ind ividual ' s drug behavior and the
concur rent use of drugs by h i s f r iends . The relat ionship is stronger
when based on adolescents ' pe rcept ions of the fr iends ' behavior tha n
on the f r iends ' self-reports (Good e , 1970 J Johnson , 1 9 7 3 J Kandel ,
1973 J Goldste in , 197 5 J O ' Donnell e t al . , 1976 Brook et al . , 1977 J
Je ssor and Jessor , 1977 1 Kandel et a l . , 1 978a J Orcutt , 1978 J Saart et
al . , 1978 J Huba et al . , 1 9 7 9 ) . On no other characte r i stic except age
and sex i s the s imila r i ty within adolescent fr iendship pai r s as h igh
as it is for use of mar i j uana (Kandel , 1 97 8c ) . Such s imilar ity
r e sults not only from soc ial i zation , the influence of one fr iend on
the other , but also from a process of interper sonal select ion
( assor t ive pai r ing ) , in which adolescents with s imilar values and
behavior seek each other out as fr iends . Long itud inal data on the
format ion and d issolut ion of f r iendships ind icate that selection and
sociali zat ion contr ibute about equally to the simila r i ty in value s
a nd behavior s (Kandel , 1978d ) . Available data on sex d i f ferences in
pee r influence ind icate that females are more suscept ible than male s
to such influence (Jessor et a l . , 1973 J Margulies et al . , 1 9 7 7 ) .
Suscept ibil ity to peer influence i s related to involvement in
peer-related act ivities , e . g . , dat ing or getting together with
f r iends , and to degree of attachment to and rel iance on peer s rathe r
t han parents (Jessor and Jessor , 1978 J Kandel et al . , 1978a J Brook
et a l . , 1 9 8 0 ) . Contact with othe r use r s inc reases the l i kelihood
t hat the ind ividual will have i ncreased opportunit ies to get the
drug . Peer-med iated approaches have been shown to be an effective
vehicle for intervent ions to prevent smok ing of tobacco in
adolescents (Evans , 1977 J Mcli ster , 1 9 7 9 ) . The powe r ful role o f
peer i nfluence o n the use o f mar i j uana would seem to suggest that it
would be also useful for preventive mar i j uana prog rams .
SUMMARY
Ther e has been a steep r i se in the use of mar i j uana and othe r illic i t
d rug s i n the past decade . S o far i t i s pr imar i ly a youth phenomenon .
Since 1971 there has been at least a doubling of l i fetime exper ience
w ith mar i j uana in every cohort in the 12- to 24-year age group . Of
all psychoactive drug s invest igated ( includ ing inhalants , hallucino
g ens , cocaine , heroin , st imulants , sedat ives , and tranqu i l i zer s ) ,
mar ij uana i s by far the most COIIIDOn ly used illicit drug . Legal drug s
for adults , such as alcohol and tobacco , are the most widely used of

51
all drug s among adolescents . Although substant ially more student s
have ever u sed alcohol in the i r l i fetime than have ever used
mar i j uana , more h igh school senior s use mar i j uana on a daily bas i s
( 9 percent ) than use alcohol that frequently ( 6 percent ) . Da i ly
use r s report the use o f mar i j uana i n school , whereas da i ly use o f
a lcohol tends t o occur after school and on weekends .
Some trends in use of mar i j uana are apparent . The continuing
d ramat ic r ise in the use of mar i j uana has recently slowed . I t is too
early to tell whethe r this decrease will continue or is merely a
pause in the r i se . The overall prevalence of use of mar ij uana has
remained at approx imately 60 percent of h ig h schoo l senior s for the
year s 1 9 7 8 , 1979 , and 1980 . Between 1 9 7 5 and 1978 there was an
almost twofold increase i n dai ly use of mar i j uana f rom 6 percent i n
1 97 5 to a peak rate o f 1 1 percent i n 1 9 7 8 . In 1980 the da i ly use
rate of h ig h school senior s dropped by 1 . 2 percentage points , or more
t han 1 0 percent . Thi s may s ignal a reversal of the upward trend in
daily use unless h igher absentee i sm and school drop-out of da ily
u sers are s ignif icant factor s in the decline . Mult iple sources
suggest that out-of-school ag e mate s are heavier use r s than those i n
schoo l . Other trends have not slowed . There was a cont inu ing r i se
in 1 9 8 0 of the propor t ion of h ig h school senior s who dur ing the yea r
had u sed some i ll ic i t drug other than mar i j uana , from 2 8 percent in
1979 to 3 0 percent i n 1 98 0 .
Throughout the 1970s , as a cor relate of cont inu ing r i se in
prevalence rates , there was a trend toward younger age s of first u s e
of all of these d rug s . Po r mar i j uana t h i s age trend cont inues but
has slowed somewhat . In 1979 , 23 percent of senior s who had u sed
mar i j uana star ted the i r u se in the e ighth g rade or below as compared
to 2 5 percent in 1980 .
Daily use of mar i j uana in h igh school and in early adult l i fe
i s very h igh and mer its special attention . Drawing on data from
Monitor ing the Future , character i st ics of da i ly use r s were
desc r i bed . Pbr h igh schoo l senior s the rate of daily mar i j uana us e
i n 1 980 was 9 . 1 percent . Such use r s have very high involvement wi th
other drug s and beg in the i r use of drug s at very early ages . Da i ly
u sers are predominantly urban although rates do not vary by geographi
cal reg ions of the country , whe reas use among white student s i s double
t hat for blacks . Da i ly use is only slightly h igher in d isrupted or
single parent homes than in nuclear fami l ies , and use is assoc iated
with poor schoo l achievement , absenteei sm , and dropout . Non-college
bound students are twice as li kely to be da i ly use r s as were
s tudents planning to attend college . Rel ig ious comm i tment and
self-rat ings of strong bel ief in law-abiding behav ior are associated
with lower da i ly use rates .
Da i ly u sers are involved in more
automobile acc idents and de linquency .
Post-high schoo l da i ly user rates are lowest among full-time
college students and those living i n a college dormitory . Da i ly
u se among non-college students was not related to j oblessness ,
employment , or mil itary service . S ingle persons are twice as l i kely
as marr ied per sona to be da i ly user s . Among the mar r ied , those
with chi ldren had very low rate s of dai ly use . The da i ly use

52
habi t ha s a remar kable stab i l i ty . By 4 year s afte r h igh school , 8 5
percent of da i ly using senior s in the class of 1975 were still
using mar i j uana , with 51 percent of them continuing to be da i ly
u sers .
In these stud ies , students repor t reasons for using ma r i j uana :
to have a good t ime with fr iends , to get hig h , to rel ieve boredom ,
to enhance the e ffects of other drug s , and to cope with stress .
oa i ly users are deeply immer sed in a drug-using c ircle of fr iends .
Some da i ly users have d iscont inued the ir habit . Reasons g iven
for stopping use of mar i j uana are loss of interest in getting h igh ,
concern about harmful phys ical or psycholog ical effects , and concer n
about the i r loss of energy or ambi t ion .
More i s known about the antecedents of using mar i j uana than i s
known about the consequence s of using ma r i j uana ( to be d i scussed
f ur ther i n the chapter s that follow) . Long itud inal stud ies have
establ ished that use of mar i j uana i s preceded by acceptance of a
c luster of beliefs and values that are favorable to use of mar i j uana
and also by the adopt ion of deviant behavior s . The deviant psycho
social attr ibutes of mar i j uana users that were desc r i bed almost a
decade ago , when use of ma r i j uana was a rare event , are j ust a s
c haracte r i st ic o f mar ij uana users today , when 6 0 percent o f all high
school senior s repor t some exper ience with the use of mar i j uana .
Daily users show the extremes of these deviant behavior s but less
deeply involved user s also exhibit some deviancy . Fr iendship
patterns and peer influence play a uniquely powerful role in
determining youthful mar ij uana use . Negat ive parental relationship s
do not appear to be assoc iated as an antecedent to use of mar ij uana .

Add it ional research needed i ncludes ( 1 ) epidemiolog ic stud ies on
patterns of use of drug s among young adolescents , inc lud ing those who
leave schoo l , ( 2 ) long i tud inal stud ies to invest igate the antecedents
and consequences of use of ma r i j uana , and ( 3 ) stud ies of the effec t s
o f mar i j uana in combinat ion with u s e o f other drug s .
Because sample s of h ig h achoo l senior s exclude youths most a t
r isk for h igh mar i j uana i nvolvement , namely adolescents not regula r ly
attend i ng the high school , add it iona l cohor t-sequent ial ep idemiolog ic
surveys beg inning with prepuber tal children are needed in order to
follow development and behavior from ear ly in l i fe . An all-conclus ive
approach would be both a prospective ( concur rent ) cohor t study and a
retrospect ive case-control study of poss i ble outcome s of and r i sk
f actor s for mar i j uana use ( this recomme ndat ion i s desc r ibed in deta il
in Chapte r 6 ) .
oa i ly user s have been understud ied and may have the most severe
r i s k in terms of loss of lear ning potent ial , biolog ical r i sk , and
p sychosoc ial hand icap . Stud ies should be under taken to pred ict who
among the large number s of young people who try ma r i j uana are at r i s k
o f becoming da i ly users .

53
Research on the factor s involved i n cessat ion of the uae o f
marij uana should also be car r ied out . TObacco smoking i a declining
among youth (National Institute of Educat ion , 1 9 7 9 ) . The reasons fo r
this decline could be appl icable to mar i j uana uae and should be
sought .
Stud ies should be undertaken to learn how peer influence can be
reliably used to moderate or prevent mar i j uana uae in young
adolescents .
P roperly planned long itud inal cohort atud iea should be conducted
on both the behavioral and physiolog ical antecedents and consequence s
of the uae of mar i j uana . Detailed and cont inu ing med ical and
psychosocial data are needed on the life career s of Amer ican adult s
who u ae mar ij uana daily . Retrospect ive atud iea of middle-aged and
elder ly persona who have a hi story of chronic heavy uae of mar i j uana
would be systemat ically stud ied for med ical and psychosocial
attr ibute s and for effects on job performance . These are especially
needed for u rban industr ial ized populations .
Little is known about the consequences of using ma r i j uana i n
combinat ion with other d rug s . Inasmuch aa the rates o f uae o f other
drug s are so high , thi s ia of g reat salience . Interd isc iplinary and
collaborat ive effor ts are cruc ial if the complex it ies of mult iple
drugs and intercorrelated behavior s are to be d i sentangled .
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( eds . ) Drugs and the Youth Culture . Bever ly H i ll a , Cal i f . : Sage
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effects , and reasons for using and qu itting . Pape r presented a t
a Conference on Treat ing the Mar i j uana Dependent Per son ,
sponsored by the Amer ican Counc i l on Mar i j uana and Othe r
Psychoactive Drug s , Bethesda , Md . , May 4 , 1981 .
Johnston , L . D . , O ' Malley , P . and Eveland , L . Drug s and delinquency :
A search for causal connect ions , pp . 137-1 5 6 . In Kandel , D . B .
( ed . ) Long itud inal Research on Drug Use : Empir ical Findings and
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Johnston , L . D . , Bachman , J . G . , and O ' Malley , P . M . Highl ight s from
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K andel , D . B . Drug and dr ink ing behavior among youth . Ann . Rev .
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Kellam , S . G . , Ensminger , M . E . , and S imon , M . B . Mental health i n
f irst g rade and teenage drug , alcohol and c igarette use . J . Drug
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EFPBCTS OF MARIJUANA ON THE RESPIRATORY

AND CARDIOVASCULAR SYSTEMS
RESPIRATORY SYSTEM
Per formance ( Pulmonary Funct ion )
The lungs a re the natural target for the harmful effects of smoked
mater ials . Thi s i s as true for ma r ij uana as for tobacco .
I n both
i nstances , smoke i s drawn into the lung s where i t can harm not only
the cell a that line the a i rways ( trachea , nasopharynx , bronchi , and
a lveol i ) and constitute the lung t issue , but also impa i r such cella
as lung macrophage& , wh ich are par t of the immune system . As a
r esult , the smoke may inf l ict inj ury d irectly on parts of the system
and also make the lung s vulnerable to agents that normally are held
a t bay by self-cleans ing and self-protecting mechanisms .
Different effects would be expected f rom tobacco and ma r i j uana
smok ing because of the str i k ing d ifferences in the way in which the
two substances are smoked : mar i j uana smoke usually i s drawn deeply
i nto the lung s by one or a few del iberately deep breaths , whereas
tobacco smok ing is gene rally more automat ic , repet itive , and var iabl e
i n pattern . Moreover , because mar i j uana is a street drug , it not
only i s inconsi stent i n i t a content but also is subj ec t to contamina
t ion . Also , f i lters are not usually used by ma r i j uana smoker s ,
although water p ipes are used occasionally . Consequently , unde r
natural cond it ions i t is d i f f icult to j udge dosage of act ive
ingred ients , to sort out the influence of contaminants , and to
compare the consequences of ma r i j uana and tobacco smoke .
Exper ience ove r the yea r s with c igarette smok ing has shown tha t
cont inued exposure to tobacco smoke enta ils the r i sk of produc ing
chronic bronchi t i s and/or carcinoma of the lung . But , although
c annabis products have been smoked for centur ies , remar kably little
is r ecorded about the i r effec t s on the lung s . Whateve r contemporary
i nformat ion ex ists i s confounded by the fact that moat mar i j uana
smoker s are also tobacco smoker s .
I n r ecent year s , interest has he ightened i n the smok ing of
mar i j uana as a therapeutic measure . The inhalat ion route takes
advantage of the large sur face a rea afforded by the lung s for
admini ster ing the effect ive const ituent s of ma r i j uana . However , thi s
57

58
pract ice entai l s the d i sadvantage o f administe r i ng a therapeu t i c
agent in a c loud of a i r pollutants .
I n br ief , our appr a i sal must assess the impact of chroni c
b ronchial i r r itat ion and infl amma t ion o n the a i rway s and
gas-exchang ing surface s of the lung s .
Acute E ffects
Mar i j uana affects the control of the breathing pattern in d i f ferent
ways depending upon the dose , the preparat ion , and its psychotropic
e ffect on the consumer . One mar i j uana c igarette generally st imulates
vent i lat ion ( a i r exchange between the lung s and the ambient a i r ) in
conj unct ion with an increase in the metabolic r ate and a he ightened
response to carbon d iox ide (C0 2 ) as a regu latory st imu lant (Vachon
et a l . , 1 9 7 3 r Zwi llich et al . , 1 9 7 8 ) . On the other hand , larger doses
of smoked mar ij uana may depress the vent i lation and responsiveness to
t he C02 st imulus (We i l et a l . , 1968 r Bellville et al . , 1 9 7 5 ) . The
i ntravenous administrat ion of 6-9-THC in equ ivalent doses has much
leas of an effect e ither on the vent ilat ion or on the e ffect iveness
of C0 2 as a resp i ratory st imulant (Ma l i t et al . , 197 5 ) .
Much more cons istent and pred ictable is the effect of ma r i j uana
on the a i rways . The inha lat ion of small amount s of mar i j uana smoke
c auses bronchial d i lat ion in per sons without demonstrable lung
disease ( Tashk i n et a l . , 1 9 7 3 r Vachon et al . , 1 9 7 3 ) . The
bronchod ilat ion is easi ly demonstrable r the inhalat ion of
i soproterenol ( 12 5 0 Pg ) , a potent bronchod i lator , cau sed less of a n
improvement i n a i rways conductance than the peak effect observed
Ingest ion
after smok ing 2 percent mar i j uana ( Tashkin et al . , 1 9 7 3 ) .
o f 6 - 9-THC is leas effect ive than smoking mar ij uana in produc ing
broncbod i lat ion r the bronchod i lator effects of smoked mar i j uana last
as long as 60 minutes r that of ingested 6-9-THC up to 6 hours .
Aerosol i zed 6 - 9-THC has a local i r r i tating effect on the a irways ,
wh ich often ove r r ides the bronchod i lat ing effect to the point o f
mak ing i t unsu itable for therapeut ic purposes ( Taahk in et a l . , 1977a) .
Except for bronchod i lat ion , acute exposure to mar i j uana has
l ittle e f fect on breathing as measured by convent ional pulmona ry
teats . Thus , in young mar i j uana smokers ( 21-3 0 years of age ) who
smoked at least four c igarettes per week and no tobacco for at least
6 months before , vent i latory mechanics and gas exchange were norma l
by convent ional teats ( Tashk in et a l . , 1 9 7 6 ) .
In contrast , heavy
ma r i j uana smok ing , i . e . , at least 4 days per wee k for 6 to 8 week s
d id cause mild a irway obstruct ion ( Taahk in et al . , 1 9 7 6 ) .
Acute smok ing of mar i j uana , as well as the ingest ion o f
6- 9-THC , a l so causes bronchod i lat ion i n i nd ividuals w i t h mild to
moderate asthma ( Tashk in et al . , 1 9 7 4 ) . Mar i j uana smoking or
ingest ion of 6-9-THC also d i lated a i rways in asthmat ic s in whom
broncboconst r iction was deliberately provided e ither by exercise or
by the inhalat ion of methacholine , a bronchoconstr ictor ( Shapiro e t
a l . , 1 9 7 6a ) . The mechanism by which bronchod i lat ion is e ffected i s
not c lear , but does not involve st imu lat ion of beta-adrenerg ic

59
receptor s or blockade of muscar i nic receptor s i n a i rway smoo th muscle
( Shap i ro e t a l . , 1976a) .
Add ing to the diff icult ies of
interpretat ion are the psychotropic effects of mar i j uana a four o f
t he ind ividuals who had previously used cannabis could dist ing ui sh
the mar i j uana c igarette f rom the placebo on the baai a of the
i ntox icat ing exper ience afforded by the mar i j uana smoke . Although
the four subj ects without previous cannabis exper ience d id not
exper ience any central nervous ayatem effects , they d id note mild
somnolence or light-headedneaa afte r mar i j uana uae .
Among the exper iments with i nduced asthma were some that employed
the inhalat ion of cannabinoid-free mar i j uana smoke (Taah k i n et al . ,
1 97 5 ) . The results ind icate that the smoke of the mar ij uana c igarette
does not prevent methacholine-induced bronchospasm (Taahk i n e t al . ,
1 9 7 6 ) . Smok ing of mar i j uana d id not agg ravate or perpetuate
bronchoconatr iction in stable asthmat ics , and it promptly reve r se d
exper imentally induced bronchospasm ( Taahk in et al . , 1 978 ) . Add it ion
of A-9-TBC to placebo smoke caused a prompt , complete , and
susta ined reversal of methacholine- induced bronchospasm . Although
ingestion of A-9-TBC in a aeaame oil veh icle baa produced
bronchodi lat ion in asthmatic pat ients , leas d i lation waa noted than
after smaller doae a of A-9-TBC delivered by smok ing ( Taahkin et
al . , 1 9 7 4 ) .
A lthough it appear s that the mechanism of A -9-THC-induced
bronchial d ilat ion ia med iated by the autonomic nervous ayatem , the
process of d i lat ion ia not understood (Gill and Paton , 1970 J cavero
e t al . , 1972 J Shapiro et a l . , 1973 ) .
Subacute Effects
Pu lmonary funct ion testa in 2 8 healthy young exper ienced cannabis
uae r a before and afte r a 47-5 9-day per iod of heavie r than customary
mar ij uana usage (group daily average of 5 . 2 c igarettes , with a dai ly
mean range of 1 . 7 to 1 0 c igarettes per subj ect ) disclosed the
development of mild but s igni f icant decreases in spec i f ic a irway
conductance and forced expi ratory flow aa well aa in d i f fus ing
c apac ity ( Taahk in et a l . , 1 9 7 6 ) . Cessat ion , by reduc t ion in smok ing ,
gradually restored the testa toward normal . The clinical
s ignif icance of these abnormal i t ies i a uncerta i n . The mar i j uana
smoked and the impai rment in pu lmonary funct ion , coupled with the
observat ion that reve r s ibility of funct ion waa incomplete 1 week
afte r mar ij uana smok ing had stopped , auggeata that heavy mar i j uana
smok ing over a much longer per iod could lead to cl inically
signif icant and leas read i ly revers ible impai rment of pulmonar y
f unct ion .
Chronic Effect s
A study of 31 Amer ican sold ie r s stat ioned in West Germany who smoked
large quant ities of hashish ( 100 g rams or more per month for pe r iod s

60
o f 6 to 15 months ) found the i r a i lments to be princ ipally respiratory ,
inc luding bronchiti s , sinusitis , asthma , and rhinopharyng i t i s
( inflamma t ion o f the nasopharynx ) (Tennant et al . , 1971) .
In
one-third of the soldiers , sputum-producing coughs , d i ff iculty i n
breathing , and wheezing followed 3 to 4 months of regular use of
hash i sh . However , they had a normal cheat radiog raph and norma l
sputum . Antibiotics fai led to relieve the symptoms . The symptomatic
patients could not wor k and fou r requi red hospitalization . An
unspec if ied decrease in hashi sh consumpt ion improved the i r aymptaaa .
Pulmonary function testa in these individuals showed mi ld a i rway
o bstruction after 3 days of lessened hashi sh intake . Moreover , the
response of these individuals to i soproterenol suggested that
rever s ible bronchospasm and/or the accumulat ion of flu id in the
bronch i was involved in the pathogenes i s of the a i rway obstruction .
Patch and serolog ical testa failed to implicate allergy as a cause of
the uppe r respi ratory symptoms and s igna .
In Jama ica (Ball , 1 9 7 5 ) , where mar i j uana usage i s heavy , chronic
bronchi t i s is frequent . However , ma r i j uana smoking i s usually
a s soc iated with tobacco smok ing , which confounds interpretation of
the effects of mari j uana alone . Add ing to the uncertainty about the
e ffects of mar i j uana as a cause of chronic regulatory abnormal i t ies
are two other stud ies , one in Jama ica (Rubin and Comi tas , 1975) and
the other in Costa Rica ( Bernandez-Bolanoa et al . , 1976 ) , which
fai led to f ind any d ifference in the prevalence of chron ic
r espi ratory d i sease between smokers and nonsmokers of mar i j uana .
These results cannot be accepted a s conclusive , because in each study
the number of mar ij uana smokers was small , the subj ects were not
randomly selected , and the use of tobacco was not taken into account .
Much more convinc ing i s a recent study ( Taahk in et al . , 198 0 ) of
7 4 per sona who smoked mar ij uana for 2 to 5 years , typ ically as
f requently as several t imes per day , 3 to 6 days per week . care was
taken to obtain proper control g roups . The results ind icated that
habitual smok ing of mar i j uana causes a mild but s igni f icant inc rease
in resi stance to a i r f low in the large a irways without an appreciable
e ffect on convent ional testa .
Another study was of 2 0 0 Amer ican sold iers stat ioned in West
Germany who voluntar i ly sought med ical attention for such respi ratory
symptoms as pharyng i t i s , s inus i t i s , bronchit i s , and asthma related to
chronic heavy hashish smok ing ( Henderson et a l . , 19 7 2 ) . Analysis of
the hashish ava i lable and in u se in the locale of this study showed
concentrat ions of 5 to 10 percent 6-9-TBC . Two to 3 percent of
auaplea were contaminated with coca ine , opium, morphine , apices , or
feces . Two aspects of hash ish smok ing are relevant to the quest ion
of lung injury produced by haahiah 1
1) hash ish is usually smoked in
a pipe (occasionally i n a water pipe ) , although it is occasionally
eaten , drunk as a tea , or rolled into a c igarette and smoked , and 2 )
hash ish smoke generally i s regarded by users a s burning much hotte r
t han tobacco smoke .
S old iers with pharyng i t i s usually smoked leas than 2 5 g rams of
hash ish monthlY J those with bronch i t i s and asthma consumed more tha n
5 0 g rams per month . The common compla int of sore throat in these

61
heavy hashish smokers occ u r red most often in those w ho smoked hash ish
in a pipe without a screen or cotton f i lter J in them , the roof of the
mouth and the back of the throat were inflamed . Per s i stent rhinit is
( inf lamma t ion of the nasal mucous membranes ) was present i n 26
patients . As a rule , allergy could not be implicated in the
nasopharyngeal mani festat ions . Treatment with ant ibiotics ,
d econgestants , and phenylephr ine ( a vasoconstr ictor ) relieved the
symp toms , but they recur red in those who continued smok ing hashish .
Twenty high-dose hashish smokers (more than 50 g rams/month ) had
chronic bronchi ti s as manifested by a chronic sputum-produc ing cough ,
s hor tness of breath , and decreased exerc ise tolerance . On physical
examinat ion , abnormal respi ratory sounds--rhonch i , wheezes , and
r ales --we re present . Chest rad iographs were consi stently normal , but
pulmonary funct ion was abnormal J the vital capac ity ( the maximum
volume of gas taken i n ) was 15 to 40 percent below normal .
In s ix of
these subj ects who a.>ked 50 or more g rams per month , biopsy of
bronchial muoosa revealed changes that resembled the abnormalities
that occu r i n older heavy a.>ke r s of tobacco (Auerbach et al. ,
1 961) . The biopsies also turned up atyp ical cells not found in
tobacco smokers .
The s tudy of a respiratory d isease in hashi sh or mar i j uana
smoker s i s d i ff icult because the g reat major i ty also a.>ke tobacc o
c igarettes . Also , the i llegality of mar i j uana smok ing prevents
peop le from volunteer ing informat ion and coope r ating i n exper imenta l
s tud ies . Baeline phys iolog ical or clinical studies are d i f f icult ,
beca use the subj ect i s not ident i f ied unt i l he seek s med ical help .
Rats ( Plei acbman et a l . , 1979 ) and dogs ( Ror et al . , 1 9 7 6 ) have
been exposed exper imentally to mar i j uana smoke ove r long pe r iods ( 1
year and 9 00 day s , respect ively ) to determine its morpholog ical
effects on the lung s . At autopsy , the animals demonstrated d amag e of
th a i rways and also of the lung substance . However , it is d i f f icult
to relate the results of these animal exper iments , in wh ich the
a r t i f ic ial pattern of smok ing d i ffered markedly from that of the
human smoker , to the effects that chronic mar i j uana smok ing might
e lic it in man .
Defense Mechanisms (Alveolar Macrophages )

Little i s known about the effects of mar i j uana on the defense
mechanisms of the lung s . Although some observat ions have been made
on the alveola r macrophage , an important element in thi s system , the
r esults have been incons i stent . ror example , some stud ies of the r at
lung found that macrophage& obtained by washing out the lung and
expos ing them to mar i j uana smoke mani fested a depress ion in
bacter ic idal activity ( Huber et a l . , 197 5 , 1979a , b , 1 9 8 0 ) . On the
o ther hand , another repor t fai led to d isclose a s ignif icant effec t ,
not only o f mar i j uana , but also o f tobacco smoke on the bacter ic ida l
activi ty of mac rophag e& (Drath at a l . , 1 9 7 9 ) . Finally , others have
found that alveolar macrophages d i f fer slightly in the i r morpholog ica l
r esponses to tobacco and to mar i j uana a.>ke . The s ig n i ficance of

62
these d i fferences , especially in terms of the i r long-term effect on
pulmonary defense mechani sms , rema ins to be def ined .
Explants of lung have also been examined after exposure i n
c ulture to mar i j uana smoke ( Leuchtenbe rger e t al . , 1973a , b J
Leuchtenberger and Leuchtenberger , 197 6 ) . Str i k ing changes have bee n
observed in the appearance and g rowth characte r i st ics of exposed
cells .
Carc inoma of the Lung

The effec t of mari j uana a s a carc inogen for lung , ai rways , and uppe r
r e spiratory organs has not been systemat ically explored . Evaluating
the carc i nogenic i ty of mar ij uana i s d iff icult , because most mar i j uana
smokers alao are tobacco c igarette smokers and because such
carc inogenic ity could have a long per iod of latency , studies o f
tobacco carc inogenesis ind icate that 2 0 t o 30 years of exposure must
occur before tumor s appear in the lung .
I t i s under standable that
i nformation concerning the carcinogenic properties of mar ij uana are
not yet ava ilable , part icula rly in the United States , where the agent
has come into extensive use only dur ing the past two decades . An
impor tant problem in evaluating carcinogenic ity i s the fac t that the
leaf is used by igniting it and the inhaled products of its
combust ion may be carc inogen ic , as in the case of tobacco products .
E ven i f i t proved to be carc inogenic , the quest ion would still rema in
as to what constituent in mar i j uana smoke was at fault .
The potency of a substance as a mutagen ( ability to change
genetic mater ial ) can provide a clue as to its possible role as a
c arc inogen .
Induct ion of genet ic mutat ions by a substance in test
stra ins of bacter ia cor relates with induct ion of tumor s in test
animals . Fract ions from extracts of mar i j uana smoke part iculates
( tar ) have bee n found to produce dose-related mutat ions in fou r ou t
of f ive test stra ins of bacter ia ( Busch et al . , 1979 J Seid and Wei ,
1979 J Wehner et a l . , 19 8 0 ) . By itself , 6-9-TBC was not active as a
mutagen in bacter ial strains ( Glatt et a l . , 1979 ) or in mamma l ian
test systems ( van Went , 19 78 ) .
The extent to which mar i j uana smoke d iffers from tobacco smoke i s
discussed in deta i l in Chapte r 1 . I n general , except for the
p resence of cannabinoids in one and tobacco alkaloids ( n icot ine ) in
the other , the combustion products of tobacco and mar ij uana are
quali tat ively s imilar . On occ a sion , however , d ifferences that may be
meaning ful have been found .
For example , one study ( Hoffmann et al . ,
1 9 7 5 ) repor ts that tobacco smoke contains more isoprene and volat i le
phenols , whereas mar i j uana smoke oontains about SO percent more
c arc inogenic hydrocarbons .
Tumorigenicity of mar i j uana and tobacco smoke condensates on
mouse s k i n have been repor ted .
In mice pa inted three t imes weekly
w i th a tar suspension of smoke condensate , survival at 74 week s was
better in the ma r i j uana g roup than in the tobacco g roup . S ix of 10 0
m ice pa inted with mar i j uana condensate developed skin tumor s , all of
which were benign , whereas 14 of 100 in the tobacco condensate g roup
d eveloped tumors , two of them malignant ( Hoffman et al . , 197 5 ) .

63
Because mar ij uana smoke has adver se actions similar t o tobacco
smoke on cell funct ion in the respi ratory and card iovascular systems ,
it has been proposed that mar ij uana smoke , rather than only the
c annabinoid , should be used to obtain informat ion about effects on
cell inj ury and response ( Leuchtenberger and Leuchtenberger , 1971) .
Exposure of human lung cells in culture to freshly generated mar i j uana
smoke for up to 2 months resulted in increased mitot ic ind ices ,
s t imulat ion of DNA synthe si s , and an increase in the populat ion of
cell s with four t imes the DNA content of control cells or those
exposed to tobacco smoke ( Leuchtenberger et al . , 1973a , b) . Long-term
exposure of hamste r lung cells to the smoke of eithe r ma r i j uana or
tobacco led to abnormal prol i ferat ion and malignant transformat ion
within 3 to 6 months of exposure ( Leuchtenberger and Leuchtenberger ,
1 9 7 6 ) . S ince malignant transformat ion was also noted in unexposed
lung cells after 12-2 4 months of culture , it appear s that the smoke
of ma r i j uana or tobacco accelerates , rather than init iates , the
mal ignant change .
Although no instance of human lung carc inoma attributable solely
to mar ij uana smok ing has yet been repor ted , abnormalities suggest ive
of cancerous les ions have been recorded . FOr example , in several of
the u.s. servicemen who smoked SO g rams of hashish or more per mont h
and developed upper respiratory d isorders , mucosal biopsy showed
extensive cellular abnormal i t ies , includ ing loss of c i lia ,
p rol i feration of basal epithelial cells , and atypical cells ( Tennant
et a l . , 1971 J Henderson et al . , 1 9 7 2 ) . Compa r i son of 30 Amer ican
hashish smokers ( 2 5-150 g rams/month for 3-24 months r 23 also smoked
tobacco and 7 d id not ) , 3 tobacco smoker s ( 1 . 6 packs/day for 11 . 3
years ) who d id not smoke mar i j uana and 3 nonsmokers of tobacco or
hashi sh , ind icated exposure to combined ma r i j uana and tobacco smoke
produced more harmful effects than that produced by e ither substance
alone (Tennant et al . , 19 8 0 ) .
In the hashish smokers who d id not
smoke tobacco , abnormali t ies in the tracheal biops ies were no more
frequent or severe than in those per sons who smoked only tobacco .
Exception has bee n taken to the idea of an add i t ive effect of
tobacco and hashish smoke . A Greek study that compared chronic
hash i sh and tobacco users with tobacco smok ing controls found that
although the hashish smoker s had cons iderably more throat irr itation
and cough , the prevalence of bronchitis in both g roups was about the
same (Boulougour i s et a l . , 1 9 7 6 ) J no biopsies were taken . The
d i fferences between the Greek and Amer ican stud ies may reflect
d i fference s between the two popu lat ions : The Amer ican study , done i n
Ge rmany , favored inclus ion o f men with severe respi ratory d isturbances
(Tennant et al . , 1980 ) , whe reas the Greek study (Boulougour i s et al . ,
1 9 7 6 ) appears to have included per sons with less severe i llness .
The f i nd ing of known carcinogens in mar i j uana smoke and the
p resence of epi thelial abnormalit ies known to be the precursor s of
lung cancer in heavy smoker s of tobacco suggest the possible
development of lung cancer in chronic , heavy users of mar ij uana and/
or hashish after a prolonged per iod of use , espec ially i f they are
a lso smokers of tobacco . However , evidence to suppor t this
hypothes i s i s not avai lable . Because mar i j uana smok ing i s an anc ien t

64
custom i n Asia and the Middle East , lung cancer would be expected to
be more prevalent in these parts of the world i f a causal
relationship d id ex ist . Unfortunately , no reliable data have bee n
g athered to settle thi s quest ion . Heavy smok ing of mar i j uana , in
quant itie s canparable to that of tobacco , has been relat ively
uncommon in the United S tates . Therefore , the contr ibut ion of
mar i j uana smok ing to the inc idence of pr imary lung cancer cannot ye t
be answered with any author i tative data .
Summa ry z
Respi ratory System
Lung Punct ion and Defense Mechani sm s

The most impor tant quest ion about the effects o f mar i j uana o n the
health of the respi ratory system i s whethe r acute or chronic
mar ij uana smok ing cause detectable structural or functional
impa irment of the lung s . Mild but measurable a i rway obstruct ion ,
a ffect ing both large and small a i rways , can be shown to ex ist after 6
to 8 week s of smok ing mar i j uana da i ly , averag ing f ive mar i j uana
c igarettes a day , this decrement in function is reversible , but does
not return to normal within one week of abstaining from smok ing .
In per sons with h i stor ies of heavy smok ing , par t icularly of
hash i sh , chronic inflamma tory changes are seen in the bronchi and
uvula , often in assoc iat ion with chronic sinu s i t i s . These mani festa
tions of uppe r respi ratory d i sturbance have been desc r i bed in
i nd ividuals with hi stor ies of mar i j uana smok ing usually in excess of
3 year s and are reversible when ma r i j uana smok ing is stopped .
Acute exposure of alveolar macrophages in vitro to mar ij uana
smoke causes a reduct ion in phagocytic activity , a cell defense
mechani sm . The agents responsible for this change in macrophage
funct ion are in the vapor phase of ma r i j uana smoke and are not
related to the presence of 6-9-TRC . Also , lung explants exposed to
mar i j uana smoke in vitro show changes in the chromosomal structure of
nuc lei .
There i s as yet no informat ion about the effects of prolonged
smok ing of mar i j uana , that i s , beyond 5 years . Although some
populat ions have been examined for the effects of chronic mar i j uana
smok ing , controlled stud ies are spar se and populations exposed to
mar ij uana smoke only--without exposure to tobacco--apparently are not
avai lable . Par t icularly conspicuous i s the lack of information about
t he effect of chronic mar i j uana smok ing begun in late childhood or
adolescence and oont inued to adulthood . Such stud ies would requ ire
morpholog ical examinat ion of biopsy mater ial from the bronchi and
respiratory passages to determine the presence of structural change s
that ind icate the development of chronic bronchitis and/or lung
cancer . Morpholog ical changes associated with smok ing mar i j uana
could be compared with the morpholog ical abnormalities assoc iated
with chronic tobacco smok ing .
The acute response to inhalat ion of mar ij uana is an apprec iable
bronchodi lat ion , both in normal subj ects and in individuals with

65
bronchial asthma . However , the bronchod i lator effects of mar ij uan a
a re a response to acute exposure 7 chronic exposure usually evokes
bronchccon str ict ion .
With respect to therapeut ic applicat ion , the effects of smok ing
mar i j uana in produc ing bronchial d i latat ion do not exceed those that
follow the i nhalat ion of beta-agonist drug s . Moreover , the doses
requ i red for bronchod i latat ion usually elic i t the psychotropic effect s
of mar ij uana and may be assoc iated with changes in the structure of
bronchial and parenchymal lung cells , the s ignif icance of which
remains to be assessed . For these reasons therapeut ic usefulness as
a bronchod i lator drug is open to ser ious quest ion ( see Chapter 7 ) .
Carcinoma of the Lung

One of the g reat uncerta i nt ies about mar ij uana smoking i s its
neoplastic potent ial . No rel iable data are ava i lable concerning the
i ncidence of carc inoma of the lungs and upper respiratory passages in
long-term use r s of cannabi s .
But a var iety of exper imental stud ies has sounded the alert that
mar i j uana smok ing--just as tobacco smok ing--may be carc inogenic and
t hat a combinat ion of tobacco and mar i j uana smoke may have g reater
neoplastic potent ial than e ither one alone . Although the exper imenta l
observat ions have rai sed the suspic ion , long-term observat ions on
human subj ects--and possibly on smok ing animals--will be necessary to
settle the i ssue .
Recommendat ions for Research

Lung Funct ion and Defense Mechanisms
With respect to the per formance and defenses of the lung s , these
studies would be informat ive :
the physiolog ical , biochemical , and morpholog ical

interactions of combined exposu res of the respiratory tract to
tobacco and marij uana smoke 7
the interact ions of cannabis and alcohol on the funct ion of

the respiratory tract 1
t he long -term effects , i . e . , 10 to 30 years , of exposure of

the respiratory tract to frequent use of cannabi s in the absence and
pressure of exposure to tobacco smoke ( for th i s purpose , large-scale
epidemiolog ical stud ies may be requ ired ) 7
the phys iolog ical effects and clinical consequences o f

exposure o f alveolar macrophage& and other lung cells to long-term
exposure to mar i j uana smoke 7
the immunolog ic effects of mar i j uana smoke exposure on cells

and on the ent ire body .

66
ca rc inoma o f the Lung
With respect to carc inoma of the lung , these stud ies seem essent ial :
an epidemiolog ical survey to determine ove r the next 2 0 to

30 years if there will be an increased inc idence of pr imary lung ,
laryngeal , oropharyngeal , esophageal , nasal , or s inu s cance r in
c hronic mar i j uana smokers r
e p idemiolog ic and patholog ical stud ies in humans and

exper imental stud ies in an imals to evaluate the carcinogenic
potent ial of chronic mar i j uana smok ing on the lung , larynx ,
oropharynx , nasal , and s inus epithelium .
CARDIOVASCULAR SYSTEM
Normal Hear t and C i rculat ion
Hea r t (Direct Effects )
W ith respect to the hea rt and c i rculat ion , the most evident effect in
human be i ng s of smok ing mar ij uana , or of ingesting the active
i ngred ient (6-9-TBC ) , i s a brisk increase in heart rate
( tachycard ia ) .
Although this i s not threaten ing to the normal
hear t , the rapid hea r t act ion can be harmfu l to the heart in wh ic h
t he c irculat ion i s compromi sed by atheroscleros i s or i s on the verge
of f a i l ing .
The responses of the card iovascular system to acute exposure to
mar i j uana d if fe r between human be i ng s and most other mamma l s in that
the human subj ect typically responds with an increase in heart rate
(Br ight at al . , 1971 J Beaconsfield et a l . , 1972 J Perez-Reye s et al . ,
1 9 7 3 ) , whereas most mamma ls show a slowing in rate ( bradycard ia)
(Cavero at a l . , 19 7 3 J Graham and Li , 1973 J Rosenkrant z and Braude ,
1 974 1 Vollmer et a l . , 1974 r Adams et a l . , 1976 J Hardman and Rosko ,
1976 J Kawa sak i et al . , 198 0 ) .
Ruman blood pressure usually increase s
moderately on acute admini strat ion of 6-9-TBC , but in monkeys and
dogs acute administration is followed by a decrease in systemic
ar ter ial pressure . Typical effects on hea r t rate and blood pressur e
have been attr ibuted to altered autonomic funct ion ( Loewe , 1944 J
Joachimoglu , 19 6 5 J Ames , 1968 r Gill and Paton , 197 0 ) .
Effects on the card iovascular system are to some extent a
function of dose , route of administration , and durat ion of exposure .
Tolerance to se of the card iovascular effects in human be ing s
develops with chronic use ( Benowitz and Jones , 19 7 5 , 1977a , b J Nowla n
and Cohen , 1977 ) , but cont inued use does not result in any per s i stent
alterat ion in card iovascu la r func t ion after cessat ion of exposure
( Dornbush and Kokkevi , 1976 ) .
E ffects on Hea rt Rate
In healthy young adults , acute admini strat ion
of ma r i j uana by smok ing ( 1 0 mg tota l dose ) cause s a prompt increase
i n heart rate ( increasing by up to 90 beats/minute ) for about 1 hour .

67
Th e chang e in hear t rate caused by 6-9-TBC appea r s t o resul t from
alterat ions in both sympathet ic and parasympathetic efferent act ivity
to the normal card iac pacemaker ( Beaconsfield et al . , 1972 7 Martz e t
a l . , 1 9 7 2 7 Sulkows k i et a l . , 1 9 7 7 ) . The results o f stud ies designed
to determine whether beta-adrenerg ic st imulat ion is respons ible fo r
the tachycardia have not been conaiatent z
In one aer ies of reports ,
prior administration of propranolol , * in a dose suff ic ient to bloc k
the hear t ' s beta-adrenerg ic receptors , prevented the increase in
heart rate ( Br ight et al . , 1971 7 Beaconsf ield et al . , 1972 1
Perez-Reyes et al . , 19 7 3 ) , whereas in other reports , propranolol
fa i led to block the ma r i j uana- induced tachycardia (Kana k i a et al . ,
1 9 7 6 7 Taahk in et al . , 19 7 8 ) . Although part of the d i screpancy may be
attr ibutable to d i fference s in dosages , not all of i t can be
r at ionali zed thi s way , leaving an unexplained d i spar ity .
Effects of mar i j uana on blood pressure and
Hemodynamic Effects
c ard iac output , as ment ioned above , are a funct ion of the nature of
exposu re ( acute or chron ic ) , of the dose , and of the body poa ition 7
a lso , there a re d ifferences among human be i ng s and a number of
mamma lian spec ies .
In human be ing s ly ing supine , acute exposure to
6- 9 -THC typically causes a modest increase in blood pressure ,
although in some instances no s ig n i f icant change in pressure has been
observed ( Beaconsf ield et a l . , 1 9 7 2 r Kana k i a et al . , 1976 7 Benowitz
e t al . , 1 9 7 9 ) . On a ssuming the upr ig ht posture , blood pressure may
drop considerably . Cardiac output , in the supine pos ition following
an inj ec t ion of 6 -9-TBC , has been found to increase by as much as
30 percent (Malit et al . , 197 5 r Taahk in et al . , 1977b) . The increase
in cardiac output in the face of only a modest increase in blood
p ressure c learly results in a substantial dec rease in per ipheral
vascular resistance . The chang e in resi stance var ies among the
d if ferent vascular beds , be ing g reatest in the vessels to the
skeleta l muscles .
Chronic administration of qu i te larg e oral doses of 6 -9-TBC
exer ts d i fferent effects ( than the acute ) on the c i rculat ion
(Bernste i n et a l . , 1974 7 Benowitz and Jones , 1975 r Benowitz et al . ,
1 979 ) . Systol i c and diastolic pressu re usually fall slightly , but
these changes are not always susta ined . As the blood pressure falls ,
the heart rate slows f rom the high levels caused by init ial mar i j uana
admini stration . The decrease in blood pressure can be accentuated i f
the subj ect assumes a n upr ight posture . The extent to wh ich it drops
appear s to be a rec iprocal funct ion of the extent to which plasma
volume has increased .
Data about changes in human left
E ffects on Heart Muscle
ventr icular funct ion caused by mar i j uana are not ent i rely convinc ing
because moat stud ies have rel ied on noninvasive measurements and
* Propranolol is an agent that blocks beta-adrenerg ic neurotransmitters

and is used in treatment of card iac arrhythmias .

68
because i t has not been poss ible to oontrol separately the severa l
var iables that modify left ventr icular funct ion and are changed
administration of 6-9-TBC . Changes in heart rate , after load
( systemic vascular resi stance , blood pressure ) , or preload (plasma
volume , venous return ) individually can cause changes in heart s i ze
and ventr icular per formance .
In spite of these l imitat ions ,
conclusions can be drawn f rom the observat ions on human beings .
Def initive animal studies of 6 -9-TBC e ffects on ventr icular
per formance have not been done .
I nd ices of card iac performance usually improve after mar i j uana or
6- 9-TBC . Almost invar iably this improvement can be att r ibuted to
the i ncrease in hear t rate ( Gash et al . , 1 9 7 8 ) . The acute
administrat ion of 6-9-TBC ( 2 5 Pg/kg intravenously ) to healthy
young males elicits , i n assoc iat ion with the inc rease in heart rate ,
changes i n the ventr icula r contract ion pe r iods (an increase in
e j ect ion t ime and shortening of the preinj ec t ion per i od ) , whi le
systemic arter ial pressure i s unaffected (Wei s s et a l . , 1972 J Kanak i s
e t a l . , 1976 ) . Beta-adrenerg ic blockade by propranolol i s followed
less str i k ing changes i n the contraction t ime intervals . Anothe r
s tudy of 17 subj ects who smoked two to three c igarettes ( 2 0 mg
6- 9-TBC pe r c igarette ) found card iac output increased by 2 8 percen t
and heart rate 30 percent , in conj unc tion with a slight decrease
in stroke volume , wh ich affects pulse pressure ( Tashk in et al . ,
1 977b) .
Autonomic Nervous System

Mar i j uana could influence autonomic funct ion in several ways z
( 1 ) by
chang ing the sensitivity of reflexe s that influence and control
c ard iovascular function , thi s effect could result e ither from changes
i n the processing of nerve impulses in the central nervous system or
a utonomic g anglia (a g roup of nerve cells outside the central nervous
system) , from changes in the liberation or metaboli sm of transmitter s
a t the autonomic nerve terminals , or f rom changes in the sens i t ivity
of the pre- or postj unct ional receptors J ( 2 ) by a change in the
levels of neurotransmitters , the catecholamines ( norepinephrine ,
epinephr i ne ) in the blood as a result of actions on the adrena l
medulla , which secretes these neurotransmitters , activat ion of the
adrenals could be a d i rec t effect or by reflexes or by a centra l
act ion of 6 -9-TBC J and ( 3 ) by exer ting effects on dopamine act ivity
( an i ntermediate product in the synthes i s of norep inephr ine ) e ither
in the central nervous system or pe r iphery .
Unfortunately , it i s unclear how the effects of 6 -9-TBC are
exer ted on the autonomic ne rvous system ( Truitt and Anderson , 1971 J
Beaconsf ield at a l . , 1972 J We i s s et al . , 1972 J Eng le rt et al . , 1973 7
Ho et a l . , 1973 J Howes and Osgood , 1974 7 Bo and Johnson , 1976 J Buot ,
1976 J Benowitz and Jones , 1977a , b J Gash et al. , 1978 7 Stefanis , 1 9 7 8 ) .
The data are insuff ic ient to determine i f the effects come by way of
the central nervous system , or by per ipheral neural structures , or by
t he adrenal medulla .
I t i s also d if f icult to assess the role of

69
reflex adj ustments in the heart and systemic c i rculat ion . Finally ,
o ther possibilities , such as desens i t i zat ion or blockade of
per ipheral adrenerg ic receptor s , have not been examined .
Although the data on human beings are not adequate to determine
how ma r i j uana inf luences autonomic funct ion , evidence that it doe s
has been obtained . Por example , 6 - 9- appears to reduce a number
of autonomic reflexes a After mar i j uana , the typical changes in hear t
rate and blood pressure elic i ted by the Valaalva maneuver ( a forced
exhalat ion effort aga inst the c losed g lott i s ) are decreased , and so
are the reflex c i rcu latory responaea to immer aion of the hand in cold
water ( Beaconsfield et a l . , 1972 J Benowi tz et al . , 197 9 ) . However ,
dur ing chronic administration of 6-9-TBC , no change occur a in the
reflex decreaae in hear t rate cauaed by infua ion of a doae of the
vaaoconstr ictor phenylephr ine suf f ic ient to increase the blood
p resaure ( Benowitz and Jonea , 1975 J Benowitz et a l . , 1979 ) .
Exerc i se
Acute expoaure to 6-9-THC mod i f ies exerc i se per formance by human
be ing s . Smok ing ( 20 mg o f 6-9-TBC ) decreased the durat ion of
exerc i se but caused no change in any cardiopulmonary parameter at any
wor k load except for heart rate , which increaaed ( Shapiro et a l . ,
197 6b) .
Other Bffecta ( Plasma Volume , Sod ium Retent ion )

Acute administrat ion o f 6-9-TBC would no t be expected to have
prominent effects on aod ium balance or plasma volume . Chronic
administrat ion , on the othe r hand , ha s d i at inct effecta . With
c hronic ingest ion of large doses of 6 -9- there ia a consi stent
gain in body weight and plaama volume , the latter cauaed by aod i um
retent ion ( Benowitz a nd Jones , 197 5 , 1 977a , b) . The change in plasma
volume seems to be causally related to the dec reaae in orthoatatic
hypotena ion dur ing chronic exposure . The mechani sms responsible for
the retent ion of aalt and water have not been explored and may
include changea in renal per fusion , i nhibition of prostag landin ( a
substance that affects blood preaaure) aynthesia by 6 -9-TBC
( Burstein and Raz , 1972 J Bowea and Oagood , 19 7 6 ) , or aome
mod i f icat ion in pitu itary-adrena l funct ion ( B i rmingham and Bar tova ,
1 976 ) .
Abnormal Heart and Ci rculat ion

Although amok ing mar i j uana or the introduction of 6-9-TRC into the
body ia apparently wi thout deleter ious effect on the normal heart and
c i rculat ion , the poss ibility is g reat that the abnormal heart and
c irculat ion will not be as tolerant of an agent that speeds up the
hea r t , aomet imes unpred ictably raises or drops the blood pressure ,

70
and mod i f ies the act ivit ies of the autonomic nervous system .
Therefore , it is pert inent to examine the prospects that mar i j uana
(or 6-9-THC ) may be ha rmfu l in individuals with coronary hea rt
d i sease , cerebrovascular d i sease , hyper tens ion , and heart failu re .
Moreover , it may be impor tant to determine i f 6-9-THC interacts i n
its effects o n the abnormal heart or c i rculat ion with othe r agents
that are be ing administered for therapeutic purposes .
Coronary Heart Disease

D ata on this top ic are sparse , presumably because of the relat ively
shor t t ime that mar ij uana has been ava i lable in th i s country . Those
who have smoked mar i j uana a re j ust ente r i ng the age when coronary
athe roscleros is is common . Howeve r , it has been shown both in norma l
i nd ividuals and in ind ividuals w ith coronary artery d isease that the
acute administration of 6-9-THC by smok ing or inject ion can cause
changes in the electrocard iog ram ( ECG) (Johnson and Domino , 1971 1
Beaconsf ield et al . , 1972 1 Kochar and Rosko , 1 9 7 3 ) . Premature beat s
have a lso been noted . The reasons for the changes are unclear .
Also
not understood i s the contr ibut ion of the increase in heart rate
i tself to the ECG changes and to the premature beats .
In some patients with coronary artery d i sease , increased
c atecholamine& can induce arrhythmias .
It seems l i kely that in such
pat ients 6-9-THC could have the same effect . Also , in pat ients
with coronary artery d i sease a large increase in heart rate can
induce ang ina (pain) and even i schemic damage f rom insuf f ic ient
oxygen as a result of an obstructed blood vessel .
If 6 -9-THC were
to increase hea rt rate markedly in such pat ients , and at the same
t ime increase the need for cardiac perfusion because of the increased
c ard iac wor k and because of the i ntensi f ied effect of catecholamine&
on the heart , it seems reasonable that there oould be induct ion of
ang ina and potent ially prec ipitat ion of ischemic damag e . Furthermore ,
i f 6-9-THC dulled the apprec iation of pai n and the appropr iate
responses to pai n , the pat ient might not take su itable measure to
relieve the ang ina , thereby increasing the r i sk of damage or
a r rhythmias .
A decrease in oxygen-carrying capac i ty of blood because of
format ion of carboxyhemog lobin could also be troublesome . Exerc i s e
tolerance has been repor ted t o decrease in individuals with ang ina
after smoking ma r i j uana 1 this dec rease i s in contrast to the
u naffec ted exerc ise tolerance after smok ing a placebo mar ij uana
c igarette (Aronow and Cass idy , 19 7 4 ) . Oral ingest ion of 6 -9-THC o r
smok i ng mar i j uana apparently can cause mar ked hyper tension in
assoc iat ion with an increase in systemic vascular res i stance
( Benowitz et a l . , 1979 ) , which would place the heart with coronary
artery d i sease at r isk of damage .
These observat ions concur i n i nd icat ing that mar i j uana and
6-9-THC increase the wor k of the heart , often in many ways . The
conc lus ion seems inescapable that this increased work , coupled with
st imulat ion by catecholamine& , may tax the heart to the point of
c linical hazard .

71
Cerebrovascular Disease
There are few , if any , ind icat ions that 6 -9-THC has d i rect effects
on the cerebral c i rculat ion that would be impor tant in pat ients with
cerebrovascular d i sease .
I n the occas ional pat ient who develops
hyper tens ion after smok ing , there would be an increased r isk of a
cerebral vascular acc ident ( stroke ) . Also , because 6-9-THC
admini stered after at ropine can cause marked increases in blood
pressure , thi s combinat ion would place the patient with cerebro
vascular d i sease at r i sk , as would smok ing after ingest ion of othe r
muscarinic blockers .
In some pat ients , postural hypotens ion could be
a problem , not only for persona with abnormal cerebral c i rculat ions ,
but also with abnormal corona ry ci rculat ions .
Hypertens ion
The f actors that act to intens i fy ang ina would be of importance in
hypertens ive pat ients . Although data are lacking on the magnitude o f
c hange in blood pressure caused by 6-9-THC in hypertens ives , it
seems reasonable to assume that hypertens ives smok ing mar i j uana might
have a g reater increase in blood pressure than normals do . The
i ncrease in plasma volume and sod ium retent ion that are assoc iated
with chron ic exposure to 6-9-TRC could increase blood pressure i n
hypertens ives and the mechanisms respons ible for these changes very
li kely would interfere with the act ion of a number of
antihypertens ive med icat ions .
Hear t Fai lu r e
Because mar i j uana can cause tachycard ia , a decrease i n systemic
vascular resi stance ( requ ired for increased card iac output to sustai n
blood pressure) and salt and water retent ion might place pat ients
with severe hear t failure at a di sadvantage by exposure to 6-9-TRC .
Data on such pat ients a re lac k i ng .
I n older pat ients treated by
6-9-THC or who have smoked mar i j uana for glaucoma or cancer ,
orthostatic hypotens ion has been both d i sabl ing and a threat of
card iovascular compl ications (Merr itt et al . , 198 0 ) . However ,
tolerance to orthostat ic hypotension seems to develop dur ing
continued intake of 6-9-THC or continued smok ing of mar i j uana .
Dehydration , as dur ing vomiting or d iuret ic therapy , pred i sposes to
the orthostatic hypotensive effects and resi sts the development of
tolerance because it prevents expansion of blood volume .
Inte ract ions with Card ioactive Drug s

Few stud ies evaluate interact ions between 6 -9-TRC and other drugs
that act d i rectly or indi rec tly on the heart . Propranolol usually
attenuates the increase in heart rate caused by 6-9-TBC . Atropine

72
can g reatly potent iate the abi l ity o f 6-9-THC to inc rease sy stemi c
arter ial pressure ( Benowitz and Jones , 1 9 7 7a , b) . A number of poss ible
interact ions can be iaag ined .
I f a pat ient were tak ing a d rug that
blocked uptake of catecholamine& by nerve terainals , then those
effects of 6-9-TRC that are med iated by catecholamine & would be
intensi f ied . Because a g reat many psychotropic and ant ihypertens ive
drug s mod ify aetabol ism of neurot ransmitters in the central nervou s
system and per iphery , a wide var iety of interact ions with 6 -9-TBC
seems possible .
Summa ry a
Card iovascular System
The smok ing of mar i j uana causes changes in the heart and c i rculat io n
But there i s no evidence to
that are character ist ic of stress .
ind icate that it exerts a permanently deleter ious effect on the
normal card iovascular system . Ne i ther is the re convi ncing evidence
that mar i j uana would be of particular benef it in treat ing any of the
major foras of card iovascular d isease .
The s i tuat ion i s qu ite d if ferent for those with an abnormal hear t
o r c irculat ion . Evidence abounds that mar i j uana increases the wor k
of the heart , usually by increas ing heart rate , and in some per son s
by i ncreasing blood pressure . Thi s increase in workload poses a
threat to pat ients with hypertens ion , cerebrovascular d i sease , and
coronary atheroscleros is . The magni tude and inc idence of the threat
rema ins to be deterained because mar i j uana smok ing has largely been
conf ined to younger adults who are only now entering the age of
ser iou s compl icat ions of atherosclerosi s on the heart , brain , and
per ipheral vessels .
M ar i j uana also can cause postural hypotens ion . Th i s drop in
blood pressure could be hazardous in those ind ividual s with
compromised blood f low to the heart or bra i n , espec ial ly if they are
volume-depleted (dehydrated ) or i f other drug s have impai red reflex
control of the i r blood vessels .
M ar i j uana appear s to intens i fy the effects of the sympathetic
nervous system on the heart , an undes i rable consequence in pat ient s
w ith coronary artery d isease. and in those susceptible to arrhythmias .
Many of the undes i rable effects of mar ij uana on the card iovascular
system seem to become less seve re following chronic exposure . Whether
the relat ive pauc ity of repor ts of the i ll-effects of mar ij uana on
the abnormal cardiovascular system is a consequence of adaptat ion to
chronic u sage or to lac k of exposure to mar i j uana of a popu lat ion
t hat is suff ic iently advanced in years to be susceptible to its
untoward effects remains to be determined .
Recomme ndat ions for Research

Add it ional stud ies are needed both ( 1 ) to provide informat ion on the
mechanisms respons ible for the observed effects of mar i j uana on the
card iovascular system and ( 2 ) to provide new data on the ef fects of
mar i j uana in patients with known forms of card iovascular d i sease .

73
The aanner in which A-9-TBC acta on the heart to chang e

tbe rate and force of contract ion needs c lar if icat ion . Direct
effects on the hear t are not l i kely to d iffer among spec ies , and thu s
exper iments can be planned for a standard heart preparat ion .
Direct effects on electr ical act ivity , which might relate t o

reports of changes in e lectr ical activity and product ion of preaature
impulses a a well aa changes in s inus rate , should be evaluated with
s tandard methode and standard preparat ions .
Di rect effects of A-9-TRC on vascular smoot h muscle should

be explored . Por this purpose , i t would be essent ial to use 8Cile
veaaela that d id , and other s that d id not , .have funct ioning nerve
terminals .
It would be impor tant here to include stud ies on selected
coronary vessels and on veaaela which play a dominant role in the
r egulat ion of systemic vascular resistance .
A number of related studies are needed before the effects on

humans can be explained in ful l , par t icularly the effects of
A-9-TRC on the renin-ang iotensin ayatea in the k idney , wh ich
provides control of arterial pressure , and on the seve ral sequences
of prostag land in metabol i 81l .
S tud ies also are i nd icated to obta in new data about the effects
of aarij uana on a
persona with hypertens ion , coronary artery d i sease , and

cerebrovascular d isease '
i ncreases in systemic arter ial pressure in low- and

h igh-renin hypertens ion and the interact ions betwee n A -9-TRC and
several c laaaea of ant ihypertensive med icat ions ,
the interact ions between the salt and water-retaining effect

of A -9-TIIC and d iuret ics that could be employed both in
hypertensives and those with heart fai lure .
Add it ionally , stud ies should be done on the use of standard
moni tor ing technique s to quant i fy any effect of aar i j uana smoking o n
tendenc ies toward arrhythmias , a nd o n interact ions o f A -9-TRC with
drug s that mod i fy synapt ic tranBiliaa ion in the central nervous system .
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77
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4
EI'PEC'l'S OF MARIJUANA ON 'l'HE BRAI N
The moat c learly e stabli shed effects of cannabi s are upon behavior .
These effects , descr ibed in Chapte r 6 , ind icate that aajor act ions o f
c annabinoids are upon the bra i n . The ways in which mar i j uana alters
the brain to produce ita behavioral ef fects are not known .
Efforts to d iscover the causes of the behavioral effects have
included stud ies on brain morphology , physiology , and chemi stry to b e
r eviewed in t h i s chapter . Effects o f mar i j uana o n brain electr ical
act ivity and on brain chemistry have been measured , but the i r
s ignif icance for brain funct ion i s not known because o f our l imited
knowledge of brain-behavior re lat ions . Ma r i j uana causes temporary
i ntox icat ion and results i n changes in brain phys iology and chemistry
s imi lar to those caused by othe r intox icat ing drugs . Although these
k inds of stud ies may u lt imately shed l ig ht on the way mar ij uana
produce s ita behaviora l changes , they do not provide answers to
impor tant clinical quest ions . Does mar i j uana cause long-term changes
in the brain that lead to chronic psychiatr ic or neurolog ical
d isorder s ? So far , the stud ies reviewed below provide no convinc ing
evidence for long-term changes because of u se of mar i j uana .
BRAIN MORPHOLOGY
There i s substantial controversy about whethe r mar ij uana cause s
c hanges in brain structure or i n brain cella . Two stud ies have
reported that r i j uana produces changes in brain morphology . Bot h
s uffer suff ic iently f rom methodolog ic and interpretat ional defects
that the i r conclusions cannot be accepted . Furthe rmore , other
s tud ies have not found changes in morphology .
Gross Morphology
D ata suggesting that use of mar ij uana causes brain atrophy were
obta ined by pneumoencephalog r aphy ( inj ec t ion of air into spaces i n
a nd sur round ing the brain) on 1 0 u sers o f mar i j uana who had sought
med ical attent ion because of neurolog ic complaints (Campbell et al . ,
1 97 1 ) . The s i ze of the largest brain cavities ( ventr icle s ) was
80

81
melaured to dete rmine whether loss of brain t issue had oceurred . The
author s interpreted the i r data as showing that atrophy was present .
One of the f irst c r i t ics of thi s report quest ioned the
inte rpretat ion of the rad iolog ic techniques u sed (Bull , 1971) . Th e
results also have been ser iously c r i t ic i zed because of the mar ij uana
user s stud ied . They had neu rolog ical symptoms or s igna suff ic ient to
j ust ify an i nvas ive and painful d iagnost ic teat , but there is no
evidence that such neu rolog ical complaints occur with g reater
f requency in u sers of mar i j uana than in the general populat ion .
Further , Campbell ' s pat ients d id not only use ma r i j uana , but also
u sed such behavior-alter ing drug s , as lyserg ic ac id d iethylamide
( LSD ) and amphetamines .
More recent evidence has been provided by computed tomog raphy
(CT) scans of the brain . Thi s technique , wh ich i s noninvasive ,
painless , and y ields more prec ise and quant i f iable measures of brain
atrophy , has replaced pneumoencephalography as a d i agnostic teat .
Using CT methods , two stud ies fai led to f ind evidence of cerebral
atrophy in healthy chronic mar ij uana u se r s (Co et al . , 1977 J Keuhnle
e t al . , 1 9 7 7 ) . These latter results suggest that the ear l ier
f ind ing s were attr i butable to the impr ec i s ion of convent iona l
pneumoencephalography , or to the fact that a g roup with neurolog ic
compla ints was stud ied , or to the use of mult iple psychoactive drug s
by these i nd ividuals . This last possibi l i ty i s reinforced by CT
scans of animals who rece i ved a var iety of paychoactive drugs .
Mar ij uana a lone produced no evidence of brain atrophy , whereas other
drug s , such as amphetamines , d id produce changes ( Rumbaugh et a l . ,
1980) .
Microscopic Morphology
Three post mortem stud ies on monkeys in the same laboratory have
r epor ted changes in the mic roscopic morphology of the brain at the
ultrastructural level (Harper et al . , 1977 J Meyer s and Heath , 1979 J
Heath et a l . , 1 9 8 0 ) . No s imi lar stud ies on human bei ng s have been
repor ted . The monkeys rece ived e i the r chronic exposure to mar ij uana
smoke or chronic inj ect ions of A-9-TBC . Changes repor ted to have
occu r red in the brains included alterat ion in synapt ic* cleft width ,
increased dens ity of synapt ic cleft mater ial , a decrease in volume of
rough endoplasmic ret iculum , presence of clumping of synaptic vesicles
in axon terminals (where impu lses travel away from the cell body ) ,
and an increase i n intranuclear i nclus ions . These changes appear
dramat ic , but they must be interpreted with caut ion . The three
stud ies a re baaed princ ipally upon exami nat ion of two l imited bra in
areas only i n three treated monkeys , two rece iving mar ij uana smok e
* A synapse i s the reg ion of commu nicat ion between nerve cella ,
forming the place where a nervous impulse i s transmitted from on e
nerve cell to another .

82
and one intravenous 6-9-THC ; a fou rth treated anima l was added to
the last study and more brain areas were analyzed in it ( Heath et
al . , 19 8 0 ) . Further , althoug h the mate r ial was eva luated
doublebl ind after e lectron microg raphs had been made , it wou ld
appear that f ixation , tissue preparat ion , and photog raphy were
c a r r ied out before these safeguards aga inst bias were applied . I t i s
possible that unknown but systematic d i f ferences occu r red between
exper imental ( treated ) and control animals in f ixat ion and
preparat ion of t i ssue or i n se lect ion of sample s for micrography . I n
add i t ion , i t should be noted that a t least one o f the changes noted ,
clumping of synapt ic ves icles (Harpe r et al . , 1977 ) , i s a normal
var iant in the synapt ic morphology of axon terminals in mamma lian
brain ( S ipe and Moo r e , 1977 ) and does not represent a patholog ica l
c hange . Also , these s tud ies have not been replicated and , beCause
the basi s for interpretat ion is such a l imited sample , it is con
c luded that no definit ive interpretat ion can be made at this t ime .
However , the poss ibility that mar ij uana may produce chronic , u ltra
s tructural changes i n brain has not been ruled out and should be
inve st igated .
NEUROPHYSIOLOGY
One sou rce of informat ion on the mechani sms of act ion of a d rug , such
as ma r i j uana , i s the study of its phys iolog ical e ffects . Effec ts of
ma r i j uana on the e lectr ical act ivity of the brain have been
d emonstrated by means of the e lect roencephalog ram ( EEG ) . The
standard , or clinical , EEG measu res t iny va r iations at the scalp o f
voltages produced by the e lectr ical activity o f the brain . Voltage
d i f fe rences between two points on the scalp , or between the scalp and
an inactive reference s i te , are recorded on moving paper , produc ing a
g r aph of voltage over t ime . The waves observed are class i f ied
accord ing to frequenc ies as delta , theta , alpha , and beta . Whi le the
changes i n EEG desc r i bed below are of interest , the i r biolog ical
s ig n i f icance is unknown .
Acute ( Short-Term) Effects in Wak ing EEG

Ingested ma r i j uana or 6-9-THC produces rather slight effects on th e
EEG of an awake subj ec t . Relatively h igh doses ( 210 mg 6-9-THC or
its equ ivalent/day ) have fai led to produce measu rable changes even
t hough mar ked behavioral e ffects were observed . The EEG effect most
frequently reported in recent stud ies ha s been an increased abundance
o f alpha waves assoc iated with a slight slowing ( about 0 . 2 5 Hz ) of
the alpha f requency (Rodin et al . , 1970 ; Volavka et al . , 1971 ; Fink ,
1 9 7 6 ) . However , reduced alpha abundance and increased fast f requency
act ivity ( beta ) have also been repor ted (Wik ler and Lloyd , 1945 ;
Jones and S tone , 197 0 ) . Most stud ies which report EEG changes have
noted that tolerance develops with repeated d rug administration . No
s ignif icance with respect to hazard can be infer red from the effec ts

83
o f cannabi s on the wak ing EEG .
l iterature , see Fr ied ( 1977 ) .
FOr a fur ther review of thi s
Per s istent Effects in Wak ing EEG

The occurrence of per s i stent ( long-lasting ) changes in EEG with use
of mar i j uana would cause concern even i f the i r s ignif icance for bra i n
f unct ion was unknown . However , in attempting to investigate the
quest ion of whethe r such changes occur , there inevitably a r i se crucia l
i ssues of subj ect select ion . I f one selects only chronic mar ij uana
use r s who are in good health , one may be eliminat ing systematically
those who have been adver sely affected by use of the d rug and who
might have shown EEG changes . On the other hand , i f one includes i n
such s tud ies mar ij uana users who suffer from var ious i llnesses or
behavioral d i sturbances , one might f ind abnormalities of the EEG tha t
r esult f rom these cond i t ions rather than f rom the mar ij uana .
Long-term use of mar i j uana , e ithe r in the modest doses custom
a r i ly u sed in this country or the heavy doses of hash ish and ganga
used by certain stud ied populat ions abroad , has not been shown to
produce changes in the EEG . No abnormalities were found in the EEG
of 1 0 healthy students who had smoked ma r i j uana regular ly for 1 yea r
( Rodin et a l . , 1 9 7 0 ) . Anothe r study compared clinical EEG records of
4 6 hash ish users and 4 0 matched controls in Greece ( Fink , 1976 ) .
Each record was evaluated independently by four qualif ied neurolog ist
electroencephalographer s . No d i f ferences we re observed in the
i nc idence of abnormal records in the users and controls , a result
consi stent with the absence of s ignif icant d i fferences between the
two g roups i n var ious tests of neurolog ical function .
Essent ially , the same negative results were obtained in stud ie s
o f ganga u sers i n Jamaica ( Rubin and Comi tas , 1 9 7 5 ) and mar ij uana
users in Costa Rica (Karacan et al . , 1 9 7 6 ) . In these late r stud ie s
subj ects were carefully selected to include only those in good health
who were func t ioning adequately i n the commu ni ty . As ment ioned above ,
t his method of select ion runs the r isk of eliminat ing subj ects whose
health or behavior were adver sely affected by mar i j uana and who might
have shown EEG changes . Th i s methodolog ical d iff iculty cannot be
eliminated in any small sample investigat ion of mar i j uana user s .
Acute Effects i n Event-Related Potent ials

One can employ computer averag ing to retr ieve from the EEG cer ta i n
i nformat ion that i s not detectable by vi sual inspection . In this
way , the electr ical events that follow a st imu lus may be stud ied in
subj ects who are at rest , asleep , or car ry ing out certain tasks .
These computer -averag ed potent ials provide clues to the sequent i a l
processing of informat ion by the brain .
Althoug h the literature i s incons i stent , i t i s clear that cannabi s
c an produce effects on event-related potent ials ( EPa ) ( Berning et
al . , 1979 ) . Effects on ampli tude are more often reported than effect s

84
on latency o f the event-related waves . Seve ral studies with

i nconsistent results have appeared J these inconsistenc ies result from
d i f fe rence s in task , dose , or durat ion of administrat ion . Thus , EPa
i n response to sensory stimul i are unaffected or even increased by
cannabi s i f the subj ect i s passive , but are decreased in ampl itude i f
t he subj ect i s performing a task . One study found the f i rst negat ive
wave , a component of the aud i tory EP , was reduced at a dose of 1 8 0 - 210
mg per day , but not at a dose of 70-90 mg per day dur ing acute ( 1 to
3 day s ) administration (Berning et al . , 1 9 7 9 ) . After 2 week s at the
h ig he r dosage , this effect was observed only for the more d i f f icult
tasks . Th i s study demonstrates d i f ference s in ma r i j uana effects on
EPa accord ing to dose , durat ion of admini strat ion , and task
complex ity .
Acute Effects in S leep EEG

Drug s often produce marked effects on the EEG dur ing sleep , bu t
Th i s i s the case
p roduc ing l ittle or no change in the wak ing EEG
with ma r i j uana and 6-9-THC .
In relat ively h ig h doses ( 70-210 mg/day ) , 6-9-THC and mar i j uana
extrac t produced ma r ked effects on sleep EEG ( Fe inberg et al . , 19 7 5 ,
1 97 6 ) . On initial administrat ion , the t ime spent i n REM sleep*
( stage REM durat ion) was reduced be low base line levels (placebo) by
1 8 percent and the number of eye movements by 49 percent . Some
tolerance ( return toward base line levels ) was apparent du r ing the
per iod ( 12-16 days) of drug administrat ion . On withdrawal , REM
durat ion was increased above basel ine by 4 9 percent and rapid eye
movements were increased by 67 percent . Whi le these effects are
qu ite large , the i r clinical s ignif icance is unknown . They were not
accompanied by such unusual behavioral changes as ha l luc inat ions or
d i sor ientat ion , although there wa s evidence of withdrawal-
i r r itab i l i ty , inc reased reflexes , and mild ag itat ion . With much
smaller doses of 6-9-THC , e ithe r a small reduction i n REM sleep
( Pivik et al . , 1 9 7 2 J Freemon , 1 9 7 4 ) or no change has been repor ted
(Bar ratt et al . , 19 7 4 J Bosko et al . , 1 9 7 3 J Prani koff et al . , 197 3 ) .
.
Pe r s i s tent Effects i n S leep EEG

We are not aware of any investigat ion of sleep in abstinent long-te r m
mar i j uana users . However , 3 2 male chronic mar ij uana users a nd matched
controls were studied in Costa Rica (Karacan et al . , 1 9 7 6 ) . The
u sers habitually smoked 2 . 5 to 2 3 . 3 c igarettes per day (mean 9 . 2 )
and had used the drug for 1 0 to 2 7 year s J they cont inued the i r usual
i ntake during the study ( Costa R ican c iga rettes conta in about 200 mg
* A stage in sleep dur ing which Rapid Eye Movements may be detected
and vivid dreaming u sually occur s .

85
o f ma r i j uana) . Th e subj ects selected for t h i s study had norma l
med ical , neurolog ic , and laboratory evaluat ions .
S leep waa recorded for 8 consecutive nights . Pr ior to eac h
n ight ' s record ing , the uaera desc r i bed the i r mar i j uana i ntake dur i ng
the previou s 2 4 hour s . Thi s intake waa not d i rectly monitored or
controlled by the expe r imenters , because the goal was to observe
sleep patterns under naturalistic cond it ions . The subj ects wer e
forbidden to u ae mar ij uana dur ing the 2-3 hour s pr ior to sleep
recording .
( FOr fur the r details of th i s extens ive study , aee Karaca n
e t a l . , 197 6 . )
All of the major var iables der ived f rom visual sleep stage
clas s i f icat ion were examined . The only stat istically s ign i f ican t
d ifferences between mar ij uana u sers and the i r matched controls were
i n one of the s leep latency measures and in REM percentage of total
s leep and average REM pe r iod leng th . The d i fferences were qu ite
smal l and may have been due to the subj ect s exper ienc i ng early
w ithdrawal at the t ime the i r sleep waa recorded . Th i s ia a l i kely
explanat ion for these find i ng s accord ing to stud ies desc r i bed
p reviously ( Feinberg et al . , 19 7 5 , 1 976 ) .
The Costa Rican study concluded there waa a lac k of evidence o f
major d isturbances o f EBG sleep patterns i n user subj ects stud ied in
s itu (Karacan et al . , 1 9 7 6 ) . Thus , long-term mar i j uana u se has no
been demonstrated to cause mar ked and cons istent abnormalit ies of
sleep BEG that can be demonstrated in stud ies with small samples .
E lectrophys iolog ical Stud ies in Animals

Sleep Stud ies
The f ind ings of several animal stud ies car r ied out to investigate the
effects of ma r i j uana on EEG d i f fer in some respects to those in human
be ing s . Spec ies d ifferences are thought to be responsible for some
of the var iat ions found f rom spec ies to spec ies . FOr example , 5 and
1 0 mg/kg 6 - 9-THC administered acutely to rata suppressed REM ,
reduced slow-wave sleep , and increased wakefulness (Moreton a nd
Davi s , 1 9 7 3 ) . Chronic admini strat ion caused an init ial suppression
of REM , which returned to baseline after 4 days and remained at
basel ine levels for a further 1 6 days .
I n contrast to the human
s tud ies , there was no withdrawal increase in REM above baseline
dur ing a 10-day withdrawa l pe r iod . S imilar result s we re obtained i n
a abor t-term study that employed intravenous doaea o f 6 - 9-THC ( 0 . 5
and 1 . 0 mg/kg ) to rabbits ( Fuj u imor i and Bich , 19 7 3 ) .
Apprec iable qual i tat ive d i fference s in sleep EEG response to
6- 9-TRC have also been detected in pr imates when compa red with
human stud ies . When 1 . 2 mg/kg 6- 9-THC i a admini stered to squi rrel
monkeys i n a s i ng le oral dose , da i ly for 6 0 days , no s ig n i f icant
e f fects on REM sleep durat ion occu r red r i nstead , a dec rease in EEG
stages 3 and 4 was noted ( Adams and Bar ratt , 1 9 7 5 ) .

86
EEG Stud ies i n Subcortical Structures

E lec trode implantat ion i s rarely possible in man , but i s a rout ine
and essent ial technique for the study of brain e lectrophys iology in
animals . Animal exper iments also permit use of h ig he r doses and more
prolonged administrat ion than is possible with human subj ects . FOr
these reasons , animal exper iments can yield impor tant data that
cannot be obtained in human stud ies .
In general , EEG record ing s
a fter short-term admini strat ion o f mar i j uana are s imi lar from sur face
(cor tex ) or from deep brain ( subcor tex ) reg ions . However , after
c hron ic administration of h ig h doses of - 9-THC , abnormal record ing s
have been observed in subcor t ical r eg ions o f some animals , read ing s
not seen i n the cor tex . Althoug h these f i nd ing s have not been
r epl icated , they are of par t icular concern , beCause they r a i se the
poss ibi lity that chron ic exposure to h ig h doses of mar i j uana produce s
long-lasting effec ts on brain phys iology .
Afte r intravenous admin i strat ion of a range of - 9-THC dose s
( f rom 0 . 0 5 to 1 2 . 8 mg/kg ) to r hesus monkeys , a general increase in
EEG synchrony was observed J and at hig her dose ranges , there wer e
spec i f ic EEG changes i n the l imbic system , f rontal cor tex , thalamus
and fast ig ial nuc le i (Martine z et al . , 197 2 ) . I n thi s study , the
i nc rease in h ig h-voltage activity showed a good dose-response
relat ionship .
In a second study , oral dos ing of three rhesus monkey s
w ith a c rude mar i j uana extract containing 2 5 percent - 9 -THC
produced dose-related EEG changes , includ ing slow waves in the
h ippocampu s , amygdala , and septum ( S tadnick i et al . , 197 4 ) .
Tole rance to the behavioral and EEG changes occurred with daily
treatment , which was stopped after 51 days . Behavioral withdrawa l
e ffects were noted , but EEG changes dur ing wi thd rawal we re min imal
and there was no evidence of EEG changes pe r s ist ing beyond the pe r iod
of -9-THC ingestion .
Two stud ies that monitoed EEG record ing f rom deep brain s i tes
afte r chronic administrat ion of h ig h dose s of ma r i j uana found change s
i n EEGs f rom deep brain s i tes that were not observed in sur face areas
after drug withdrawa l ( Feh r e t a l . , 1976 J Heath , 1976 J Heath et al . ,
1 97 9 ) .
Stud ies of two rats w i th electrodes implanted in the anter ior
neocor tex , dorsal h ippocampus , and mesencephal ic ret icular format ion
1 year after exposu re to 20 mg/kg for 6 months ( Fehr et al . , 1 9 7 6 )
yielded h ippocampa l record ing s w i t h epi lept iform abnormalities , i n
contrast t o one control and t wo alcohol-t reated an imals .
The second study was carr ied out on thi r teen feral-ra i sed rhesu s
monkeys ( Heath 1976 7 Heath et a l . , 1 9 7 9 ) . Ten monkeys had electrodes
implanted in deep s i tes and i n brain cor tex . Fou r monkeys were made
to smoke mar ij uana three t imes a day , 5 days per week for 6 months 7
two othe r monkeys with implants were g iven 0 . 6 mg/kg 6-9-THC each
day , 5 days per week for 6 months 7 s t i ll other monkeys were used as
controls or rece ived smaller doses of ma r i j uana . In three h igh-dose
monkeys , two smok ing and one ingest ing - 9-THC , changes in EEG
could be detected in record ings from deep brain s i tes , the changes
continued 7 months after cessat ion of ma r i j uana exposure . No EEG
a bnorma l i t ies were present in record ings f rom the bra in sur face .

87
One of the major c r itic i sms of both these stud ies i s the i r u se of
small numbers of animals . Fu r the rmore , there have been no attempts
a t repl icat ion by other workers . Never theless , because these
finding s provide some of the only ev idence for a poss ible
i r reve r s ible effect of chron ic h igh dose s of mar i j uana , they are
ment ioned here with a st rong urg ing for add it ional stud ies in an
e ffort to repl icate these f ind ing s .
EPILEPSY
Because of the e f fects of mar i j uana on brain e lectr ical act ivity ,
quest ions have been raised about its assoc iation with ep i lepsy . Two
quest ions are raised in the l i terature . First , does mar ij uana
produce se i zures? Second , doe s ma r i j uana or a der ivat ive prevent
sei zures? The f i rst quest ion will be d i scussed here . The second i s
reviewed in Chapter 7 , wh ich i s concerned with the potent ial
t herapeut ic u ses of cannabis .
There are anecdotal reports in the l i terature that suggest
se i zures may be induced by ma r i j uana in some pe r sons with a known
s e i zu re d i sorder . A r igorous study , using adequate numbers of
pat ients with documented se i zure patterns , has not been done .
Reports of exper imental animal stud ies a re conflict ing and var ied
( Feeney et al . , 1 97 3 , 1979 7 Lemberger , 1 9 8 0 ) . There are some
c i rcumstances i n which cannabi s admini strat ion does not alter certain
type s of se i zures such as the photosens i t ive se i zures in the baboo n
( Meldrum et al . , 1974 ) , and others in which it seems that se i zures
are induced . A sing le rabbit that responded to 6-9-THC administrat ion with sei zures was bred to establ i sh a colony of rabbits with
s imi lar response (Consroe and Fish , 1981) . I t will be of consider
able i nte rest to determine mechani sms of se i zure induct ion and
pharmacolog ic response patterns in thi s unusual animal model .
However , as descr ibed furthe r in Chapter 7 , the bulk of the animal
l i terature and some data from human stud ies suggest that the mor e
p rominent effect of mar i j uana der ivat ives , espec ially cannabinol and
cannabid iol , i s to decrease rather than i nc rease se i zure suscept i
b i l i ty ( see Karler and Turkanis , 1981 , for review) .
NEUROCHEMISTRY
Our knowledge of the effects of mar i j uana on brain chemistry has come
largely f rom stud ies in animals . cannabi s and some of its
d erivat ives have been shown to cause chemical effects in the brain ,
as demonstrated by effects on neu rotransmitters and on nuc leic
acids . The evidence i s reviewed below .
Neurotransmitter s
The bra in i s composed of many informat ion-processing networks of
nerve cells . Within each of these networks the transfer of informa -

88
tion from one nerve cell to anothe r i s dependent upon chemical s

c alled neurotransmi tters .
These substances are produced by nerve
ce lls , released when the cell s are st imulated and ac t to alte r the
Neurot ransmitters play an
exc itab i l i ty of ne ighbor ing nerve cells .
essent ial role in the transm i s s ion and processing of informat ion , and
i t is not surpr i s ing that many d rug s that alter behavior do so by
the i r act ions on neurotransmitte r s .
The unde r stand ing of the ef fect s
o f mar i j uana on the brain must inc lude knowledge of its effects on
neurotransmitter systems .
Seve ral d i fferent c lasse s of chemicals act as neu rotransmi tters .
The f i r st chemica l to be demonstrated to have thi s function was
acetylchol ine , and it i s now e stabl i shed that acety lcholine is the
A
neurotransmitte r for several nerve cel l network s in the brain .
n umbe r of stud ies in animals have examined the effect of mar i j uana on
brain acetylchol ine ( see Dom i no , 1 9 8 1 , for a brief review of the
extensive li terature) .
The most c lear-cut effects have been on
acetylchol ine turnover , a measure of the leve l of activity of neu ron s
p roduc ing the chemical .
Smal l doses of 6 -9-THC cause a reduct ion
in acetylcholine turnover in the hippocampus (Domino et al . , 1 9 7 8 r
Revue lta et al . , 1 9 7 8 r Domino , 1 9 8 1 ) and thi s results from reduced
act ivity of the acetylcholine neurons .
It is noteworthy that the
effect i s produced by small dose s and only by cannabinoids .
Administration of physostigmine , a drug that enhances acetylcholine
action by part ially bloc k i ng its breakdown , to f ive healthy human
volunteer s ( 2 hours a fter ingestion of 20 to 40 mg of 6 -9-THC )
produced enhancement of the lethargy and somnolence occu r r ing late in
the cou r se of the 6-9-TRC intox icat ion ( Freemon et al . , 1 9 7 5 ) .
The
results of thi s study , and othe r s in man and animals ( El-Yousef et
al . , 1 9 7 3 r Low et al . , 1 9 7 3 r Drew and Mi ller , 1 9 7 4 J Freemon et al . ,
1 9 7 5 ) , have led to the conc lus ion that 6 -9-THC acts to inhibit
acetylcholine nerve cell network s .
The exact nature of thi s act ion
is not known , but it may be related to the memory deficits produced
( Domino , 1 9 8 1 ) .
There have been stud ies of cannabinoids on several other
neu rotransmitter s in brain , inc lud ing catecholamines , se rotonin , and
g amma aminobutyr ic ac id ( Bane r j ee et a l . , 1 9 7 5 r Braes et a l . , 1 9 7 5 ) .
Althoug h some ef fects have been repor ted , they e i the r are produced by
a very h igh dose or are so f r agmentary that the i r implicat ions are
unclear .
The effects of cannabinoid s on neurotransmi tter s that have
been stud ied to date , othe r than acetylcholine , are not str i k ing .
In
part icular , there is no ev idence for any sign i f icant , long-term tox ic
e f fect of cannabinoids on any of the nerve cell networks that produce
iden t i f ied neurotransmitter s .
Prote ins , Enzymes , Nuc le ic Ac id s

A very few stud ies have examined the ef fects of mar i j uana o n
neurochemical var i abless other than neurotransmitters ( Luthra and
Rosenkrantz , 1 9 7 4 r Luthra et al . , 1 9 7 5 , 1 9 7 6 ) .
Afte r chronic
adm ini strat ion to rats e ither of 6 -9-THC or mar ij uana smoke ( for

89
pe r iod s from 2 8 to 180 days) , these invest igator s examined brai n
l ipid , prote in , and r ibonuc le ic ac id (RNA) content . With very high
dose s of 6-9-THC ( up to 500 mg/kg/day ) , some decrease in brain
protein and RNA was noted r no decrease was noted in l ipid content .
However , with smaller doses , or administrat ion of ma r i j uana smoke , no
cons istent or marked changes were noted .
The s ignif icance of these
ef fects is unknown .
Whethe r add it iona l effects might be obse rved
with more sophi st icated and sens itive methods d i rected to more
restr icted analyt ical problems cannot be answe r ed at present .
SUMMARY
The re i s no pe r suasive evidence that ma r i j uana causes morpholog ica l
c hanges i n the brain .
Computer tomog raphy stud ies on users of
ma r i j uana reveal no g ross changes in brain structure .
Electron
m icrog raphic stud ies of monkey bra ins ind icat ing morpholog ic changes
are methodolog ically flawed and cannot be u sed as ev idence for an
e ffect of mar ij uana on brain cell morphology .
Clear effects on brain
electr ica l act ivity in human beings and in animals have been found
a f ter drug exposure .
These effects have not been demonstrated to
pe r s ist in human be i ng s after the drug ha s been d i scont inued .
S tud ies of EEG from deep bra in structures in chronically treated
an imals have shown changes after the withdraw! of the drug .
Thes e
Stud ies in
l imited f ind ings need t o be con f irmed by further stud ies .
human be i ng s and an imal s ind icate that , despite the neurophys iolog ic
e ffects demonstrated in EEG stud ies , mar i j uana does not appear to
increase epi lept ic se i zure suscept ibi l i ty .
Cur rent ev idence ha s
shown mar i j uana causes some chemical changes in brain .
Cannabinoids
af fec t seve ral neurot ransmitte r systems , especially the cholinerg ic
system .
At h igh doses mar ij uana also has been shown to affect
nucleoprote in synthesis .
The s ignif icance of these f i nd i ng s for
brain funct ion as demonstrated by human behavior or the i r clinical
re levance is unknown .

In view of the widespread use of cannabi s , it would be worthwh ile to
carry out fur ther and more systema t ic stud ies of the e ffects of
cannabi s on brain structure , chemi stry , and elec trophys iology .
Suc h
stud ies should be closely cor related with behavior , e . g . , learn ing ,
One u sefu l approach might
psychomotor coordinat ion ( see Chapter 6 ) .
be to investigate the effects of med ium and h ig h doses of cannabis
(defined i n terms of the patterns of human consumpt ion) on j uven ile
and adult monkeys dur ing and after long-term exposure .
Juven i le
monkeys should be included because the immature nervous system may be
more sens it ive to harmful drug effects r this issue is of g reat
clin ical conce rn , because ma r i j uana use by human being s now beg in s
quite early i n l i fe ( see Chapter 2 ) .
Obse rvat ions also should be
made dur ing long-term abstinence after pr evious long-term exposu re to

90
dete rmine whether any per s i stent abnorma l i ties have been produced .
systematic approach to these que st ions u s i ng modern methods of
measu rement and analy s i s cou ld extend ou r present knowledg e
substant ially .
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( eds . ) Ma r i huana : Biolog ical Ef fects . Analys i s , Metabol i sm ,
Cellular Responses , Reproduct ion and Bra i n . OXford : Pergamon
Press , 1979 .
Heath , R . G . , Fitzjarrel l , A . T . , Fontana , C . J . , and Garey , R . E .
cannabi s sat iva : Effects on brain funct ion and ultrastructure i n
Rhesus monkeys . B iol . Psychiatry 15 : 6 57-690 , 1980 .
Berning , R . I . , Jones , R . T . , and Pe ltzman , D . J . Changes in huma n
event related potent ials with prolonged
delta-9-tetrahydrocannabinol ( TBC ) use . Electroencephalogr .
C l i n . Neurophysiol . 4 7 : 556-570 , 1979 .
Bosko , M . J . , Kochar , M . S . , and Wang , R . I . H . Effects of orally
admini stered delta-9-tetrahydrocannabiol in man . Clin .
Pharmacol . Tber . 1 4 : 3 4 4 -3 5 2 , 1973 .
Jones , R . T . and S tone , G . C . Psycholog ical stud ies of mar i j uana and
alcohol in man . Psychopharmacologia 18 : 1 0 8-11 7 , 1970 .
K a racan , I . , Fernandez-Salas , A . , Cogg ins , W . J . , et al . S leep
electroencephalog raph ic-e lectroocu log raph ic characteristics o f

92
chron ic ma r i j uana users : Pa rt I . Ann . N . Y . Acad . Sc i .
2 82 : 348-374 , 1976 .
K ar ler , R . and Turkanis , S . A . The cannab inoids as potent ial
antiepi lept ic s . J . Clin . Pha rmacol . 2l ( Suppl . ) : 4 3 7 5-4485 , 1981 .
K uehnle , J . , Mendelson , J . H . , Davi s , K . R . , and New, P . F . J . Computed
tomog raphic examinat ion of heavy ma r i j uana smokers . JAMA
2 3 7 : 1 2 3 1-12 3 2 , 1977 .
Lemberger , L . Potential the rapeut ic usefulness of mar i j uana . Ann .
Rev . Pharmacol . Tox icol . 20 : 151-17 2 , 19 8 0 .
Low , M . D . , K lonoff , H . , and Marcus , A . The neurophys iolog ical basis
of the ma r i j uana exper ience . Can . Med . Assoc . J. 108 : 157-1 64 ,
1973 .
Luthra , Y . K . and Rosenkrantz , H . Cannabinoids : Neurochemical
aspects afte r oral chron ic administration to rats . Toxicol .
Appl . Pharmacol . 2 7 : 158-1 6 8 , 197 4 .
Luthra , Y . K . , Rosenkrantz , H . , Heyman , I . A. , and Braude , M . c .
Different ial neurochemistry and temporal pattern in rats treated
orally with 6-9-tetrahydrocannabinol for pe r iods up to s ix
months . Tox icol . App l . Pharmacol . 3 2 : 418-4 3 1 , 19 7 5 .
Luthra , Y . K . , Rosenk rantz , H . , and Braude , M . C . Cerebral and
cerebellar neurochemical changes and behavioral man ifestat ions in
rats chronically exposed to mar i j uana smoke . Tox icol . ApPl .
Pharmacol . 3 5 : 455-4 6 5 , 1976 .
Ma r t inez , J . L . , Stadnicki , s . w. , and Schaeppi , U . N . Delta-9 tetrahydrocannabinol : Effects on EBG and behavior of Rhesus
monkeys . Life Sc i . 11 : 643-6 5 1 , 197 2 .
Meldrum , B . s . , Far iello , R . G . , Pu i l , E . A . , et al . Delta-9tetrahyd rocannabinol and epi lepsy in the photosensit ive baboon ,
Papio papio . Epileps ia 15 : 2 5 5-264 , 1974 .
Moreton , J . E . and Davi s , W . M . Electroencephalog raph ic study of th e
effects of tetrahydrocannabinol& on sleep in the rat .
NeuropharmacologY 12 : 897-90 7 , 1973 .
Myer s , W . A . and Heath , R . G . Cannab is sat iva : Ultrastructural
changes in organelles of neurons in brain septa l reg ion of
monkeys . J. Neurosc i . Res . 4 : 9-1 7 , 1979 .
Pivik , R . T . , Zarcone , v. , Dement , w . c . , and Hollister , L . E .
Delta-9-tetrahydrocannabinol and synhexl : Effects on human sleep
pattern s . Clin . Pharmacol . Ther . 13 : 426-435 , 19 7 2 .
P ran ikoff , K . , K aracan , I . , Larson , E . A . , et al . Effects of
ma r i j uana smok ing on the sleep EEG : Preliminary studies .
J . Fla . Med . Assoc . 60 : 28-31 , 1973 .
Revuelta , A . v . , Moroni , F . , Cheney , D . L . , and Costa , E . Effect o f
cannabinoids on the turnove r rate o f acetylchol ine i n rat
hippocampus , str iatum , and cortex . Arch . Pha rmacol . 304 : 107-110 ,
1978 .
Rod in , E . A. , Domino , E . F . , and Por zak , J . P . The mar ihuana-induced
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Rubin , v. and Com ita s , L . Ganj a in Jama ica : A Med ica l
Anthropolog ical Study of Chron ic Mar ij uana Use . The Hague :
Mouton and Co . , 19 7 5 .

93
Rumbaugh , C . L. , Fang , B . c . B . , Wilson , G . B . , et al .
Cerebral C T
Clinical and exper imental observat ions .
f ind ings i n drug abuse a
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S ipe , J . C . and Moo re , R . Y .
The late ral hypothalamic area a
An
ultrastructural analys i s .
Cell Tiss . Res . 179 a l 7 7-196 , 1977 .
Stadnic k i , s . w. , Schaeppi , u . , Rosenk rant z , B . , and Braude , M . C .
Crude mar ihuana extract :
BEG and behavior al effects of chron ic
Psychopharmacolog ia
oral administrat ion in rhesus monkey s .
3 7 : 2 2 5-23 3 , 1974 .
Volavka , J . , Dornbush , R . , Feldste in , s . , et al .
Mar i j uana , BEG and
behavior .
Ann . N . Y . Acad . Sc i . 191 : 206-215 , 197 1 .
W ikler , A . and Lloyd , B .
Effect o f smok ing mar i j uana c iga rettes on
cort ical electr ical activity .
Fed . Proc . 4 : 1 41 , 1945 .

EFFECTS OF MARIJUANA ON
OTHER BIOLOGICAL SYSTEM S
Th i s c hapte r cove r s what l i t t le is known about the e f fects o f

cannabis o n male and female reproduct ion and endoc r i ne systems ,
d e fect s and teratogen ic effects , genet ics ,
birth
the immune system , and
body tempe rature .
MALE REPRODUCTIVE FUNCTION

A var i ety of stud i e s
ind icate that mar i j uana and some of it s

d e r ivat ives have reve r s ible , suppr e s s i ve e f fects upon test icular
func t ion in an imals and men .
The se have been measured in terms o f
d imini shed we ights o f the prostate g land ,
semina l ve s icle s , or
testes , and in dec reased leve l s of te stoste rone
( the male hormone )
in
b lood plasma or suppress ion o f spe rmatog ene s i s following chronic o r

acute adm i n i st r at ion o f cannab i s o r -9-THC .
App ropr i ate obse rva
t ion s have i nd icated that the e f fect s of cannabinoids on the ma le
reproduct ive t r act and on test icu lar funct ion were completely
r eve rsed 1 month a fter d r ug withd rawal .
Ther e i s no gene r a l ag r eement as to the cause or magnitude o f
t hese e f fects .
The maj or reasons for this lac k o f ag r eement re late
to major d i f fe rences in study des ign ,

monkey , or rodent ) ,
inc lud ing spec i e s stud ied
(man ,
route of drug admini strat ion , and pu r ity of the
drug u sed .
Human Stud i e s
In 1974 ,
a g roup o f 2 0 m e n were Stud ied who had u sed ma r i j uana a t
least 4 days a wee k for a min imum of 6 months wi thout the use of
othe r drug s
(Kolodny et a l . ,
1 97 4 ) .
Plasma testoste rone levels i n
s ubj ec ts smok ing f ive t o n ine mar i j uana c igare ttes per week we re
s ig n i f icantly lowe r than cont rols
t he norma l r ange ,
i.e. ,
( howeve r , only 2 had leve l s out o f
below 4 0 0 ng/d l ) J
all but 1 of the men
smok ing more than 10 mar i j uana c igarettes pe r wee k had te stoste ron e
levels be low 4 0 0 ng/d l .
The se results suggest that there was a

Plasma
dose-dependent e f fect of mar i j uana on testoste rone levels .

levels of luten i z ing hormone
( LH ) and fol l ic le-s t imulat ing hormone

94

95
( FSH ) , gonadotrop ins that cont rol the g rowth of the ovar ies or testes
and the i r hormonal act ivit ies , were in the normal range ; howeve r , in
men smok ing more than 1 0 mar ij uana c igarettes per wee k , the FSH leve l
was s ign i f icantly lowe r than for those who smoked 5 to 10 mar i j uana
c igarettes per week . Because only random samples of blood were
obta ined for gonadotropic measurements , small but s ig ni f ican t change s
could have been missed . Levels of prolact in , the female hormone
involved in lactat ion and also present in small quant itie s in men ,
were all in the low normal range .
In add i t ion , the men who smoked
more than 10 mar ij uana c ig a rettes per wee k had s ignif icantly lowe r
sperm counts than those who smoked the lesser quant ity ( 26 ver sus 6 8
mill ion/ml ) . These individuals obtained mar i j uana from a var iety of
sources , and there was no way to determine whethe r they were tak ing
othe r drug s that could lowe r plasma te stosterone .
Later in 1974 , another study reported that plasma testosterone
levels were not suppressed in 27 men stud ied in a research ward
( Mendelson et a l . , 1974 ) These ind ividuals smoked mar i j uana
c igarette s suppl ied by the federal government . For unexplained
r easons , the mean testosterone levels in these individuals were
greater than 1 , 0 0 0 ng/dl ( h ighe r than the normal mean ) before and
dur ing the smok ing pe r iods . Thi s is in marked contrast to the mean
value of 7 4 2 ng/dl for nonsmoker s in the study of Kolodny et al .
ment ioned above . The re was no report of gonadotropic values or semen
analysis in the Mende lson Study .
A study of 1 6 pat ients on a metabolic ward who smoked NIDA
cigarette s ( Hembree et al . , 1979 ) showed that 5 to 6 week s o f
h igh-dose ( 2 percent ) mar i j uana administ rat ion ( 8-20 c igarettes/day)
wa s assoc iated with a decline in sperm count dur ing the f i fth ad
s ixth week s a fte r init iation of drug exposure . Thi s was preceded by
a decrease in sperm mot i l ity and an increase in abnormal forms of
sperm . Once a week dur ing the study f ive blood samples were obtained
at 1 5-minute inte vals for measurement of testosterone , LH , and PSH .
No change in these hormone levels was noted throughout the s tudy
( althoug h no values were reported ) . The relationship in t ime of
.
these samples to the last previous c igarette was not ment ioned ,
therefore the test would not have excluded a trans ient decline i n
hormonal leve ls after each c igarette . However , because hormonal
suppression of spermatogenesi s takes longer than 4 weeks and usually
i s not assoc iated with an increase in the nber of abnormal forms
and a dec rease in mot ility , the author s concluded that the effec t
upon the seminiferous tubular epithelium was d irect rather than by
suppress ion of gonadotropins . Th i s i s the only reported study in ma n
that measured the hou r-to-hour fluctuat ions in gonadotropic levels .
Anothe r study (Cogg ins et al . , 1976 ) evaluated the health statu s
of 84 mar i j uana smoke rs who had used the agent three or more t imes
per week for a min imum of 10 yea r s . Testosterone levels were
measu red in 38 u sers and 38 nonuse r s . The mean levels and ranges
were virtually ident ical . Thi s hete rogeneous group of men pat ients
s tud ied in Costa Rica was not recruited for the purpose of study ing
the pitu itary-gonadal ax is . No gonadotropic levels or semen sample s
were stud ied .

96
Endoc r ine funct ion stud ies are br iefly mentioned in a pape r by
Cohen ( 1976 ) . Subj ects were recruited on the basis of heavy ma r i j uana
use and were stud ied in a metabolic wa rd . They smoked an average of
f ive mar i j uana c igarettes per day , which was bel ieved to be the
equ ivalent of 103 mg of -9-THC . Dur ing acute admini strat ion , mea n
leve ls of plasma testosterone decl ined f rom 7 54 to 533 ng/dl over a
3-hour per iod . After 9 week s of smok ing , plasma testosterone levels
had decl ined f rom 7 4 0 to 509 ng . Plasma LH levels were reported to
have fallen afte r the fourth week ' however , no absolute values we r e
g iven . In add i t ion , no standard errors a re g iven for any o f the
means presented in this paper . The refore , it is imposs ible to
evaluate the s ignif icance of the repor ted f ind ing s .
In Greece , a populat ion of 4 7 ch ronic hashish users was stud ied .
E lectron microscope stud ies of the acrosome , the head of the spe rm ,
showed abnormality in some pat ient s ( Issidor ide s , 1979) . I t i s
d if f icult t o evaluate the study because no quant itat ive data were
pre sented .
An imal Stud ies

All of the studies mentioned be low are substant ially d i fferent from
t hose of human beings because , with one except ion , the act ive agent
(usually -9-THC ) was admini stered intrape r itoneally at a dose of
2 . 5 to 2 5 mg/kg . Based on calculat ions g iven by Cohen ( 1976) , 3 to 6
mg/kg/day would be cons idered a large dose in human beings . * Also ,
human be ings self-administer the drug ove r many hou r s r ather than as
a s i ng le dose .
In castrated rhesus monkeys , plasma LH and FSB fell acutely
following acute admini strat ion of -9-THC ( Smith et a l . , 1980 ) .
Dur ing this suppress ion per iod , both gonadotropins could be
st imulated by luteni z ing hormone-releas ing factor ( LHRF) , which
c auses the release of LB . The effect o f -9-TRC was t o suppress
prolact in release , which , in turn , could be st imulated by
thyrotropin-releasing hormone ( TRB ) . Studies in othe r spec ies have
tended to confirm these observat ions in monkeys .
The results are compat ibe with the hypothes i s that the ef fec t o f
mar i j uana and its der ivatives is on gonadotropic secret ion ( Ha rcle rode
et al . , 1979) . Test icular cytochrome P-4 5 0 (an enzyme ) dec reased in
the rat following 2 to 9 weeks of treatment . The concentrat ions of
thi s enzyme , plu s a var iety of other testicular markers , were restored
w i th FSB and LB therapy . The effect of var ious cannabinoids has been
stud ied on sperm morphology in the mouse ( Z immerman et al . , 1979) .
* Rosenk rantz ( 1981) considers 0 . 6-3 . 0 mg/kg by inhalation and 1 . 8-9 . 0

mg/kg orally to be large dose s in human be ing s . FOr the monkey ,
1 . 8-9 . 0 mg/kg by inhalat ion and S-2 7 mg/kg orally wou ld be cons idered
(These concentrat ions are equivalent to s ix
a high dose .
c igarettes/day . )

97
Mice were g iven f ive daily intrape r itoneal inj ect ions of -9-THC ,
cannabid iol , or cannabinol at doses approaching or exceed ing the
LD s o ( the dose necessary to kill SO percent of the an imals ) .
Thi rty-five days a fter the last treatment , animals were k i lled and
sperm were evaluated by scann ing e lectron microscopy . Control
animals had 1 . 5 percent abnormal forms . Animals that received LDs o
dose s of the var iou s der ivat ives had 2 . 4 to s . o percent abnormal
forms .
Only a few stud ies have examined the effects of cannabi s on
spermatogenesis ( Huang et al . , 1979) . Mar i j uana wa s administered t o
r ats in a smoke machine . After 30 days of exposure , mar ij uana smoke
lowered the sperm counts in animals s ignif icantly , as d id
c annabinoid-free smoke . By 7 5 days , however , only the mar i j uana
smoke g roup ma intained a low sperm count . In the mar ij uana-treated
g roup , there was an increased number of abnormal forms , par t icular ly
with an increase in d i ssoc iat ion of sperm heads and tails .
In the
d iscussion of this paper , the authors reported elevated serum FSH
levels following ma r i j uana exposu re , but d id not present data . They
concluded that mar i j uana has a d i rect effect on the test is . A
var iety of in vitro stud ies support thi s suggest ion (Jakubov ic e t
a l . , 1977 , 1979 ) .
Mar i j uana and its der ivat ives also have been shown to be
antiand rogenic ( antagonistic to male hormones ) ( Puroh i t et al . ,
1 9 8 0 ) . Several const ituents , includ ing -9-THC , can bind to the
receptor for androgen . Mar ij uana also has been demonstrated to be
estrogenic ( like female sex hormone s ) in vivo , and recent stud ie s
suggest that these effects may be med iated via the est rogen
receptor . These observat ions have been d i sputed by other s ( reviewed
by Purohit et al . , 1980 ) . The abi lity to inh ibit or mimic the act ion
of sex steroid s provide s one mechan ism by which these agents can
produce the i r e ffects . There obviously are many othe r s .
FEMALE REPRODUCTIVE FUNCTION

The e ffect of cannabi s on female reproduct ion has been stud ied in
rats , mice , rabbits , and monkeys . The work in rhesus monkeys is o f
part icular importance , because of the s imilar ity in the menstrual
cycle among pr imate spec ies , includ ing human be ing s .
Human Studies
Ther e i s only one study reported on the effects of ma r ij uana on
r eproductive funct ion in women . The wor k has appeared in print as a
report of the proceedi ng s of a 1978 symposium held in Mex ico C ity
( Bauman et al . , 1979 ) and as par t of the cong ress ional record
subsequent to testimony before a Senate comm i ttee hear ing ( Bauman ,
1 98 0 ) . These publicat ions do not provide details on methodology or
on ind ividual hormone values . Difference s between the control and
exper imental g roups , recogni zed by the invest ig ator s , could be of

98
impor tance , alcohol use , for example , wa s more frequent i n the
mar ij uana-using g roup .
The study attempted to establ i sh the endoc r i ne
( hormonal ) prof i le and menstrual patte rns of women who used mar i j uana
on a chron ic and f requent bas i s .
Twenty-s ix women who used it at
least three t imes a week for 6 months we re compared with 17 women wh o
had never u sed the substance .
The numbe r of cyc les stud ied for each
var iable invest ig ated is not c lear from the publ icat ions .
Th i s
d i ff iculty notwithstand ing , the repor t reveals no d i fference in plasma
levels of LH and FSH between the two g roups and no change in peaks
and basal values of the female hormones estrad iol or progesterone ,
the cr itical hormone levels controll ing the process of ovulat ion .
It
would be expected that no maj or d i fference was found i n the inc idence
of anovu latory cyc les between the two g roups .
By combining anovula
t ion and shor tened luteal phase , however , the authors report a
stat i st ically s ign i f icant d i fference in the mar i j uana-us ing group ,
which could be c lin ically important in caus ing aubfe r t i lity .
Thi s
ev idence i s , at best , only suggest ive .
The obse rvat ion that
testosterone levels in mar i j uana-u s ing women are elevated i s
d i f f icult t o interpret in terms of clinical s ignif icance , apparently ,
t he subj ects d id not report ep isodes of acne , abnormal hai r iness , or
othe r testosterone-dependent a ide-effects .
Accord ing to the authors ,
serum prolactin levels are lower in mar i j uana users than in controls .
The impl icat ions of thi s obser vat ion for fer t i l i ty , lactat ion , or the
d eve lopment of breast cancer a re not c lear .
The abaence . of othe r stud ie s on u ser s of mar i j uana make s i t
d i f f icult to d raw conclus ions on the impl icat ions of the data c ited
above .
Several of the e ffec t s noted are d i fferent from the more
extensive and exper imentally controlled observat ions in rhesus
monkeys and othe r laboratory animals .
This s i tuat ion calla attention
t o the u rgent need for more comprehensive endocr ine and gynecolog ic
investigat ions of women who use mar i j uana .
An imal S tud ies

Administration of c r ude mar i j uana extract to rata or mice resulted
g enerally in suppress ion of ovar ian funct ion and in var ious a spects
of e strogen act ivity , such a s uter ine metabol i sm , ight , g lycogen
content , and levels of RNA and sialic ac id (Chak ravar ty et al . , 197 5 J
Dix i t et a l . , 1 9 7 5 ) .
The admin i strat ion of c rude mar i j uana extract for 30 days to rats
and mice aboli shed the estrus cycle and caused a s ig n i f icant r educt ion
in the s i ze of the ovar ies and in some pr imord ial ova ( D ix i t et al . ,
Intraper itonea l admin i strat ion of -9-THC to rata ,
1975) .
appropr iately t imed , has also been reported to bloc k ovulat ion (Nir
et al . , 1 9 7 3 ) .
Th i s ef fec t of -9-THC was exerted by suppress ing
the cha r ac te r i st ic preovulatory surge of plasma LH .
Other
invest igator s have reported suppress ion also of plasma FSH an d
p rolacin when -9-THC is g iven j ust before ovulat ion (Ayalon et
al. , 1977) .
The substance was found to depress plasma concentrat ion
of LH in ovar iectomi zed rats (Marks , 1 9 7 3 J Tyrey , 1 9 7 8 , 1980 ) and

99
rhesus monkeys (Besch et al . , 197 7 ) . Asch e t al . ( 1 9 7 9 ) also showed
in the rabbit , a reflex ovu lator , that a precoital s ing le dose of
A-9-THC blocks the postco ital LH su rge and ovulation .
Administrat ion of LHRF was able to br ing about the release of LH
in A-9-THC t reated rats and rhesu s monkeys (Smith et al . , 1979) .
These results ind icate a d i rec t effect of cannabinoid s at the leve l
of the hypothalamus , pa rt of bra in important in reproduct ive hormone
r egulat ion . The ovulat ion-block ing effect of the cannabinoids was
furthe r invest igated by Cordova et al . ( 1980 ) . Natu ral and
c hemically mod i f ied cannabinoids blocked ovu lat ion in rats .
Admin i strat ion of A-9-THC to rhesu s monkeys du ring the foll icu
lar phase resulted in prolonged per iods of amennorhea ( absence or
abnormal stoppage of the menstrual f low) , absence of midcycle LH
surge , and progesterone levels character i st ic of anovu lat ion ( Asch et
al . , 1981) .
BIRTH DEFECTS AND TERATOGENIC ITY

Because A-9-THC crosse s the placenta it is a potent ial teratogen ,
an agent that causes defects in the developing embryo . Th i s effect
could occur in e i the r of two ways :
( 1 } exposure to cannabis pr ior to
concept ion could harm the sex cells ( the ova and sperm) , or ( 2 ) the
fetu s could be harmed d i r ectly dur ing organogenesis .
In add it ion ,
A- 9-THC can be secreted in breast milk and , therefore , can be tox ic
postnatally .
Human Stud ies

The evidence for teratogen ic ity in human beings i s ve ry d i ff icult to
interpret . Although there is widespread use of mar ij uana in young
women of reproduct ive age , there i s no evidence yet of any te ratogenic
e ffects of h igh frequency or cons i stent assoc iat ion with the drug .
There are isolated repor ts of congenital anomalies in the offspr ing
of mar i j uana users , but there i s no evidence that they occurred more
often in user s than in nonuse r s and in those cases there was
coinc ident use of other d rug s . Subtle development e ffects in
off spr ing , such as nervous sy stem abnormalities , and reduct ions i n
b i rth weight and he ight may indeed exist ( Finnegan , 1980 ; Fr ied ,
1980 ; Hingson et al . , in press) . Add it ional carefully des igned ,
p rospect ive stud ies should provide valuable informat ion in th i s area .
An imal Studies
C rude mar i j uana extract and A-9-THC are teratogenic at certain
doses in an imals . *
* B ibl iog raphy ava i lable upon request from the Inst itute of Med ic ine ,
Nat ional Academy of Sc iences .

100
One study reported that subcutaneou s inj ect ion of pregnan t
h amste r s and rabbits with var ious dose s of crude mar i j uana extract
caused malformat ions of the brain , spinal cord , forel imb , and l iver ,
a s we ll as edema of the head and spinal reg ion in developing embryos
(Gerber and Schramm , 19 6 9 ) .
In hamsters , s ign i f icant embryocidal and
g rowth retardat ion e ffects also were noted .
It was concluded that
dose s g reate r than 2 0 0 mg/kg in hamste r s and 2 5 0 mg/kg in rabbit s
were teratogenic .
Caut ion in inte rpret ing these f ind ing s must be
exerc i sed because the te ratogenic effects may be caused by any
combinat ion of const i tuents of the cannabis extract .
In a study of mice , the teratolog ical effects of -9-THC we r e
evaluated for doses rang ing f r om 3 . 0 t o 4 0 0 mg/kg by var ious routes
of administration--intravenous , subcutaneous , and intragast r ic
( Jonej a , 1976 ) .
S ig n i f icant fetal g rowth retardat ion was induced at
h ighe r dose levels and by some route s of administ rat ion .
For
example , a h igh dose of 4 0 0 mg/kg was s ig n i f icantly teratogenic by
the intragastr ic route ; 12 . 1 pe rcent of the live fetuses we re
malformed .
I n a study of female monkeys g iven an oral dose of 2 . 4 mg/kg
-9-THC for 1 to 4 yea r s , a nonspec i f ic pattern of reproductive
d i f f icult ies was observed cha r acte r i st ic of high-r isk pregnanc ies ,
includ ing a high r ate of of fspr ing loss dur ing pregnancy or in the
early postnatal per iod ( Sassenrath et al . , 197 9 ) .
GENETIC EFFECTS
The potent ial gene t ic effec ts of mar i j uana a re of maj or concern
because of its prevalent u se by young people in the i r reproductive
years ( see Chapter 2 ) .
Although there i s a g rowing amount of
ev idence that drug s can induce mutat ions , and an improving abi l i ty to
u se tox icolog ical methods to evaluate agents for the i r mutagenic
potent ial ( such as the Ame s test , wh ich detects change s or damages i n
t he genet ic mater ial ) , the ava ilable informat ion on the genet ic
hazard s or even on the potent ial genet ic hazard s of the use of
mar i j uana is extremely l imited .
Mutagenic ity
E lsewhe re in this repor t (Chapter 3) the sc ient i f ic evidence that
mar i j uana smoke and ta r are mutagenic has been d i scussed .
Lung
explants of mice and human f ibroblast cultures exposed to f resh smoke
showed abnorma l i t ie s of ce ll d iv i s ion , as well a s changes in
c hromosome structure and in DNA synthe s i s ( Leuchtenbe rger and
Leuchtenberger , 1971 ; Leuchtenbe rger , et al . , 1 9 7 3a , b) . Moreover ,
extracts and smoke condensates of mar i j uana are mutag enic when
evaluated by the Ame s test (Busch et al . , 1 9 7 9 ; Seid and We i , 1 9 7 9 ;
Wehner et a l . , 1 980 ) .
Animal stud ies on rodents pa inted with
ma r i j uana tar , three t imes weekly for 1 year , resu lted in skin
papilloma s , carc inomas , and f ibrosarcomas (Hoffmann et al . , 19 7 5 ) .

101
However , extensive testing with A-9-THC us ing three established
tests for mutagenesis failed to detect any mutagenic effect , or any
effect as an inhibitor of DNA repa i r (Legator et a l . , 1976 J Glatt et
a l . , 1979 J Z imme rman et a l . , 1978 ) .
Cytogenet ic Effects
The numbers and k inds of chromosomes ( structures in a cell nucleus
that contain and transmit genet ic informat ion car r ied in DNA) are
h ighly characte r i st ic for a g iven species . Structural var iat ion and
changes in numbers of chromosome s may be evidence for genet ic damag e
produced by drug s and other chemical agents . Unfortunately , the
lite rature on the effects of mar i j uana on chromosome s is l imited and
conf l ict ing . Stud ies suggest ing that mar i j uana probably does not
brea k chromosome s are fairly conclusive . The re i s less evidence tha t
mar i j uana may produce aneuploidy ( abnormal numbers of c hromosomes) in
some daughter cells dur ing ce l l division .
Does mar i j uana cause chromosome breaks? The we ight of the
evidence f rom in vitro cultures of human cells and f rom in vivo
animal and human studies is that neither mar i j uana nor A -9-TRC
causes chromosome breaks .
In Vitro and An imal Stud ie s

Cultures of human leukocytes , exposed to d i ffe rent concentrat ions of
A-9-TBC , showed no increase in the inc idence of chromosome breaks
or g aps when compared to controls ( Stenchever and Allen , 1972 ) .
Stud ies of golden hamster s g iven subcutaneous inj ections for 1 0 day s
of mar i j uana extract d isti llate containing 1 7 . 1 percent A -9-TRC
(Nicholson et al . , 1973 ) , and of beag le dog s tra ined to smoke high
doses of mar i j uana ( 3 g/day/week for 3 0 months ) , showed no s ignif ican t
d ifferences in chromosome gaps or breaks when compared with control
groups (Genest et al. , 1976 ) .
Human Stud ies

Cytogenet ic analysis of chromosomes f rom per ipheral blood leukocytes
and cultures of subj ects exposed to mar i j uana smok ing , mar i j uana
extract , or synthetic A-9-TRC revealed no increase in chromosome
breakage attr ibutable to these compounds (Nichols et a l . , 1974 J
Matsuyama , 197 6 J Mor ishima et al . , 1979) . Doses ranged from 20 mg
A- 9-TRC per day to 1 2-16 mar i j uana c igarettes per day . Stud ies
that have reported chromosome breaks or g aps in cell cultures of
use r s of mar i j uana have largely been carr ied out on mu lt iple drug
u ser s , and the breaks and g aps may be due to other factor s assoc iated
with a life of heavy drug use (Gi lmou r et al . , 1971 J Berha and Obe ,
1 9 7 4 ) . However , in a retrospect ive study on college students ,
chromosome break s were found in blood cultures of 4 9 l ight (one o r

102
les s exposure pe r week ) and heavy (more than two exposu res pe r week )
u sers of mar ij uana ( Stenchever et al . , 1974 ) . One problem in this
study i s the poo r dose characteri zat ion . Fur thermore , the increase
i n the numbers of breaks in both l ight and heavy use r s of mar i j uana
was not dose-related , the same frequency of breaks wa s observed i n
both g roups . Although the evidence i s inconclus ive , it suggests that
mar i j uana doe s not cause ch romosome break s .
Doe s mar ij uana interfere with cell d ivis ion and chromosome
seg regat ion , the reby result ing in abnormal numbe r s of chromosomes ?
There i s conflict ing evidence in the l i terature . On the one hand , no
sign i f icant effects of mar i j uana smoke or 6-9-TRC on chromosome
complement have been reported us ing the micronucle i test in mice or
in cytogenet ic stud ies in dog s (Genest et al . , 1976 J Legator et a l . ,
1 97 6 ) . On the other hand , more extensive stud ies have demonstrated
aneuplo idy resulting f rom in vitro exposu re of cells to mar i j uana a s
well as i n vivo studies of animals and human be ing s .
In Vitro and An imal Studies

Exposure of mouse lung and adult human lung t i ssue culture to
mar ij uana smoke in vitro resulted in abnorma l cell prol iferat ion and
abnormalities in DNA content ( Leuchtenberger and Leuchtenbe rger ,
1971 1 Leuchtenberger , et al . , 1 9 7 3b) . Add ition of 6-9-TRC and
olive tol , a compound with a r ing st ructure s imi lar to cannabinoids ,
to norma l human leukocyte cultures induced hypod iploidy (defined a s
metaphase nucle i with a chromosome complement o f less than 30
chromosomes--a normal human cell contains 4 6 chromosomes) (Mor ish ima
e t al . , 1976) . Hybr id mice t reated for 5 consecutive days with
6-9-THC , cannabinol , and cannabid iol at a dose of 10 mg/kg had a
three- to f ive fold increase of micronuc le i over controls . The number
of micronucle i increased with increasing 6-9-TRC dosage . Examina
t ion of bone mar row mitos i s in these same mice showed a f ive- to
sevenfold increase in chromosome number aber rat ions dur ing metaphas e
( Z immerman and Raj , 1980 ) .
Human Studies
S tud ies of lymphocytes cultured f rom human mar i j uana smokers def ined
e ither as moderate use r s ( at least one ma r i j uana c igarette per
week , range 1-10 for a minimum of two years) or heavy users (more
than three t imes per week ) all of whom consumed between 12 . 9 and 15 . 3
mar i j uana c igarettes per day dur ing the exper iment , turned up a
s ignif icantly large r numbe r of cells with les s than 3 0 chromosome s
t han would be found in normal cont rol cultures (Mor ishima et al . ,
1 9 7 9 ) . These posit ive f ind i ng s suggest that mar i j uana may affect
c hromosome seg regat ion dur ing cell d ivis ion and result in cells with
fewe r than the normal numbe r of chromosomes . What these findings
mean in terms of r isk for abnormalit ies in offspr ing or pos sible
disease is not known . Findings in lymphocyte cultures may not be
r elevant to what is happen ing in the germ cells ( sex cells) .

103
TH E IMMUNE SYSTEM
The immune system funct ions in protec t i ng the body ag a i nst v i ruses ,
and othe r i nfect ions
I t also play s a maj or role i n
bacte r ia ,
p revent ing the g rowth and d i ssem inat ion of cancerous cells .
Ther e have been repo r t s that cannabis i s immunogen ic , capable o f
a c t i vat ing components i n the immune system .
These components inc lude
such cells as lymphocytes ,
some of wh ich produce ant i bod ie s i n

r e sponse to i nva s ion by a fore ign ag ent , and mac rophag e & , wh ich can
be st imu la ted by i n f lamma t ion to i ngest i nvader s .
Human S tud ies

Ther e have been repor t s that canna b i s interferes with components in
the immu ne system i n man .
mar i j uana in some people ,
Ant i bod i e s will deve lop i n r e sponse to

a long with an alle rg ic response , wh i le
( Li s ko w
othe r s deve lop ant i bod ie s wi thout appa rent alle rg ic reaction
et al. ,
However ,
1971 ;
Shap i ro et al . ,
1974 ,
1976 ;
Lewi s and S lavin ,
1 97 5 ) .
the stud ies r epor t ing these ef fects we re not des igned t o
d ete rmine which components o f t he mar i j uana a r e immunogenic and wh ich

are a lle rgen ic .
S tud ies of var ious aspec ts of the immune system in pe r sons who
were chron ic u se r s of mar i j uana have ind icated m i ld decrease s i n
act i v i ty of one o r anothe r component o f the system ; howeve r , othe r
invest ig ato r s have noted no changes outs ide of the norma l range
( Gupta et a l . ,
Lau e t al . ,
Pete r sen e t a l . ,
19 7 5 ,
1 9 7 6 ; Wh i te et al . ,
1 9 7 6 ; Rache lefsky et a l . ,
1974 ;
1976 ;
S i lve r ste in and Lessin ,
1 976 ; Cushman and K hu r ana ,
1 9 7 7 ; McDonoug h et al . ,
1980 ) .
19 7 5 ;
These
apparent i ncon s i stenc i e s may stem f rom the va r iab i l i ty in the amoun t
of mar i j uana consumed among use r s
in d i ffe rent stud ies and the
d i f ferences i n the immune system assays .
Hash ish , a s d i st inct f rom
mar i j uana , was shown to have a s l ight temporary st imu latory effect on
the immune system
(Kak laman i et a l . ,
1 9 7 8 ; Ka lofout i s e t a l . ,
1978) .
An imal Studies
A numbe r of s tud ies have shown that -9-THC and other cannabinoids
i nduce immunolog ical defects i n rodents
1976 ;
Lefkow i t z and K lage r ,
Lefkowi t z ,
1978 ) .
per i tone a l ly )
1978 ,
1978 ;
The doses var ied f rom 5 to 25 mg/kg
to 1 0 0 mg/kg
(orally ) .
d iminut ion of immune response ,

assay s .
( Peter sen and Lemberger ,
Le f kow i t z et a l . ,
Preuss an d
( intra
At the h igher doses the re wa s a
as measured by standard immunolog ica l
De lta-9-THC had t h e same effect s o n ce lls g rown i n vitro .
O ther c annabinoids also have been tested for the i r e ffects .

Cannabinol , -8-THC , and 1-methyl-6-8 -THC had the same
immu nosuppress ive e f fec ts as -9-THC , but c annabid iol had no
immunosuppress ive effec t .
Immun i z ing rabb i t s with -9-THC
r e sulted in t he produc t ion o f ant i bod i e s
(Ch i arott i et al . ,
1 98 0 ) .

104
BODY TEMPERATURE
Regulat ion of body temperature i s a complex process that can be
inf luenced by drug s .
In several spec ies of an imals , A-9-THC
produces a lowe r ing of body tempe r ature { hypothermi a ) .
The e ffect i s
seen when animals are housed at normal r oom tempe ratures , and i t i s
g reater with colder ambient temperatures ( Per twee a nd Travendale ,
19 7 9 ) .
Ma r i j uana apparently causes a decrease in heat produc t ion fo r
r easons that are unclear .
I n exper iments with human subj ects , mar ij uana has produced little
or no change in body temperature when g iven in a cool environment
( Beaconsfield et a l . , 197 2 1 Hanna et a l . , 197 6 ) .
In a hot envi ronment
( 40 C ) mar i j uana caused inhibition of sweat ing and a consistent r i se
i n body temperature (Jones et al . , 1980 ) .
Thus , there i s evidence
that ma r i j uana does inte r fere with tempe r ature regulat ion , althoug h
t here i s no currently known c linical s ignif icance to this f ind ing .
Cannabi s appear s to inter fere with temperature regulat ion , bu t
t he clinical s ignif icance is unknown .
SUMMARY
Male Reproduct ive Function
I n animals , mar ij uana and its der ivat ive s can acutely lower
gonadotropic secretion when admini stered intrape r itoneally .
There i s
a lso some evidence i n animals to suggest that these agents can
In man , sperm numbe r and
d irectly affect the semini ferou s tubule .
From the
mot i l i ty are decreased dur ing chronic mar i j uana use .
avai lable stud ies , it appear s thi s was due to a direct effect of the
c annabinoids e ithe r on the semini ferous tubular epithelium or the
Due to conf l icting and incomplete evidence , it i s
epid idymal spe rm .
not possible to conclude at the present t ime whether mar i j uana
smoking has a s ignif icant effect upon gonadotropic and testosterone
concentrat ions in humans . Whether the decrease in spe rm numbe r or
mot i l ity has any effect on fe r t i l ity i s not known .
Female Reproduct ive Func tion

There i s only one study of human be ing s that attempts to establis h
t he endoc r ine prof i le and menstrual patte rns of women who used
By combining catego r ie s
ma r i j uana on a chronic and frequent bas i s .
of anovu lat ion and shortened luteal phase , a stat ist ically
s ignif icant d i f ference was not iced in the ma r i j uana us ing group .
It
i s not known i f this leads to problems with fer t i l i ty or lactat ion ,
or i f it lead s to cance r of the reproduc t ive organs .
Animal stud ies have shown that A -9-THC lower s the serum
gonadot rop ic levels .
It is unknown i f there i s a d irect effect on
the reproduct ive t i ssues , par t icularly unde r prolonged use of
c annabi s products .

105
B i r th Defects and Teratogenc ity
Cannabis is teratogen ic at high doses in animals . The re is no
evidence of obvious teratogenic ity or structural defects in the
offspr ing of human users . But the data are not adequate to reveal a
long-range functional impai rment or a very low leve l of terato
genic ity i f one is present .
It may be imposs ible to ident ify a
distinct role for cannabi s in the product ion of subtle effects in
offspr ing , because of the confound ing inf luences of malnutr ition ,
smok ing , and alcohol .
Genet ic Effects
Mar ij uana and -9-THC do not appear to break chromosomes , althoug h
there i s some conflicting evidence on this point . Mu lt iple drug use
seems to be cor related with an increase in the number s of gaps and
breaks i n the genetic mater ial . Furthermore , mar i j uana may affect
chromosome seg regation dur ing cell d ivision , result ing in abnorma l
numbers of chromosomes in daughter cells . While these conflict ing
results are wor r isome , the i r clinical s ignif icance is not known .
Further i nvestigat ions , espec ially controlled prospect ive stud ies , of
human be ing s are needed .
The Immune System
The data from animal studies suggest that A-9-THC and some of its
analogues have a mild , trans ient , immunosuppressant e ffect in both jn
vitro and in vivo systems , the effects are mild compared with known
immunosuppressant drug s . The stud ies i n human be ings are contrad ic
tory , some demonstrated mild , immunosuppress ive effects , but others ,
u sing the same or s imi lar method s , d id not f ind any d i fferences in
the tmmu ne system between normals and chronic marij uana smokers . At
the present t ime , there have been no human or animal stud ies that
have determined if mar ij uana smokers are more prone to infect ions or
other d i seases . Because of the widespread use of mar i j uana , even
weak immunosuppress ive ef fects are a conce rn . S i nce further researc h
may not demonstrate definit ive f ind ing s , immunolog ic effects should
be studied along with othe r var iables in a larger investigat ion . I f
mar ij uana i s t o be used o n immunosuppressed pat ients ( for example ,
for ant iemetic purpose s dur ing cancer chemotherapy) , even minor
add i t ional suppress ion might be dangerous .

The comm i ttee recomme nds the following types of studies .
Fur the r obse rvations should be made regard ing the relat ion
of mar i j uana u se to r eproductive defects in human be ing s , espec ially

10 6
on young users whose reproduct ive biology is unde rgo ing rapid change .
The pr inc ipa l need i s fo r assessment of endocr ine prof iles and seme n
analysis in male users versus nonuse r s , with adequate cont rol of
confound ing var iable s--for example , d iet , alcohol , othe r d r ug use .
I n women , the princ ipal need i s for more data on endoc r ine and
menstrual patte rns in user s ve r su s nonuse r s , with part icu lar
a ttent ion to the leng th of cycles , the pre sence or absence of
ovulat ion , and the exi stence or absence of subfe r t i l i ty .
More
s tud ies a re needed to detec t subtle , low-f requency , or cumu lat ive
effects on reproduct ive funct ion in long-term , heavy u se r s .
Although routine test ing of teratogenic ity in human be ing s
i s not recommended at this t ime , the col lec t ion of prec ise
epidemiolog ic informat ion on the outcome of human preg nancy i n
mar i j uana use r s is of g reat importance and must be carefully
cont rol led .
The re are no good an imal mode ls for study ing the e f fec ts of
smok ing mar ij uana , but cytogene t ic stud ies in an imals after exposu re
to -9-THC by othe r route s than smok i ng wou ld be of some value .
The most relevant s tud ies s t i l l would be in vivo human stud ies .
Mar ij uana has been found to have mild immunolog ical effect s
in a var iety of test systems , but stud ies of its inf luence on the
body ' s immune defense ag ainst microorgan i sms are lac k ing and need to
be conducted .
C r i tical exper iments are needed to test the hypothe s i s that
6 -9-THC causes d isrupt ion of thermoregulatory e ffector responses
rathe r than an alteration of the leve l of thermoregulat ion .
I nhe r i ted var iat ion in the way some drug s are metaboli zed i s
widely recogn i zed .
Th i s type o f var iat ion must be eva luated i n
respect t o suscept ibil ity t o ma r i j uana .
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110
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"

BEHAVIORAL AND PSYCHOSOC IAL EFFECTS

OF MARIJUANA USE
The mind-alter ing ef fects of ma r i j uana under l ie its widespread and

i ncreasi ng popula r i ty .
Mar i j uana users who expe r ience e ffects on
mood , pe rcept ion , and mot ivat ion repor t that they see k the hig h and
the mellowing-out . However , under some c i rcumstances many of these
same effects can be cons ide red adve r se .
Perceptua l d i stort ions tha t
a re sought by users pose r i sks for d r i ving car s or u s i ng othe r
mach i nes .
There is reason to be concer ned about effects on lea rning
by students using ma r i j uana in school .
Older adults rece iving
6- 9-THC as ther apy may be h ighly intole rant of altered consc iousnes s
Thu s , i t has become a matter of
and perce ived loss of control .
prac t ical as well as sc ient i f ic interest to learn more abou t the
e ffects of mar i j uana on the brain and behavior .
Many psycholog ica l and neuropsycholog ical stud ie s have bee n
c onducted to investig ate spec if ic e f fects of mar i j uana on behavior .
These inc lude stud ie s of intellectual funct ions , such as memory ,
a ttent ion , sequential i nformat ion process ing , and dec is ion-mak ing , a s
The re i s a methodolog
we ll as pe rceptual and psychomotor func t ions .
ical chal lenge in t rying to des ign expe r iments that will d i scr iminate
rel iably among these funct ions and dete rmine preci sely wh ich is be ing
For
a f fected when a d rug produces a part icu lar behavior al outcome .
example , one ' s abi l i ty to process and respond to envi ronmenta l st imul i
r epresents a chain of events .
The sequence beg ins with a sensat ion
or percept ion .
Drug s can inf luence the manne r , speed , and accuracy
w i th which this i nput is rece ived .
The informat ion mu st then be
stored in memory , even i f only ve ry br iefly , and then retr ieved f rom
memory to be integrated with recalled pr ior exper iences and other
sensory i nputs .
The response f rom the subj ect is the result of the
i nteg rat ion of new and old informat ion .
A drug ac t ing at any point
i n this chain of events can alter behavioral per formance .
S tud ies of the e f fects of mar ij uana on complex behav ior must be
carefu lly interpreted , because there are nume rou s var iables that can
i nf luence the results .
First , the re is the drug i t se l f .
The dose ,
type of preparat ion , route of adm i n i strat ion , and speed of administra
t ion must be spec if ied .
Next , the user--h i s per sonal ity , leve l of
innate ab i l i ty , mot ivat ion to pe r form , and espec ially h i s prev iou s
exper ience with mar i j uana , a re power ful influences on test results .
Fina l ly , there i s the type of behavior a l test and the se t t ing in
112

113
whic h i t i s per formed .
S imple r and we ll-pract iced sk i ll s a r e les s
s u scepti ble to d i srupt ion by drug effec ts than are novel or complex
The stud ies in the l i te r ature vary in the i r at tent ion to
task s .
these factor s .
Most of the se stud ies have been car r ied out on male college
students who voluntee r for ma r i j uana research .
Although t h i s
age-g roup ( 1 9-2 5 ) repre sent s a per iod of peak u se of mar i j uana , i t
cannot be assumed t hat f i nd i ng s from a col lege popu lat ion will
The d iffer ing
g ene r a l i ze to other sector s of the you th populat ion .
motives of student voluntee r s ser iously confound the interpretat ion
of results in intellec tual areas , where i t has been e s tabl i shed that
Some
mot ivat ion play s a s ig n i f icant role in dete rmining per formance .
d ed icated users want to do we ll and demonstrate that mar i j uana has no
ha rmfu l effect .
Othe r s are s imply inte rested in obta ining the drug
a nd enjoy i ng its effec ts w i th l i ttle interest in the exper iment .
Add i t ional methodolog ica l i ssues that recur in th i s body of researc h
i nclude :
( a) rel iance on self-repor ts by subj ec ts regarding per sor.al
history of frequency and intens ity of drug use , ( b ) occas ional
r e l i ance on self-repor ts of drug dose and leve l of intox icat ion at
the t ime of the exper iment , ( c ) lac k of standard i zed dosages and
methods of admin i strat ion of -9-THC even when the drug i s
administered by the inve st ig ator , and ( d ) lac k o f attent ion to
mot ive s and be l iefs of use r s and nonuse r s with whom they interact .
A repre sentat ive sample of stud i es will be reviewed he re , and a
summa ry table of 88 repor ts of the re lat ionship between ma r i j uana use
and behavioral and psychosocial funct ion i ng i s ava i lable from the
Inst i tute of Med ic ine by reques t .
PERCEPTUAL AND PSYCHOMOTOR FUNCTIONS

Acute Effec t s
The stud ies repor ted here cove r the range o f commonly used doses*
from ve ry low up to 0 . 2 5 0 mg/kg of -9-THC in ma r i j uana c igarette s
at a s ing le s i tt ing .
The se are acute e ffects--changes that can be
seen after a s i ng le dose .
The effects beg in to be seen at abou t the
same dose level at which a h igh i s perce ived ( 0 . 0 50-0 . 1 50 mg/kg
In othe r word s ,
Generally the effects are dose-related .
6-9-THC ) .
low dose s have small e ffect s , h igher dose s tend to have g reater
effects .
* Dose s are repor ted in m i l l ig r ams per k i log r am (mg/kg ) where provided
by the author s or as total dose s in m i l l ig r ams with the route of
admin i stration .

114
Coord inat ion
Mar ij uana has been found to impa i r motor coord inat ion at dose s
commonly used i n soc ial setting s by both na ive and ch ron ic use r s .
The f unc t ions s tud ied inc lude :
Ma r i huana ,
sway
hand stead ine s s
1 9 4 4 : Clar k et al . ,
( Mayor ' s Comm i ttee on Mar ihuana ,
Evans et a l . ,
e t al . ,
197 3 ) ,
(Mayor ' s Commi ttee on
1 9 7 0 : Mi lste i n et al . ,
197 5 ) ,
and acc u r acy of execut ion movements
1 9 7 3 : M i l s te i n e t a l . ,
body
1 9 4 4 : K ip l i ng e r e t al . ,
1 9 7 5 : K valse th ,
1977) .
1971 :
( Rafae 1 se n
Stud ies have
also s howed a dose-related inc rease in impa irment of postu r a l

s tabi l ity as measu red by inc reased body sway
(K ip l i ng e r e t a l . ,
1971 ) .
React ion Time

React ion t ime i s def i ned as the t ime lag between a s ig nal and the
response a subj ec t make s to that s ignal .
Most stud ie s examine the
t ime t hat i t takes a subj ec t to r e spond to a v i sual or aud itory

s ig nal .
The ef fec t s of ma r i j uana on e i ther speed of i n i t i a l
d e tect ion of the s ignal or speed of response have been incons i stent
at dose s common ly u sed i n soc ial sett i ng s
( low to mode r ate ) .
same subj ects are impa i red at some t ime s ,
but not at othe r t ime s
(Mayor ' s Comm i ttee on Ma r i huana ,
1 9 4 4 : Clar k et al . ,
The
1 9 7 0 1 Dornbus h
1 9 7 1 1 Mo skowitz et a l . , 1 9 7 2 , 1 9 7 4 : Borg et al . , 1 97 5 :
Schaefer et al . , 1 9 7 7 : Pee k e e t a l . , 1 9 7 6 1 S t i llman et al . , 1 9 7 7 ) .
e t al . ,
The mean i ng of th i s i ncon s i stency is unc e r ta in , but

involve s an effect on attent ion mecha n i sms .
i ntox icated with mar i j uana ,
the reac t ion t ime task .
it probably
When a subj ec t i s
he i s probably le s s l i kely to attend to
Per haps it
is when he doe s pay attent ion to
t he task that f unct ion on t h i s te st is not impa i r ed .
Trac k i ng
Trac k i ng
is the term u sed to desc r i be the act of following a moving
st imu lus .
s kills .
I t i s an impor tant component of d r ivi ng and f ly i ng

Trac k i ng behavior is h ig h ly sen s i t ive to the e ff ec t s of
mar i j uana .
Impa i rmen t of t r ac k ing occu r s even at ve ry low dose s
mg by smok ing )
in naive subj ec ts
(We i l et al . ,
1968) .
(4. 5
Stud ies of
The
expe r ienced use r s have a l so demonstrated con s i stent impa i rment .

t rac k ing
impa irment has been found to pe r s ist for 4 to 8 hour s , we ll
beyond the fee l ing of intox icat ion

( Moskow i t z and Sharma ,
( h ig h )
by one labor atory
1 9 7 9 : Moskowitz et al . ,
1981) .
No othe r
stud ie s have measured the e f f ec t s of ma r i j uana beyond 2 hou r s .
Th i s
f ind ing on t he long-la st ing e f fec ts has ve ry impor tant impl icat ion s ,
as w i l l be d i scussed late r when the e f f ec t s of mar i j uana on d r iving
a re reviewed ,
and ,
the refore ,
such s tud ies shou ld be r epeated by
othe r invest igator s .

Wh i le react ion t ime stud ies
results ,
t r ack ing behavior
( as noted above )
showed i ncon s i stent
is regu lar ly and s ig n i f icant ly d imini shed
by mar ij uana at dose s u sua l ly u sed i n soc ial sett ing s .
Trac k ing

115
task s d i f fer from reac t ion t ime stud ies , because the subj ec t mu s t
cont inuou sly pay attent ion t o the task .
S ince reac t ion t ime tests
are intermittent , cont inuou s at tent ion i s not requ i r ed , and th i s may
expla in why r eac t ion t ime s tud ies fail to show cons i s tent mar ij uana
effects .
Sensory and Perceptual Func t ions

Tests that measu re a subj ect ' s abi l i ty to detec t a br ief flash of
l ight show s ignif icant impa i rment by low to moderate dose s ( 2- 3 mg
a r e examples ) of smoked mar i j uana ( Sharma and Moskowi t z , 19 72 , 1 9 7 3 ,
1974 ; Moskowitz et al . , 1972 , 1 9 7 4 ; Ca sswell and Marks , 1 9 7 3 1 Jone s
and S tone , 1 9 7 0 ) .
Sustained attent ion is r equ i red in s ignal
detect ion tasks , and the relat ion between this susta ined attent io n
S ig nal
r equ i rement and mot ivat ion e ffects has not been explored .
detect ion tas k s a r e prototypes of pe rceptual demand s found in
man-machine i nteract ions .
The large reduct ions in s ignal detect ion
that occu r unde r the inf luence of mar ij uana may suggest a substant ial
r isk for users who are operating machine s .
Other visual funct ions ,
such as v i sual search , that depend on eye movement s are not impa ired .
I ntellectual and Cogn i t ive Func t ions

The effects of ma r i j uana on such intellectual and cogn it ive function s
a s verbal f luency , shor t-term memory , learning abi l ity , calcu lat ion
s k i l l s , abil ity to follow complex d i rect ions , and t ime sense have
been i nvest igated and are r eported below .
Howeve r , this a rea of
study has been hamper ed by the lac k of standard measu res of
f unc t ion ing in the intellectual and cog n i t ive areas tested .
Ove rall ,
the inve s t igat ion of mar ij uana ef fects on intellectual and cogn i t ive
f unc t ioning has not fol lowed a log ical prog ress ion .
When studying the effects of drug s on learning ,
Lea r n ing and Memory
i t i s d i f f icult to control all of the factors that might influence
the results , for example , as noted above , how ha rd a subj ect tr ies t o
per form can make a big d i fference even in the presence of a sedating
drug .
Thus , it i s not surpr i s ing that ear ly studies of mar ij uana ' s
e ffects gave incons istent results .
More recently , several stud ies have demonstr ated that a sing l e
moderate dose of mar ij uana impa i r s shor t-term memory .
Thi s effec t i s
espec ially not iceable in the phases of shor t-term memory tha t are
heavi ly dependent on attent ion , such as informat ion acqu i s i t ion and
stor age (Abel , 1970 , 1 9 7 1 1 Dornbush et al . , 1 9 7 1 1 Dittr ich et al . ,
1 97 3 ; Melges et a l . , 1 9 7 4 ; Belmore and Miller , 1 9 8 0 ) .
Rxamples of
the type s of impai red task s wou ld be remember ing a sequence of
numbers or syllables or memor i z ing and following a sequence of
d i rect ions .
Phys iolog ical changes have been mon i tored in some of the same
stud ies in which inte llectual impa i rment has been repor ted .
Mille r

116
and Cornett ( 19 7 8 ) found that increases in hear t rate are produced by
mar i j uana to about the same deg ree as impa i rment on intellectual
tasks . This link ing of a physiolog ical marker with stud ies of
behavioral effects is a useful model for research in this f ield .
Time Sense
Anothe r intellectua l function inf luenced by ma r i j uana i s
t ime sense . Under the influence of moderate doses of the drug , most
invest igator s repor t that subj ects cons istently overestimate the
amount of t ime that has e lapsed . Thus , under the inf luence of
mar i j uana , a g iven event i s repor ted to last longer than it actually
does last ( Clar k et al . , 1970 1 Vachon et al . , 1974 1 Tink lenberg et
a l . , 1976a) .
State-dependent learning refers to a
S tate-Dependent Learning
situat ion in wh ich mate r ial that i s learned while under the influence
of a drug is remembe red best in the state of drug intox icat ion in
which i t wa s originally learned . A ser ies of stud ies were conducted
w ith oral doses of 20 mg ( in a subsequent study this dose was
calibrated to 0 . 3 mg/kg ) of -9-TBC to invest igate the extent to
which learn ing and memory are l inked to the state of intox icat ion
(Dar ley et a l . , 1973a , b , 1974 , 1 9 7 7 ) . This modest dose of ma r i j uana
caused learning to take place more slowly than when the subj ect was
drug-free . Once learned , recall of the learning that occu rred dur ing
intox icat ion was best when the subj ect was again under the inf luence
of mar i j uana . Although state-dependent learning occurs with
mar i j uana , the quality of learning and recall i s impa i red beCause the
informat ion or problem-solving sk ills learned in the ma r i j uana
i n tox icated state will be reduced or impa ired . These invest igator s
believe that the major def ic i t i s in the attention-storage phase of
l earning .
Oral Commu nication
Marij uana use in low to mode rate doses impairs oral communicat ion ,
espec ially clar ity of sequent ial dialogue with other pe rsons
( Dornbush et al . , 1971 1 Paul and Car son , 1973 1 Zeidenberg et al . ,
1973 1 Crockett et al . , 1976 1 Miller et al . , 1977a-d , 1978a , b , 1979 1
Pfefferbaum et a l . , 197 7 1 Mi ller and Cornett , 1978 r Natale et al . ,
1979 r Belmore and Mi ller , 1 9 8 0 ) . Mar i j uana at moderate doses
d isrupts continu ity of speech by impa i r i ng shor t-term memory ( 6-18
seconds duration ) ( Belmore and Miller , 1980 ) . Commu nication while
i ntox icated i s also impaired by the intrusion of irrelevant words and
idea s into the stream of commun icat ion . When a list of words i s
learned and then the cubj ects a r e asked t o recall those words without
regard to sequence , words that were neve r in the or ig inal l ist ar e
i nserted dur ing recall more often by subj ects g iven -9-THC than by
those who were d rug-free ( Pfefferbaum et a l . , 1977 1 Mi ller and
Cornett , 1978 1 Mi ller et al . , 1978a , b) . Ze idenberg et al . ( 1973 )
administered 5 mg -9-THC orally and found that , in a soc ial
context , phrases bec ame shor ter , speech became slower , and there was

117
greate r lag t ime between the cue to talk and the actual onset o f
talking .
These subj ects were also less able t o recog n i ze three
lette r nonsense syllables to wh ich they had previously been exposed .
Further , when expe r imental subj ects were all g iven the same dose of
-9-TRC , they repor ted d i f ferent subj ect ive levels of intox ication .
Those who repor ted more intox icat ion showed g reater d i srupt ion of
two-per son commu nication ( Pau l and Car son , 1 97 3 ) .
Exper imental subj ects who were asked to tell stor ies about
ambiguous pictures ( the Themat ic Appe rcept ion Test ) demonstrated drug
impaired organ i zat ion and integ ration of stor ies .
The authors
reported a t ime less , nonnar rat ive quality , with g reater d i scontinuity
i n thought sequence and more f requent inclus ion of contrad ictory
ideas ( Roth et al . , 197 5 ) . When asked to talk for f ive minute s o n
any topic , subj ects under -9-THC demonst rated decreased var iabil i ty
of language and an i ncrease in per sonal references , a s well as less
deta i l ing of items ment ioned in the monologue and less cr i t ical
evaluat ion of those i tems ( Natale et a l . , 1 9 7 9 ) .
Auto Acc idents

S imulator Stud ies
A dr iving s imulator i s a laboratory instrument that requ i res the
subj ect to per form a sample of the behavior requ ired in automobile
d r iving s i tuat ions .
S imulators d i ffer f rom most of the laboratory
stud ies desc r i bed above in that complex behavior is requ i r ed .
Although s imulator s are representative of the multitask character of
dr iving , no one s imulator is capable of present ing all aspects of
d r iving s imultaneously .
The behavior sampled var ies across
s imu lators , however , in compa r i son to car dr iving s i tuat ions , the
s imu lator has the advantage of present ing a standard st imulus to all
subj ects .
Most s imu lator s tud ies reveal impa i rment of dr iving s k i lls
following moderately intox icating doses of ma r i j uana such as 10-1 5 mg
( Crancer e t a l . , 1 9 6 9 1 Dott , 1 9 7 2 J Ell ingstad et al . , 1 9 7 3 J Rafaelsen
et al . , 1 9 7 3 J Moskowitz et al . , 1 9 7 6 J Smi ley et al . , 1 9 8 1 ) .
These
impai rments have been repor ted in s imulators that test the perceptual
functions as well as those that te st motor s k i lls of car control . *
*Another type of s imulator study examined mar i j uana ' s effect on

per formance in a fly ing s imulator ( Janowsky et al . , 1 9 7 6 ) .
Subj ect s
smoked mar ij uana c igarettes with 0 . 0 9 mg/kg - 9-TRC , a dose of
- 9-TRC commonly used in soc ial setting s .
S ig n i f icant impa irment
of short-term memory wa s noted .
Subj ects were unable to recall whe r e
t hey were i n the execut ion o f a task . O n the s imulator they tended
to forget where they were in a g iven f l ight sequence .

118
Test Cour ses
Exper imental stud ies of the e ffects of mar ij uana on closed course
automobile dr iv ing per formance show that this s k i l l is impa ired by
mar i j uana . Car handling sk ills were reduced , as shown by object ive
measu res (Klonoff , 1974 ; Hansteen et al . , 1976 ; Attwood , in press) .
I t should be noted that these stud ies , involving subj ects under the
inf luence of mar i j uana , exami ned per formance in less complex
s i tuat ions than are actua lly met in r eal-l i fe d r iving situat ions .
However , a closed course has the advantages of standard cond itions
and safety factor s . I n real-l ife dr iving s i tuat ions , the perceptual
and cogn it ive demand s are cons ider ably more complex . The K lonoff
( 19 7 4 ) study of dr iving per formance on city streets ind icates that
smoked mar ij uana ( 5-10 mg -9-THC ) impairs j udgment and
concentrat ion in add i t ion to impa i r i ng car hand ling sk ills .
Accident Sur veys

Exper imental evidence of impa irments caused by mar ij uana on
psychomotor functions , j udgment , and motor sk ills involved in dr iving
has led to research on the relat ionsh ip of the use of mar ij uana and
automobile acc idents . A strong ly pos it ive re lationship between use
of alcohol and increased dr iving r isk has long been establ i shed . The
techn ique s used to e stablish the relat ionship of alcohol to acc ident s
might appear to offer an excellent parad igm for comparable mar ij uana
acc ident research . However , there have been practical reasons why
the roadside survey model of us ing breath samples obtained from
acc ident dr ivers and compar ing those to breath samples of randomly
selected d r iver s who are passing the acc ident site in the same
direction , the same t ime of day , and same day of the week has no t
wor ked for mar ij uana stud ies . Whe reas there has been 9 7 percent
cooperat ion for alcohol breath analysis , mar i j uana determination
r equ ires a blood sample , and only a minor i ty of dr ivers willing ly
cooperate . Fur ther , mar i j uana has a qu ite diffe rent body
d istr ibut ion pattern due to its h igh fat solubi lity . Delta-9-THC i s
not only technically qu ite d i f f icult to detect in samples of body
f lu id , but i t may be active in the nervou s system long after it is
not detectable in blood . The detr imental effects on dr iving skills
( Moskowitz and Sharma , 1979 ; Moskowitz e t al . , 1981) may even pers ist
4 to 8 hou rs beyond the t ime when the user has had subj ect ive
f eelings of euphor ia or sleepiness .
Several reports of acc ident su rveys have recently been published
( Teale et a l . , 1977 ; C imbura et al . , 1980 ; McBay and Owens , 1981) ,
bu t all suffer from the problems d i scus sed above and par t icularly
f rom the lack of a reasonable compar ison g roup . For example , one
study repor ted that 16 percent of Boston dr ivers had -9-THC in
their blood ( Sterling-Smi th , 1 9 7 5 ) . There was no descr ipt ion of the
g roup who declined to g ive a blood sample but provided breath or
u r ine samples instead . Also , there is no informat ion as to the
frequency of find ing -9-THC in the blood of those dr ivers who have

119
not had an acc ident or othe rwi se come to pol ice attent ion . I n
add i t ion , many u sers o f mar i j uana also u se other drug s so that data
are avai lable on only a few subj ects who only used ma r i j uana .
In an e ffor t to obta in some reference point for the assoc iat ion
of mar i j uana with acc idents as compa red with othe r drug s , War ren e t
al . ( in press) reanalyzed the C imbura e t al . ( 1980 ) data . Twelve
percent of the fatally inj ured d r ivers and pedestr ians in that study
had been found to have -9-TRC in the i r blood . The pre sence of
othe r drug s was also determined and a culpabi l i ty index was deve loped .
A culpabi l ity index compares the frequency that a drug is found in
d r ive r s assigned respons i b i l ity for cau s i ng a coll is ion with the
frequency in individual s from the same sample who had not caused a n
acc ident .
Aspir in was found to have a culpabi l i ty index of 1 . 0 . That i s ,
it was no more frequent in ind ividuals ass igned respons ibi l ity for a
coll i s ion than on those who were not . Th is is of some s ignif icance
because it serves as an internal chec k on the technique , ag ree ing
w ith the a pr ior i assumpt ion that i t would be unl i kely for aspir in
use r s to be overrepresented among those respons ible for acc idents .
In contrast , subj ects with cannabinoids pre sent in the ur ine were
found to have a culpabi l i ty index of 1 . 7 , the same culpabi l i ty leve l
found for the presence o f a lcohol . Th i s ind icates an excess of
9-THC-pos itive dr iver s in the category responsible for
acc idents . The presence of antihistamines produced a culpability
index of 1 . 5 , and tranqu i l i zer s/ant idepressants , 1 . 8 .
Given the d i fficult ies in executing epidemiolog ic stud ies where
it is so d i f f icult to obtai n adequate control groups , it would appea r
that only tentat ive conclus ions about mar i j uana ' s role in acc idents
can be reached . Suppor t ive ev idence that ma r i j uana is a contr ibuting
c ause of acc idents comes from surveys of mar i j uana users who repor t
they rece ive a h igher-than-average numbe r of t ickets for dr iving
v iolat ions and are involved in a h igher-than-average number of
acc idents (Johnston , 1 9 8 0 ) . Never theless , the problems descr ibed
above are yet to be solved . But the culpabi l i ty index model presents
a methodology that may be refined and ut i l i zed i n future stud ies .
Alcohol-Mar ij uana Interact ions

Surveys show that mar ij uana and alcohol are frequently consume d
together ( Fishburne et al . , 1980 1 Johnston et al . , 1 9 8 0 ) . Thu s , it
is impor tant to determine what interact ions , if any , occu r betwee n
these two drug s . As both drug s have sedative propert ies , an add it ive
effect would be expected and has been found in the few systemat ic
i nvestigat ions of the effects of this combinat ion . One study
repor ted that 0 . 0 5 percent blood alcohol leve l concentrat ion ( BAC )
i ncreased the impa i rment produced by 5 mg of smoked -9-TRC on
track ing behavior (Manno et a l . , 1971) .
In a study using two doses
of a lcohol and two dose s of mar i j uana , even the low dose of alcoho l
( 0 . 0 7 percent BAC ) and the low dose of -9-TRC ( 1 . 4 mg ) impa ired
complex tracking in an add i t ive fashion (Bansteen et al . , 1976) .

120
Higher doses produced more pronounced decrements . A combination o f
6- 9-THC ( 0 . 320 mg/kg ) and ethanol ( a dose that produces a peak
blood level of less than 0 . 0 8 percent BAC ) has a lso produced an
add it ive effect on the abil ity to per form on a psychomotor tes t
( Belg rave et al . , 1979 ) . Th i s add it ive effect would be of concern to
those operating a motor veh icle .
The issue of alcohol-mar ij uana interactions is an impor tant one ,
but cur rently few data are ava i lable . Clear ly , more stud ies of
mar i j uana ' s interact ion with a lcohol and other commonly used drug s
are needed .
Ch ron ic Effects
Animal Studies
S tud ies of chronic effects are necessary to determine whether a drug
produces changes that per s i s t after admini strat ion ha s stopped . I n
v iew o f the theoret ical poss ibi l i ty of cumulat ive o r per s i stent
ma r i j uana effects , it i s surpr i s ing that only a few laborator ies have
conducted exper iments i nvolving repeated dos ing and test ing for
res idual effects . Mice inj ec ted with 10 mg/kg 6-9-THC for 20-40
days were found to be pers istently impa ired in new learning 100 days
after the inj ect ions stopped ( Radouco-Thoma s et al . , 1976) .
S imilarly , rats g iven 20 mg/kg of 6 -9-THC orally for 180 days had
learning still impa ired 2 months after the 6-9-THC treatment
stopped ( Fehr et al . , 197 6 ) . Th i s was confi rmed by the same g roup i n
t wo subsequent stud ies ( Fehr e t a l . , 1979 ; Stig l ick and Kalant , in
press) . Anothe r g roup of invest ig ators , however , could f ind no
r es idual learn ing effects in monkeys 20 days after stopping
comparable doses of 6- 9-THC ( Fer raro and Gr illy , 19 7 4 ) .
Human Stud ies

C l inical repor ts of memory impai rment , lack of concentrat ion ,
lethargy , etc . , in non intox icated chronic user s of ma r i j uana have le d
to s tud ies in which psycholog ical testing was admin istered to users
of mar ij uana and controls . The results of these stud ies are
i nconclusive . Several stud ies show impa ired per formance in users as
compared to controls (Agarwal et al . , 197 5 r Soue if , 1976 r Wig and
Varma , 1977 r Mendhiratta et al . , 1 9 7 8 ) ; others found no s ignif icant
res idual effects in the ma r i j uana use r s ( Bowman and Pihl , 1973 r Rubi n
a nd Comi tas , 197 5 r Satz e t al . , 1976 ; Ray e t al . , 1978 r Schae ffer et
al . , 1981) . Al l of these stud ies can be c r i t ic i zed on methodolog ica l
g rounds , and the results have been d isputed . Th is is not surpr i s ing ,
because it i s techn ically ve ry d i f f icult to obtain a sample of
c hronic mar i j uana user s , get them into a truly d rug-free cond i t ion ,
test them , and s imila r ly tes t an appropr iate g roup of controls .
Several g roups of invest igators (Dornbush et al . , 1972 ; Frank et
al . , 1976 r Har shman et a l . , 1976 ; Ross i et a l . , 1 9 7 7 ) examined

121
chronic mar ij uana users before and after 21-9 4 days of chronic
i ntox icat ion in a research hospital sett ing . None of the
invest igator s found any psycholog ical changes dur ing postdrug
testing . However , 2 months of u se i s a relat ive ly short per iod of
time for a change to be detected , and the subj ects had already been
u s ing marij uana for at least a year pr ior to enter ing each study
(Fehr et a l . , 19 76 ) .
The ava ilable stud ies of chronic behavioral effects lead to no
clea r conclusions . Althoug h some animal studies demonstrated a
learning def ic it that pers i sted for months after da ily mar i j uana
exposure wa s d i scont inued , the human stud ies have such methodolog ica l
weaknesses that they cannot be interpreted . A prospective concur rent
cohort study and a retrospect ive case-control study of possible
outcomes of and r isk factor s for u se of mar ij uana could add useful
informat ion .
( See research recomme ndat ions at the end of this
chapter . )
CLINICAL SYNDROMES
I n thi s sect ion we will d i scuss both acute and chron ic behaviora l
changes that have been repor ted in the clinical l i terature to be
associated with the use of mar i j uana . An association based on cas e
r eports does not imply causality . Stud ies o f appropr iate control
groups are necessary .
In general , acute or immed iate clinical
e ffects of drug s can be determined sc ient i f ically much more read ily
than chronic or delayed effects . Th i s i s as true for mar ij uana as i t
i s for a lcohol and other drug s . Thus , the acute effects of mar ij uana
are based on more sol id evidence than are the reported chron ic
e ffec ts .
Acute Effects
The acute clinical effects of mar i j uana seem to occu r on a cont inuum
In the l i terature ,
f rom mild dysphor ia to acute bra in syndrome .
three d i f ferent syndromes have been descr ibed , although there i s
blurr ing o f the boundar ies i n this classif icat ion and no general
ag reement as to d iagnostic cr iter i a .
Anx iety/Panic React ion

A maj or por t ion of the evidence for this effect comes from repor ts by
mar i j uana users themselves . Mar i j uana ' s popu lar ity notwithstand ing ,
a surpr isingly h igh proport ion of user s report react ions that they
regard as unpleasant or undesi rable .
FOr example , 3 3 percent of
regular u sers reported that wh i le intox icated they occas ionally
exper ienced such symptoms as acute pan ic , paranoid react ion ,
halluc inat ions , and unpleasant d istor t ions in body image (Tar t , 1970 1
Neg rete and Kwan , 197 2 ) . Another study repor ted that 16 percent of

122
regular users reported anx iety , fear fulness , confu sion , dependency ,
o r agg ress ive u rges as a usual occurrence (Hal ikas et al . , 1 9 7 1 ) .
S imilar finding s in g roups of stable , well-adj usted , mode rate use r s
have been found by other invest igators (Annis and Sma r t , 19 7 3 1 Marcus
et a l . , 1 9 7 4 ) . First-t ime users are more l i kely than are exper ienced
u se r s to r eport adver se react ions . The frequency of such react ions
appears to be higher when the sett ing for use is not a favorable one J
for example , when the u se r sees the envi ronment as threatening .
These adverse psycholog ical react ions also have been observed i n
s u bj ects of laboratory exper iments with mar ij uana . Such control led
observat ions of persons whose immed iate pr ior mental statu s and whose
dosage were known g ive a bas i s for conclud ing that acute adverse
psycholog ical react ions can occu r unde r sing le moderate doses of
mar ij uana . These e ffects are more l i kely at higher doses . They
usually last no longer than 2 to 4 hou r s . Acute paranoid react ion s
unde r these controlled cond it ions have been reported (Mendelson and
Meyer , 1 9 7 2 1 Tassinar i et al . , 1 9 7 3 1 Frank et al . , 1976 1 Me lges ,
1 97 6 ) . Ingest ion , in which t itration of dose (dose adj ustment as
occurs dur ing smok ing ) is d i f f icult , may be more l i kely to produce
adve r se effects than administrat ion by smoking mar i j uana . However ,
chronic use and inte raction with other psychoact ive substance s a r e
not required .
As frequent ly as these adverse react ions are observed and
self-repor ted , med ica l treatment i s rarely sought . FOr example , a
college student health clinic repor ted only s ix students per year
sought med ical treatment for an adverse react ion to mar ij uana out o f
a student populat ion of 2 0 , 0 0 0 (Pi llard , 197 0 ) . In the general
popu lat ion , a diagnos is of acute cannabis reaction was found in only
1 0 cases out of 700 , 0 00 hospital admiss ions in the Un ited States
(Lundberg et al . , 1971) . In the u . s . Army , only 18 such cases we r e
treated over a several-year per iod f r om a military populat ion of
3 3 , 0 0 0 (Tennant and Groesbeck , 1 9 7 2 ) . There are no recent f igure s
showing requests for medical treatment now that the use of mar ij uana
is more intense , wide spread , and reaching younger ag e-groups .
However , a unique monitor ing of drug causality behavior document ing
emergency room encounte r s conducted by the Drug Enforcement
Administrat ion and the Nat ional Institute on Drug Abuse ( U . S .
Depar tment of Health and Human Services , 1 9 7 9 ) may i n the futur e
provide addit ional information about the frequency of adver se
react ions to use of mar ij uana .
Dysphor ic Reac tion
Therapeut ic tr ials have been car r ied out test ing 6 -9-THC as a
poss ible treatment for mood d isorders ( see Chapter 7 ) . Severe
dysphor ic react ions character i zed by d i sor ientat ion , catatonial i k e
immobi lity , acu te panic , and heavy sedat ion have occu rred in several
pat ients . The dysphor ic symptoms appeared at moderate doses compa r
able t o those used in soc ial setting s . They lasted only a few hour s
and responded t o d i scont inuation o f the drug and reassurance o f the
pat ients (Kot in et a l . , 1973 1 Ablon and Goodw in , 197 4 ) .

123
S imilar dysphor ic react ions have been repor ted i n cancer pat ients
who were on a the rapeutic tr ial of 6-9-THC to control the nau sea
assoc ia ted with chemotherapy . The symptoms , course , and response to
ceasing use of the drug were ident ical to those descr ibed above .
I nvest igators have suggested that the dysphor ic response is more
likely to occu r in older pat ients not accustomed to drug use for whom
the mood-altering effects are unantic ipated and unwelcome (Shil ing
and Sti llman , 1 9 8 0 ) .
Acute Brain Syndrome

D iagnost ic criter ia for the syndrome now cal led de lir ium and
prev iously called acute brain syndrome appear in Diagnost ic and
S tat istical Manual of Mental Disorders , Thi rd Edi t ion , 1980 (DSM
( a ) a cloud ing of consc iousness as man ifested
I I I ) . These include :
by impa irment of abi l i ty to susta in attent ion to environmental
stimuli , or impai rment of abi l i ty to sustain goal-d i rected th ink ing
or goal-d irected behavior r ( b) a d i sorder of memory or or ientat ion r
(c ) perceptual d i stur bances r and (d) a change in sleep pattern and/o r
a change in psychomotor act ivity . The symptoms develop over a short
per iod of t ime and f luctuate rap idly .
Both the symptom pattern and the course of the acute brain
syndrome fit the descr ipt ions of one type of behavior d i sorde r
a ssoc iated with u se of mar ij uana . I t has been reported to develop in
per sons who have a history of prolonged , regular , heavy use of
marij uana . I t is def ined as an acute brain syndrome beCause it
come s on dur ing the per iod of drug use and i t gradually d i sappear s
a f ter the d rug i s stopped . The maj or ity o f case repor ts have come
from Eastern countr ies where the cannabis products customarily used
have h igh potency ( Spencer , 1970 r Chopra and Smi th , 1974 r Meyer ,
197 5 ) . I t has also been reported in u . s . Army pe r sonnel stat ioned i n
Viet Nam ( Talbott and Teague , 1969 ) a nd i n Europe ( Tennant , 19 7 2 ) ,
where sold iers had access to very h igh 6-9-THC concentrat ions in
cannabi s substances .
I n contrast to the Ind ian publ ic mental hospital
pat ients who were hospitali zed for many weeks , u . s . soldiers recovered
i n 3 to 11 days and returned to duty . Th i s d i f ference in durat ion
may reflect soc iocu ltural d i fferences in length of in-pat ient
t reatment more than a d ifference in the d isorder .
Withdrawal Syndrome
S tud ies of animals and human subj ects g iven moderate to h igh doses of
mar i j uana orally or by inhalat ion several t imes pe r day have
demonstrated tolerance to many of the effects of mar i j uana ( see
Chapter 1) . When such use of mar i j uana is stopped after several days ,
a wi thdrawal syndrome occurs . I n human subj ects , this resembles the
typical mi ld wi thdrawal symptoms seen after prolonged sedat ive use
( Jones and Benowitz , 197 6 ) . Subj ects show i r r itabi l i ty , ag itat ion ,
insomnia , and BEG changes ( see Chapter 4 ) . These symptoms are
self-l imiting r they peak at 3 0 hours and d isappear by 9 0 hour s .

124
There i s no clinical ev idence that phys ical dependence plays an
i mpor tant role in per s i stent use of mar i j uana . Withdrawal symptoms
would not be expected in inte rmittent users 1 however , da i ly
r ound-the-clock use r s of h igh-dose mar i j uana may be expected to show
some symptoms of withdrawal soon after stopping regula r use .
Chron ic Effects
Cannabis Psychos i s
Cannabis psychos is refers t o a chronic psychot ic cond it ion (out of
contact with real ity) repor tedly seen in heavy mar ij uana users , bu t
extend ing beyond the per iod of acute intox icat ion . Some authors have
descr ibed a schi zophren ialike p icture with delus ions and halluc ina
t ions , and others have stressed the ex istence of organic mental
confus ion . Most of the repor ts have come from observation of
hospitali zed pat ients in As ian and Afr ican countr ies ( Asun i , 1964 J
Chopra and Smith , 1974 1 Thacore and Shukla , 197 6 ) . There are no
r eports in the North Amer ican l i te rature . At this t ime , there is
insuf f ic ient evidence to say that cannabis psychos i s ex i sts as a
separate clinical ent ity (Murphy , 1963 J Edwards , 1976 ) .
Amot ivational Syndrome

C l inic ians coined the term amot ivat ional syndrome to describe a
characte r i stic set of personal i ty changes seen in some da i ly users o f
mar ij uana (McGlothlin and West , 1968 J Smi th , 1968 ) . The changes
include apathy , loss of amb it ion , loss of effect iveness , d iminishe d
ability to carry out long-term plans , diff iculty in concentrating ,
and a dec l ine in school or work pe rformance . As usually described ,
t hese changes are seen in frequent or da i ly users , and thu s they may
be cons idered a form of chron ic intox icat ion . The term amot ivat iona l
syndrome is not an off ic ial d iagnos is , but there is agreement among
many clinic ians who treat young people that this constellat ion of
symptoms is common .
It may . a l so be seen in nonmar i j uana users , and
da i ly use of mar ij uana i s not always assoc iated with los s of
mot ivat ion .
The evidence presented for the l ink ing of this syndrome with
mar i j uana cons ists of case repor ts . For example , Baker and Luca s
( 19 6 9 ) descr ibed the case of a man whom fr iend s descr ibed as
previously consc ientious , capable , and effective J but after smok ing
hashish daily for 3 years , he changed into a person for whom use of
drug s wa s a way of l i fe and in whom a ser ious deter iorat ion of soc ia l
function was observed . Other r epor ts cons ist of g roups of cases with
s imilar h istor ies (Thur low , 1971) . The symptoms ment ioned , in
add i t ion to loss of motivat ion , include falling g rades , difficult ies
in concentrat ion , intermittent confus ion , and impa i red memory . Some
authors repor t improvement when use of mar i j uana is stopped (Kolansky
and Moor e , 1971 , 19 7 2 ) .

125
A var iety o f othe r data support such a cond it ion . In a larg e
s urvey , daily mar i j uana u sers were asked about the drug ' s adverse
effects (Johnston et al . , 1980) . The most common response was 1os s
of energy ( 4 2 percent ) . Near ly a third ( 3 2 percent ) of the dai ly
user s thoug ht that mar i j uana caused them to be less interested i n
other activities than they had been before , and a third ( 34 percent)
thought that i t hur t the i r school and/or j ob per formance . Anothe r
type of evidence comes f rom compar i sons of college students who use
ma r i j uana with others who do not . Several such stud ies (Shean and
Fechtmann , 1971 J Linn , 1972 J S imon , 197 4 J Finnell and Jones , 197 5 )
found ma r i j uana users had increased levels of psycholog ica l
d isturbance , lower academic per formance , and lower per formance on
scale s measur ing att itudes toward achievement and purpose in l ife .
But some stud ies in both the United States and foreign countr ies have
fai led to show s ignif icant d i fferences between ma r i j uana u sers and
a bstainers ( Br i ll and Chr ist ie , 1974 J Rubin and Comitas , 197 5) .
Interpretation of the evidence l ink ing mar ij uana to amot ivat iona l
syndrome i s d if f icult . Such symptoms have been known to occur in
the absence of mar i j uana . Even if there is an assoc iat ion between
this syndrome and use of mar i j uana , that does not prove that mar i j uana
cause s the syndrome . Many troubled individuals seek an escape into
u se of drug s r thus , frequent u se of mar i j uana may beCome one more in
a ser ies of counte rproductive behavior s for these unhappy people .
The ava i lable evidence does not allow a sorting of the var ious
possibilitie s i n the relat ionship between use of mar i j uana and the
complex of symptoms in the amot ivat ional syndrome . I t appears
likely that both self-select ion and authentic drug effects contribute
to the mot ivationa l problems seen in some chron ic mar ij uana users
( see Chapter 2 ) . Pe rsons who are exper iencing los s of mot ivat ion ,
apathy , and the other aforement ioned symptoms probably will worsen
the s ituat ion by tak ing any sedat ing drug . They shou ld be warned to
avoid frequent u se of mar ij uana , alcohol , and other nonprescribed
drugs .
I n 1968 , Keeler et al . reported fou r cases of the br ief spontaneous

recur rence of a mental state s imilar to that expe r ienced dur ing
mar i j uana intox ication 1 to 21 days after the last drug use . Three
of the fou r subj ects complained of halluc inat ions comparable to
f lashbacks usually assoc iated with LSD ( Horowitz , 1969 ) . Three
separate repor ts of mar i j uana flashbacks followed ( Smith , 1968 r
Favaz za and Domino , 1969 r We i l , 1970 ) and all of these latter
I n a survey of 7 2 0
subj ects had u sed LSD pr ior to mar i j uana .
servicemen , not a single case of flashback in any subject for whom
hashish was the only drug consumed wa s documented (Tennant and
Groesbeck , 197 2 ) . But in the same sample , 1 5 subj ects were
identif ied who had LSD f lashbacks prec ipi tated by use of ma r i j uana .
A larger sample of 2 , 0 01 army personnel ( Stanton et al . , 19 7 6 )
revealed that u s e o f mar ij uana had the h ig hest and only statist ically

126
s ig n i f icant assoc i a t ion with the prec ip itat ion o f LSD flashbac k s
among f ive c lasses of abused d rug s .
C l i n ical s tud ies also have
prov ided ev idence that mar i j uana prec ip i tates a recu r rence of the LS D
f lashbac k s expe r ience
1 9 7 6 1 Abr aham , 1 9 8 1 ) .
( Holsten ,
The ex i s tence of flashbac k s fol lowing use of e i the r LSD o r

mar ij uana i s ent i r e ly based o n self-repo r t s ,
d i st inc t ive phy s ical s igns or
t h i s cond it ion .
the phenomenon ,
exist .
Still ,
tes t s ,
because the re are no
suc h as EEG changes ,
to ident i f y
The re i s no cur rent pha rmacolog ical explanat ion o f

and data regard ing dose and t ime par amete r s d o no t
the repo r t s by u se r s a re reasonably cons i stent .
Thu s ,
the r e i s c l inical ev idence that use o f ma r i j uana by those who have

p reviou s ly u sed LSD i nc reases the l i ke l i hood of recu r rence of the LSD
expe r ience .
E f fec ts on Pr eex ist ing Mental I llne ss

The only ev idence ava i lable regarding th i s i s sue cons i s t s of cas e
r epor ts of patients who had r ecove red a nd appa rently were doing we l l
unt i l they used mar i j uana .
Th e r e i s no informat ion o n the numbe r o f
mentally i l l pat ients who have u sed mar i j uana w i thout complicat ions .
The avai lable data ,
mental i llness .
Still ,
the refore , do not prove that mar i j uana wor sen s

the r e are suf f ic i ent numbe r s of uncont rol led
c l i n ical repor t s showing a temporal assoc iat ion between use of

mar i j uana and return of mental symptoms ,
so that pat i ents shou ld be
war ned of t h i s poss i b i l ity .

Pat ients w i th a h i story of sch i zoph renia may be par t icular ly
sens i t ive to ma r i j uana ' s e f fec t s .
Fou r schi zoph renic pat ients who
were othe rwise we ll control led with med icat ion suffered ser iou s
relapse of the i r sch i zophrenic symptoms fol lowing use of ma r i j uana
( Treffe r t , 1 9 78 ) .
Othe r case s have been repor ted ( Smith and Mehl ,
1970 J We i l , 1970 J Be rnhardson and Gunne , 1 9 7 2 ) .
The se all we r e case s
i n which mar i j uana was purchased on the s t reet ,
so the dose and
pu r i ty we r e unknown .
Pat ients with mood d i sord e r s have also been repor ted to show
wor sening of mental symptoms afte r u se of mar i j uana .
FOr example ,
f ou r cases are known in wh ich mar i j uana apparently prec ipi tated a
relapse of psychot ic
1973) .
( hypomanic )
behavior
( Hard ing and K n ight ,
Fur the rmore , depressed pat ients t reated w i th -9-THC have
been observed to show a h ig h i nc idence of dysphor ic react ions

and Goodw in ,
( Ablon
1974 ) .
E f fec ts Some t imes Repor ted By Use r s

Mood Cha ng e s
There i s a gene r a l belie f t h a t u se of mar i j uana alters mood .
Th i s
prope r ty i s one of the desi red ef fec t s sought by many u se r s .

I nves t ig ator s have desc r i bed a numbe r of var i ables that. enter into
the mood response to ma r i j uana
( Jones ,
1971) .
The se inc lude dosage ,

127
pas t expe r ience ,
att i tude ,
expectat ions ,
i nd ividuals who u sed ma r i j uana

s l ightly d rowsy ,
and sett i ng .
FOr example ,
in i solat ion tended to be relaxed and
i n cont rast , when the use r was i n a g roup s i tuation ,
mar i j uana was a s soc iated with euphor ia and lack of sedat ive e ffec t
(Jones ,
1971) .
Fu r the r ev idence that
mood
changes are not attr ibu t
a ble sole ly t o t he pha rmacolog ical act ion of mar i j uana comes f rom a
study that found that e levat ion in
mood
occu r red immed iate ly befo r e
u se of mar i j uana and immed iately a fter ,
bu t t h a t mood was not
cor re lated with othe r ind icat ions of the subj ect ive leve l o f
i ntox icat ion
( Ros s i e t a l . ,
1978 ) .
Instead , mood was cor re lated
s ig n i f icantly with the mood s of othe r s , whethe r or not the othe r

per sons we re intox icated .
I t appears that preex i s t ing mood can inf luence the dec i s ion to
use ma r i j uana .
H ig h schoo l students who exh i b i t symptoms of
d epress ion a re more l i kely than are othe r s to beg in u s i ng mar i j uana
a s we l l as othe r i l l ic i t d r ug s
( Paton et a l . ,
1977) .
There is some
e vidence that students u se the d rug as a self-presc r i bed remedy for

the i r
own mood
problems ,
often report ing that they use ma r i j uana a s a
means of psycholog ical coping
( Johns ton et a l . ,
1980 J
Kaplan ,
198 0 ) .
bel i e f that ma r i j uana can be u sed to a l leviate c l i n ical
d epre ss ion is not suppor ted by othe r s tud ies ,
i nclud ing one in wh ich
6-9-THC wa s carefu lly tes ted a s an ant idepre ssant .
It wa s g iven to
depressed pat ient s a s an exper imental treatment wi thou t success

(Ablon and Goodw in ,
1974 )
( see Chapte r
7) .
I nte rpersonal Behavior

Adolescent s and young adu lts often report that they u se mar i j uana to
fac i l i tate inte r ac t ion in new soc ial s i tuat ions
1975 ) .
In a su rvey of
704
(Mi r i n and McKenna ,
m idwestern und e rg raduate s tudents , most
repor ted that ma r i j uana was a mean i ng f u l tool of soc ial bond i ng
( Linn ,
1 971) .
The re seems to be a widespread be lief that mar i j uana
smok i ng ha s seve r a l fac i l i tat ive e f fects ,

e ffec t ivene ss , c lose r soc ial bond ing ,
i nc lud ing enhanced soc i a l
he ig htened i nte rpersonal
sens i t i v i ty and empathy , and enhanced sexual pleasu re .
The
s ubcu ltu ral lore on one of the se measu re s of inte rpersonal behavior-
sexua l effec ts--ha s not been stud ied systemat ically e i the r i n survey s
or
i n expe r imental stud ies .
controve r s ia l
( see Chapter
The e ffects on sex hormones are
5) .
Stud ies in expe r imental s i tuat ion s
have f a i led to show any enhancement of soc ial inte rac t ion and ,
fact ,
al. ,
some dec rement s were noted
1979 J
Janowsky et al . ,
( Ga lante r e t al . ,
1979) .
1974 J
in
Clopton et
Data f rom natu ral sett ings rathe r
tha n expe r imenta l sett i ng s are not ava i lable .
E f fec ts on Agg ress ion

Because mar ij uana u sers have been i nvolved in delinquent behav ior ,
numbe r of i nvest igators have que st ioned whethe r use of mar i j uana
e nhances agg ress ivene ss in human be i ng s .
The re are spec i f ic concerns

128
abou t potent ial links of use of mar i j uana to agg ress ion . Bot h
r etrospective and expe r imental stud ies in human be ings have fa i led to
y ield evidence that mar ij uana use lead s to increased agg ress ion .
Most of these stud ies suggest qu ite the contrary effec t . Mar i j uana
appears to have a sedat ive effect , and it may reduce somewhat the
i ntens ity of angry feelings and the probability of interpersonal
agg ress ive behav ior (McGu i re and Megaree , 1974 1 Tink lenberg , 1974 J
Salzman et al . , 19 7 6 J Taylor et al . , 1976 1 Tinklenberg et al . , 19 7 6 b J
Hemphi l l and Fisher , 1980 ) .
SUMMARY
The re i s exper imental evidence that ma r i j uana se r iously impa i r s
psychomotor per formance . S trong evidence for impai rment has been
found in :
coord inat ion as examined by hand stead iness , body sway , and
accuracy of execut ion of movement J
track ing per formance ,
perceptual tasks 1
vig i lance ,
per formance on automob i le dr iving and flying s imulators , and
ope rat i ng automobiles on test roadways .
Less rel iable evidence of impa i rment or reliable evidence of a

small deg ree of impa i rment wa s found in react ion t ime , s imple sensory
f unct ions , and control of eye movements . Although the effects that
ma r i j uana produces on psychomotor funct ions used in d r iving are clear ,
s tud ies l inking mar i j uana to auto acc idents are inconclus ive . The
research i s impa i red by methodolog ical problems related to the
pharmacology of mar i j uana . One recent study repor ted that mar i j uana
and alcohol had a s imilar deg ree of assoc iat ion with fatal acc idents ,
but more invest igation i s needed .
S tud ie s also have shown acute effects of mar ij uana on short-term
memory . State-dependent learning also has been shown , in that
i nformat ion or problem-solv ing sk i lls learned in the intox icated
state will be reduced or impa i red in the drug-f ree state . One
l aboratory has shown tracking impa i rment to pers ist for 4 to 8 hours
beyond the feeling of i ntox icat ion . Some animal stud ies demonstrate
a learning deficit that pers i sts for months after mar i j uana exposu re
has been d i scont inued , but human stud ies do not permit secure
conclus ions .
The acute c l inical effects of mar i j uana are fai r ly we ll
establ ished , althoug h there is no general agreement as to how to
c lass ify them . Anx iety and panic react ions have been repor ted by
use r s and obse rved in exper imental situat ions . They are not
u ncommon , but they rarely requ i re med ical attent ion . When mar i j uana
i s u sed to treat nausea and othe r cond it ions , mental effects can
occur , which some pat ients , espec ially older pe r sons , may regard as
unpleasant . These menta l effects may requ i re cessat ion of the
t reatment .

129
Mar ij uana also has been found to produce an acute bra i n
syndrome . Th is i s a more severe mental problem cons i sting of
confusion and loss of contact with reali ty . I t lasts from severa l
hours to several days and appears to be more l i ke ly to occ u r with
highe r doses .
Chron ic e ffects of any drug are more d iff icult to assess than are
immed iate effects . The evidence that mar i j uana produces a chronic
psychos is is not convinc ing . The poss ible role of ma r i j uana in
causing an amot ivational syndrome is a matte r of g reat concern .
Apathy , poor schoo l work or work performance , and lack of goals
characte r i ze a numbe r of long-term mar i j uana users . But it has not
been poss ible to determine how much is caused by use of mar i j uana and
how much was antecedent J i t seems l ikely that both factors (d rug
e ffec t and self-select ion ) contr ibute to the motivational problema
seen in chronic users of mar i j uana . Ex i st ing stud ies have produced
conf l ict ing results . None of the invest igators has looked at effects
on the very young dai ly ma r i j uana user , who is regarded as potentially
at h igh r isk for daaag ing e ffects because of phys iolog ical and
psycholog ical immatur ity .
There i s c l inical evidence that mar i j uana use by former LSD users
may prec ipitate a recur rence of LSD-type halluc i nations known as a
flashback . Other c linical evidence raises the poss ibility that
ma r i j uana use can wor sen preex isting mental illness .
RECC>MENDATIONS FOR RESEARCH

The comm i ttee recomme nd s the following types of stud ies .
Systemat ic research on acute behavioral and psychosoc ial

effects of mar i j uana should be extended to other age g roups . There
are virtually no data on prepubertal child ren , young adolescents ,
older adults , and ag ing per sons .
Stud ie s of effects of da i ly use of mar i j uana on schoo l

chi ldren a r e g reatly needed . These effects should inc lude the
learning of new material , phys ical , psycholog ical , and soc i a l
d evelopment , acquisit ion o f coping ski lls , a nd tools o f dai ly living .
Systemat ic stud ies of long-term effects of mar i j uana are

increas i ng ly poss ible now that long i tud inal stud ies have ident i f ied
representat ive panels of pe r sona known to be chronic heavy user s .
These stud ies should cover interactive ef fects of mar i j uana and other
drug s on behavioral and psychosoc ial responses , espec ially
i nteract ions of alcohol and mar i j uana because of the i r frequency of
assoc iated use .
Dosage effects shou ld be restud ied , tak ing into account the
h ig her potency cannabis that i s in cur rent use . Fur ther study is
needed of the t iming and depth of inhalat ion of c igarettes with
s tandard doses of mar i j uana . More animal stud ies at vary ing doses
are needed .
In view of the long-term retent ion of ma r i j uana in body
t i ssues , further study i s needed to see whethe r or not chronic users
may have impa i rments of function even in the absence of an acute dose

130
of mar i j uana . The factor s that influence the persistence of effect s
following an acute dose are not under stood .
The cor re lat ion of changes in a phys iolog ical ma r ker , suc h
as increased heart rate , with obse rvat ions of behavioral effects
shou ld be encouraged .
Many of these recomme ndat ions , along with those of other

chapters , could be consol idated and car r ied out as part of a study
that i s both a prospect ive cohort study and a ret rospect ive
c ase-control study of possible outcomes and r isk factors with
mar i j uana use .
A cohort of d rug-na ive j un ior h igh school students could be

assembled and followed over t ime to see wh ich students become
mar i j uana users and wh ich rema i n nonuse r s . Student s would be
s ubj ected to physical and psychosoc ial testing at predetermined time
intervals . The two g roups wou ld be evaluated in terms of the
i nc idence of spec i f ic outcomes and the relat ive r isks assoc iated with
these outcomes afte r appropr iate follow-up per iods .
I n orde r to ident i fy r isk factor s for mar i j uana u se , ind iv iduals
who become ma r i j uana u se r s would be compa red to ind i v iduals who
r ema in nonuse r s using a case-cont rol methodology . By combining these
two epidemiolog ic research st rateg ies , the et iology and effects of
mar ij uana u se may be st d ied .
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the 24th Conference of the Amer ican Assoc iat ion for Automot ive
Med ic ine ( in press ) .
Wei l , A . T . , Z inberg , N . E . , and Nelsen , J . M . Clinical and
psycholog ical effects of mar ihuana in man . Sc ience
1 6 2 : 1234-1242 , 1968 .
Wei l , A . T . Adverse reactions to mar ihuana , classi f ication and
suggested treatment . N . Eng l . J . Med . 2 8 2 : 9 97-10 00 , 1970 .
W ig , N . N . and Varma , V . K . Patterns of long-term heavy cannabis use
in North India and its ef fects on cognit ive funct ions : A
p reliminary report . Drug and Alcohol Dependence 2 : 211-219 , 19 7 7 .
Ze idenberg , P . , Clar k , w. c . , Jaffe , J . , e t al . Effect o f oral
admini strat ion of delta-9-tetrahydrocannabinol on memory , speech ,
and perception of thermal st imulation : Result s with fou r norma l
human volunteer subj ects . Preliminary report . Compr . Psychiatry
14 : 549-556 , 197 3 .

THERAPEUTIC POTENTIAL AND

MEDICAL USES OF MARIJUANA
The re ha s been g rowing interest in the possibil ity that cannabi s and
i ts der ivat ive s will be valuable for the treatment of several med ical
and psychiatr ic cond i t ions .
The 97th Cong ress , for example ,
introduced a b i l l ( H . R . 4 4 9 8 ) to provide for the the r apeut ic use o f
ma r i j uana in s ituat ions involving l i fe-threatening or sense-threaten
ing i l lness and to provide adequate suppl ies of mar i j uana for such
use .
Most of the putative therapeut ic effects of cannabis are believed
to be med iated by the central nervous system .
These inc lude e f fect s
o n appet i te , nausea a nd vom it i ng , epi lepsy , muscle spastic i ty ,
anx iety , depre ss ion , pain , and o n g laucoma , asthma , and the symptom s
of wi thdrawal f rom a lcohol and narcot ics .
The l iterature on these
and othe r therapeut ic act ions be l ieved med iated by the central
nervous system will be reviewed in thi s chapte r .
I n general , the comm i ttee f ind s that cannabis shows promi se i n
s ome o f these areas , although the dose necessary to produce the
des i red therapeutic effect is often close to one that produces a n
unacceptable frequency of tox ic ( undesi rable ) s ide-effects .
What is
perhaps more encou rag ing than the the rapeutic effects obse rved thu s
far i s that cannabis seems to exe r t its bene f ic ial e f fects through
mechanisms that d i f fe r from those of othe r ava i lable drug s .
Thi s
r a i ses the poss i b i l i ty that some pat ients who would not be helped by
A
convent iona l therapies could be treated e ffective ly with cannabi s .
second poss ibility i s that cannabis could be combined with othe r
drug s to achieve a therapeut ic goal , but with each drug be i ng used a t
As a
a lowe r dose than would be requ i red i f e i ther we re used alone .
result , fewer s ide-ef fect s would be expected to occur .
It may be
possible to reduce s ide-effects by synthe s i z i ng related molecules
that could have a more favorable ratio of des ired to undes i red
act ions , thi s l ine of investigat ion should have high pr ior ity ,
because such synthet ic der ivat ive s may ult imate ly have widespread
t herapeu t ic use .
1 39

140
GLAUCOMA
G laucoma i s the lead ing cause of blindne ss in the Uni ted States. The
term i s used to desc r i be a group of ocular d i seases character i zed by
a n i ncrease in i ntraocular pressure , which damages the opt ic nerve
and leads eventually to loss of v i s ion . The d i sease affects over two
m i llion Amer icans of age 3 5 or older . Although there i s increas ing
r is k of g laucoma with increasing age , the re are forms that develop i n
i nfancy . The Nat ional Soc iety to Prevent Blindness ( 1980 ) also
estimates that 3 0 0 , 0 0 0 new cases are d iagnosed each year .
Treatment of g laucoma depends on the type and cause . I t may be
pharmacolog ical or surg ical . Surgery i s useful treatment in
r e lat ively few cases , there i s a h igh inc idence of fa i lure and
ser iou s compl ications may occur . Avai lable antig laucoma drugs a r e
e ffect ive in regulat ing intraocular pressure in many patients , and
are the ma instay of treatment in the most common form of g laucoma ,
but there are some adverse s ide-effects . Some pat ients are refrac
tory to present forms of treatment and become bl ind as the d i sease
p rog resses ' for them, there i s a par t icularly urgent need to f ind
effect ive drugs .
Cannabis ( the crude drug ) , A-9-TBC ( the pure compound ) , and
some other cannabinoid der ivat ives lowe r intraocular pressure when
admini stered by var ious routes , such as inhalat ion , oral , or
i ntravenous . However , adver se a ide-ef fects of cannabi s and A -9-TBC
also have been reported . Most pat ients with glaucoma are elder ly ,
and have a reduced tolerance for many of these s ide-effects . Even
without the adverse s ide effects , smok ing , oral , and intravenous
route s of administrat ion are not su itable for the long term . POr
e xample , to g ive adequate control for intraocular pressure , four
mar i j uana c igarettes per day of 2 percent A-9-TBC would be
nece ssa ry , this amount i s cons idered heavy usage and could pose a
ser iou s health problem in long-term use . The refore , topical
appl icat ion would be the moat salutary route of administrat ion for
the pat ient who needs cont inuous treatment .
Human Studies
Interest in using cannabis for the treatment of g laucoma wa s f i r s t
s t imulated by the observat ion of Hepler et a l . ( 1971 , 19 7 2 ) that
intraocular pressure decreased when healthy human subj ects smoked
c annabis ( 0 . 9 percent and 1 . 5 percent A -9-TBC content ) us ing an
ice-cooled water pipe .
( See Green , 1979 , for an extens ive literature
review. )
A study of the acute ocular effects of cannabis in 429 subjects
showed there wa s a dose-related and stat ist ically signif icant
r educt ion of intraocular pressure following the smok i ng or ingest ion
of cannabi s containing 1 , 2 , or 4 percent A-9-TBC ( Heple r et a l . ,
1976a ) . The amount of pressure decrease was in the range of 30
percent for the cannabi s that contained 2 percent A-9-TBC .
Nineteen hospi tal ized subj ects who smoked cannabis of 1 or 2 percent

14 1
A-9-TBC content were obse rved for 3 5 days and another 29 subj ects
were observed aa in-pat ients for a total of 94 days . There was a
cons istent drop in intraocular pressure in those smok ing the 2 percen t
cannabis and the reduct ion appeared to last 4 to 5 hours (Hepler et
al . , 1976a) . The author s noted that there d id not seem to be much of
a cuaulative effect on a i se of pupils or upon intraocular pressure
response . Studies by other invest igator s have conf i rmed this effect
o f cannabis and A-9-TBC in causing reduct ion of intraocular
pressure in humans ( Shapiro , 197 4 J PUrnell and Gregg , 197 5 ) .
Peres-Reyes et al . in 1976 investigated the effect of intravenou s
i nfus ion of s ix cannabinoida in healthy volunteers . Delta-8-THC ,
A-9-TBC , 11-hydroxy-A-9-THC , cannabinol , cannabid iol , and
8-8 -hyd roxy-A-9-TBC were tested on healthy subj ects with normal
intraocula r preaaure J A-8-THC , A-9-TBC , and 11-hydroxy-TBC caused
the g reatest reduct ion in pressure . Of these A-8-TBC caused the
largest decrease in intraocular pressure , with the least number o f
psycholog ical a ide-effects .
I n a prelimina ry study of 11 human g laucoma pat ients who smoked
aar ij uana ( 1 , 2 , and 4 percent ) or ingested A-9-TBC ( 15 mg ) , intra
ocular pressure was lowered an average of 30 percent in 7 out of 11
pat ients ( Hepler et al . , 1976a) . Another study showed that moat
pat ients had a decrease in intraocular pressure after ingest ion of
15 , 20 , or 3 0 mg of A-9-TBC and after smok ing cannabi s containing
1 , 2 , and 4 percent A-9-TBC (Hepler et al . , 19 76b) .
Ideal ly , the synthe s i s of a preparat ion that could be appl ied
topically to the eye would be moat desirable for humans , beCause this
wou ld allow for self-administrat ion . However , initia l stud ies in
humans with a topical preparat ion of A -9-TBC have not shown a
cons i stent effect on intraocular pressure (Mer r i tt et a l . , 1981) .
More wor k needs to be done on thi s possibility .
Animal Stud ies

While animal stud ies have supported the observat ion that A-9-TRC
lowers intraocu lar pre ssure after oral and topical admini strat ion in
rabbits (Green et al . , 1977a , b J 197 8 ) , and after intravenous adminis
t rat ion in the cat ( Innemee et a l . , 197 9 ) , the reduct ion in intra
ocular pressure ia not completely under stood .
It may result in par t
f rom a central nervous system e ffect , and i n part through act ion on
the adrenerg ic system in the eye , probably med iated by the neuro
t ransmitter norepinephrine .
S ide-Effects
Mar i j uana and A- 9-TBC g iven orally , intravenously , or in c igarettes
to control g laucoma cause systemic a ide-ef fects , such as increase in
hea r t rate , decrease in blood pressure , and psychotropic effects .
Some of these s ide-effects are s ignif icant enough to pose problema ,
part icular ly in patients with g laucoma , who are usually elderly . Bu t

142
o n the othe r hand , some of these e f fect s may d i sappear as tole rance
( decreased response with repeated use ) develops .
TOlerance to the Intraocular Pressure Reduc ing Ef fec t

No tolerance was detected to the ocular e ffects of cannabis in
rabbits after 1 yea r ' s topical inst i llat ion of the synthetic
c annabino ids SP-1 , SP-10 6 , and SP-204 (Green and K im , 1 9 77 1 Green et
al . , 197 7b) .
Heple r et al . ( 1976b) noted a ce i l ing effect in humans ,
i n that the smok ing of 2 2 cannabis c igarettes d id not result in a
s ign i f icant decrease in eyebal l pressure as compared with a subj ec t
w ho smoked only 2 c igarette s .
The area of tole rance w i l l need further
study , espec ially i f a cannabinoid prepa rat ion with a sat i sfactor i ly
h ig h ratio of therapeut ic to s ide-effects can be found .
Summary
Cannabis , 6-9-TRC , othe r cannabinoid der ivatives , and thei r
synthet ics , reduce intraocular pressure in humans when smoked , or
However , there are systemic
g iven intravenously or orally .
It
s ide-effects as well as psychotropic effects that are of concer n .
i s not ye t c lear whethe r an effec t ive topical preparat ion can be
developed that will not have these s ide-effects .
Future work should
determine whethe r synthetic cannabinoids or cannabinoid analogues can
be found that will be e ffect ive in treat ing g laucoma without causing
a ide-e ffects .
ANTIEMETIC ACTION
Certain cance r chemotherapeut ic agents regularly produce nausea and
vomiting after oral or i ntravenous admini stration .
Those that are
most seve r e in that respect are c i splat in , actinomyc in D, adr iamyc in ,
cyclophosphamide , methotrexate , and the n i trosoureas .
Othe r anti
cancer compounds may produce nausea less regula r ly o r in leas marked
f ashion .
B ecause cancer chemothe rapy now can produce increased survival in
pat ients with some neoplasms ( recur rent or metastatic breast cance r ,
small cell carc inoma of the lung , ovar ian cancer , and othe r s ) and
substant ial cure r ate s in several ( acute lymphoblastic leukemia ,
Hodgk ins d isease , germ cell tumor s of the test i s , etc . ) nausea and
vomiting that inter fere with pat ients ' will ingness to cont inue
therapy can be a l i fe-threatening s ide-e f fect .
Even for those
will ing to endure the symptoms , they can be extremely unplea sant and
debilitating .
E stabli shed ant iemetics (prochlorperazine and othe r phenothia
zine s ) are not very effective aga inst drug-induced eme s i s , and the r e
i s a need for new a nd more rel iable ant iemet ic agents .
Metoclopra
mide , a der ivat ive of proca inamide , has recently been shown to be

143
mo r e effect ive than prochlorperaz ine in certain s i tuat ions and seems
promi s ing ( Gralla e t al . , 1981) .
The suggestion that cannabis might have some useful ant iemetic
act ivity i n thi s setting arose about 19 7 3 , when pat ients rece iving
i ntensive chemotherapy for acute leukemia obse rved that the i r
soc ial u s e o f cannabi s appeared t o reduce the i r customary nause a
and vomiting .
C l inical Invest igat ions

Several controlled stud ie s have been repor ted . In one of the early
ones ( Sallan e t al . , 1975) , 6-9-THC in 15- or 20-mg dose s by mouth
was compared with a placebo i n a randomi zed double-bl ind crossover
tr ial in 22 pat ients whose nausea and vomit ing had been shown
r efractory to other antiemetic s .
In 14 of 20 courses of treatment ,
pat ient s obtained complete or par t ial rel ief with 6-9-THC J in
none of 2 2 courses d id pat ients report bene f i t with the placebo.
It
was observed that the ant iemetic effect o f 6-9-TBC occur red only i n
assoc iat ion with the h igh , and it was necessary to mainta in the
high in orde r to ma intai n the ant iemetic effec t .
In another controlled t r ial (Chang et al . , 1 97 9 ) , 14 of 15
pat ients with osteogenic sarcoma treated with h igh-dose methotrexate
had less nausea and vomiting with 6 -9-THC than with the placebo .
In that study , patients with other tumors be i ng treated with cytoxan
and adr iamyc in d id not respond aa well . That repor t and others like
i t suggested that the ant iemetic effect of 6 -9-THC against those
chemotherapeut ic agents that are moderate in their emetic potent ial
( e . g . , methotrexate ) was pronounced , but that 6-9-TRC was less
e f fective against those agents with severe emet ic propert ies . In a
similar study ( Luca s and Laszlo , 1 9 8 0 ) , 3 8 of 5 3 pat ients with nause a
and vomiting refractory to other ant iemet ic& repor ted good results
with 6-9-THC . Among the failure s were those treated with
ciaplat in , which has been character i zed aa one of the moat emetic
agent s used in cancer chemotherapy .
In compar i son with prochlorperaz ine , 6 -9-THC has also been
repor ted to be more effective in prevent ing nausea and vomiting
(Eke r t et a l . , 1979 J Sallan et al . , 1980 ) .
In a larger study ( Frytak et a l . , 197 9 ) , of 116 pat ients treated
with 5-fluourac i l and methyl-ccNO , 6-9-TBC was said to be no more
effective than prochlorperazine .
In that study , in which near ly all
pat ients were older than those in the othe r reported tr ials , the
major ity of pat ients considered the other s ide-effects of 6 -9-THC
so unpleasant that they preferred e ither prochlorparaz ine or the
placebo .
Another cannabinoid , a synthetic , nabi lone , has been provided to
several invest igator s for eva luation an an ant iemetic agent J it ha s
been l icensed for use in Canada for treatment of nausea assoc iated
with cancer treatment .
In the largest clinical study to date ( He rma n
e t a l . , 1979 ) , nabi lone was compared with prochlorperaz ine in a
double-blind c rossover tr ial . I t was found more effect ive than

144
prochlorperazine .
The pat ient s in that study prefer red nabi lone to
p rochlorperaz ine J the predominant s ide-effects were somnolence , dry
Halluc inat ions occurred in a few pat ients .
mouth , and d i z z iness .
Euphor ia of the type assoc iated with cannabis was infrequent in that
study .
However , a study in dog s has revealed previously unrecogni zed
late neurolog ic e ffects of nab i lone at high dose s ( Arche r et al . ,
1981) . Monkeys and rats d id not show s im i la r tox ic e f fects with long
t erm admin istrat ion of nabi lone ( Archer et a l . , 198 1 ) , and further
stud ies will be necessary to c la r i fy the safety of th i s new agent .
Levonantradol i s yet another synthet ic cannabinoid , related to
A-9-THC , which has been shown i n pre l iminary clinical stud ies to
have ant iemet ic act ion in pat ients with refractory chemotherapy
induced eme s i s ( Diasio et al . , 1 9 8 1 ) .
Uncontrolled Use of A -9-TBC

In r esponse to publ ic and pol i t ical pressures , the Nat ional cancer
Inst itute , the United State s Drug Enforcement Agency , and the POod
a nd Drug Administrat ion have ag reed to a program whereby the Nat ional
Cance r Inst itute is mak ing A-9-TBC ava i lable through the pharmac ies
of approximately 500 teaching hospitals and cancer centers to
physic ians who wish to use A-9-TBC in treating the nausea and
vomi t ing of pat ients rece iving cance r chemotherapy .
Th i s broad ,
uncontrolled prog r am , in wh ich no data other than the report ing o f
severe react ions a r e t o be col lected , may make it extremely d i f f icult
to obtai n continuing valid evaluat ions of the effec t i veness of
A- 9-TBC in the management of nausea and vomiting due to cancer
chemothe rapy .
Although the extent of use of A-9-TBC under thi s
prog ram i s d i f f icult t o evaluate , informa l commu nicat ion with the
Nat ional Cancer Inst i tute ind icates that A -9-TBC has been suppl ied
in substant ial quant i t ies to several hundred hosp ital pharmac ies .
The problem i s fur the r compl icated by the fact that the leg islature s
o f 2 3 states have author i zed the use of cannabis by any physic ian for
It
the management of nausea and vomit ing due to cancer chemothe rapy .
i s expected that l i ttle rel iable informat ion will be der ived from
such use .
Summary
There seems l i ttle doubt that A-9-TBC and othe r cannabinoids ar e
active against the severe nausea and vomit ing produced by cancer
chemothe r apeut ic agents .
The extent of thi s activity , its relation
to other antiemet ic s , and its relat ion to the other e ffects of the
cannabinoids have not yet been accurately determined .
Cannabis leaf , smoked or e aten , is also ant iemetic but ita
activity has been even less well dete rmined than that of A-9-TBC .
Studies with other synthetic cannabinoids have barely begun and much
rema ins to be lear ned in thi s f ield .

145
APPETITE STIMULANT
I t has been stated by soc ial users that the smok ing of cannabis
increases appet ite . On that bas i s , there have been sporad ic attempt s
to use i t in pat ients with advanced cancer to overcome the i r
customary debil itating weight los s .
I n several of the stud ies in which A -9-THC was used as an
ant iemet ic in pat ients rece iving cancer chemotherapy , they were
reported to have increased appetite and food intake . At thi s t ime ,
i t i s not certain whether that increase was due merely to rel ief of
nausea and vomit ing or to st imulat ion of appet ite . One compar i son o f
habitual mar ij uana users a nd cont rols matched for age and educat ional
backg round showed increased calor ic intake and we ight gain among the
u sers (Greenberg , et a l . , 197 6 ) . Fur the rmore , a double-bl ind
controlled study (Holliste r , 1971) of smokers of cannabi s or placebo
c igarettes provided with unl imited quant it ies of a h igh-calor ic
beverage ind icated an increase in calor ic consumpt ion in those us ing
cannabi s compared with those using the placebo , however , the
var iabi l ity was very large and there was some quest ion that cannabi s
could be cons idered a clinically s ign if icant appetite stimulant .
In another study of the psycholog ical effects of A-9-TRC i n
pat ients with advanced cancer , i t was observed that A-9-THC
appeared to st imu late appetite and retard we ight loss (Regelaon e t
a l . , 197 6 ) . In that study many pat ients refused to complete the
2-week tr ial because of unacceptable s ide-ef fects from A-9-THC .
The evidence to date suggests that there may be some influence of
cannabi s on appet ite . However , i t i s not possible to separate that
f rom the effect on nausea and vomiting . Furthe r stud ies are in
prog ress in cancer pat ients whose course is not compl icated by nause a
and vomi t ing .
ANTICONVULSANT ACTION
A large number of animal stud ies have been conducted us ing cannabi s
as an ant iconvulsant . These can be d ivided into several categor ies .
The f i rst to be d i scussed will be max imal electroshoc k se i zures
(MES) * both i n the rat and mouse ( Loewe and Goodman , 1947 J Sofia et
al. , 1971 J Fuj imoto , 1972 J Consroe and Man , 1973 J Karler et al. ,
1 9 7 3 J Chesher and Jackson , 197 4 J Karler et a l . , 1974 J McCaughran et
al . , 1974 J Karler and Turkan i s , 1976 J Consroe and Wol k in , 1977 J
In these stud ies the re i s a c lear dose
Turkanis et al. , 197 7 ) .
re sponse effect in the protec t ion to MES confer red by cannabinol
( CBN) and cannabid iol (CBD ) . Tolerance to the effept has frequently
been reported . However , the tolerance noted with cannabinoids i s
s imilar to that seen with phenytoin ( DPH) . Further , even though
tolerance to phenytoin develops with MES , this has not been shown to
*Electr ical shock of max imum intens ity to cause a major se i zure .

146
be a clinically s ignif icant phenomenon . In these stud ie s it i s
g enerally found that CBN i s le ss effect ive aga i nst MES and aga inst
aud iogenic se i zures , the latter produced in rodents by loud noise ,
t han CBD .
In add i t ion , Turkan i s et al. ( 1977 ) have emphasized the
fac t that CBD acts more l i ke DPH than othe r ant iconvulsant & and hence
would be expected to be effect ive ag a inst maj or se i zures rather than
aga inst minor se izures .
There i s also extens ive animal literature that CBN and CBD will
protect against electr ically i nduced , minimal ( k indling ) se i zure s
( Corcoran et al. , 1973 J Fr ied and Mc intyre , 1973 ; I zqu ierdo et al . ,
19 73 J Tu r kanis et al. , 1977 , 1 9 7 9 ) . Reduct ion of se i zures produced
by subcort ical electr ical st imulat ion in the cat has been reported
(Wada et a l . , 1973) . The re appear s to be much less ef fec t on
pentylenetetrazol-induced se i zures (Consroe and Man , 1 973 J Tur kanis
et a i . , 1979) . Any ef fect of CBN and CBD on such se i zures occur s
w i th max imal tox ic dose s ( Tur kanis et al . , 197 4 ) . Protect ion against
aud iogenic se i zures (Consroe et a l . , 19 7 3 ) and against reflex
s e i zures in the gerbil (Cox et al . , 197 5 ) have been reported .
Human studies are largely anecdotal and conf lict i ng . There i s
o ne study by Cunha e t a l . ( 1980 ) in which 1 5 pat ients suffe r ing from
par t ial complex epi lepsy with a temporal focus were randomly d ivided
i nto two g roups . Each patient rece ived , in a double-bl ind procedure ,
200-300 mg of CBD or placebo dai ly . The drugs were administered for
as long as 4 1/2 months . Throughout the study , clinical and labora
tory examinations , electroencephalog rams , and electrocard iog rams were
per formed at 15- to 30-day intervals . The pat ients continued the i r
ant iconvulsant med icat ions taken before enter ing the study , o n wh ich
a l l them had previously exper ienced uncontrolled se i zures . All
pat ients tolerated CBD well , and the re were no s igns of tox ic ity o r
ser ious s ide-effects . Four o f the 8 CBD subj ects rema ined near ly
free of convuls ions dur ing CBD treatment and 3 other pat ients
demonstrated part ial improvement in the i r clinical cond it ion .
Cannabid iol was inef fect ive in 1 patient . The placebo g roup showed
no alterat ion of se i zure f requency . A ser ies of 8 healthy volunteers
g iven CBD showed no effects of the drug .
SUDDa ry
There is substantial evidence f rom animal stud ies to i nd icate tha t
c annabinoids are effect ive in block ing both k ind ling se i zures and
MES , and thi s i s part icularly true for CBD . MES is a standard
testing procedure for evaluat ion of ant iconvulsant drug s . This i s
strong suppor t for further invest igation into the ut i l ity o f CB D i n
h uman epilepsy . The one avai lable carefully controlled h uman study
i s in accord with this rev iew .

147
MUSCLE RELAXANT ACTION
There are widespread , anecdotal repor ts that cannabi s i s effect ive in
relieving muscle spasm or spast ic i ty . Petro ( 1 9 8 0 ) has repor ted suc h
e ffec ts in two cases and has car r ied out a double-bl ind study of the
admin istrat ion of A-9-THC on spast ic i ty ( Petro and Ellenberge r ,
1981 ) . They reported that 10 mg of A- 9-TBC s ignif icantly reduced
spast ic ity by clinical measurement and that quadr iceps electromyog r am &
demonstrated a decrease in inte r ference pattern in four pat ients with
pr ima r i ly extensor spast ic i ty . These are prel iminary obse rvations ,
but they suggest that further and more r igorou s investigat ions of the
use of cannabinoids in spasticity should be sugge sted to test the i r
t herapeut ic effect iveness .
AN'l'IASTHMATIC EFFEC T
I ntensive , chronic smok ing of concentrated cannabi s produces several
adver se effects on the a irways , includ ing mild bronchoconstr ict ion .
But acute smok ing of cannabis as well as the ingest ion of A -9-TRC
produces bronchod ilat ion in normals and in subj ects with chron ic ,
clin ically stable bronch ial asthma of min imal to moderate seve r i ty
( ashk in et a l . , 1 9 7 4 ) . These bronchodilator effects were also
invest igated in individuals in whom an asthmat ic attack wa s induced
exper imentally by exerc ise or methalcholine ( Tashk in et al . , 197 5 ) .
Immed iately afte r the development of bronchospasm , subj ect s smoked a
c igarette conta ining 500 mg of cannabis a ssayed at e ither 1 or 2
percent A-9-THC .
Methalchol ine inhalat ion promptly caused s ignif icant broncho
constr ict ion ( an average decrease in a irway conductance o f 40-55
percent ) and s ignif icant hyper inflat ion ( mean increases in thorac ic
gas volume of 3 5-4 3 percent ) . Afte r placebo smok ing or sal ine
i nhalat ion , a i rway conductance increased only modestly , remaining
signif icantly less than initial control values for 30 to 6 0 minutes ,
and t horac ic gas volume decreased only g radually , rema ining
sign if icantly increased for 1 5 minutes . However , after 2 percen t
cannabis , and after i soproterenol , there was a prompt return of
airway conductance and thorac ic gas volume to control values .
Exerc ise in the asthma-prone ind ividual resulted in average
decreases in a irway conductance of 30-39 percent and average increase
i n thorac ic g as volume of 2 5-35 percent . After placebo or saline ,
there wa s only a gradual return to control value s dur ing 30-60
a inute s , but after cannabis , a irway conductance and thorac ic gas
volume returned promptly to preexercise values . Four of the subject s
who had previou sly used cannabis could detect pleasurable sensat ions
afte r smok ing cannabis , wh ich d i st ingui shed these effects from those
In that sense these exper iments were not
of the placebo c igarette .
str ictly bl ind . The four subj ects who had no previous exper ience
w ith cannabis d id not exper ience any central nervous system effects
but d id note mild somolence or l ight-headedness after cannabis . The
results of this study suggest that any bronch ial i rr itant effects of

148
p lacebo cannabis smoke were not suff ic ient to agg ravate o r perpetuate
ex ist ing acute bronchospasm to an extent g reater than that wh ich
m ight result from the i r r itant effect of inhaled sal ine . The results
also demonstrate that inhaled A-9-THC causes a prompt and complete
sustained reversal of methacholine-induced bronchospasm and cor rection
of the associated hyperinflat ion . These effects were not s igni fi
c antly different f rom those observed after isoproterenol , although
there was a tendency toward a g reater degree of bronchial di lat ion
a fter i soproterenol . S imilarly , after inhalat ion of A -9-TRC , there
was a prompt return of a irway conductance and thorac ic gas volume
dur ing exerc ise-induced bronchospasm to the preexerc ise value . Afte r
exerc ise the effects of 10 mg A-9-THC was not as eff icac ious as
1. 2 5 mg isoproterenol .
The way in which A-9-THC induces bronchial dilat ion has not
been determined , but previous stud ies have shown that this effect is
not med iated by beta-adrenerg ic st imu lat ion or inhibit ion of muscar ine
r eceptors ( Shapi ro et al. , 1 9 7 3 ) . A vagolyt ic mechanism is possible ,
as suggested by othe r stud ies carr ied out on the dog sal ivary gland
( Cavero et a l . , 1972 ) and on guinea pig i leum (Gill et al . , 1970 ) .
Although ingest ion of A-9-THC in a sesame oil vehicle has
produced bronchod ilat ion in asthmatic pat ients ( Tashk in et al . ,
1974) , less d ilat ion was noted than after smaller doses of A-9-THC
de livered by smoking . I ts s ignif icant bronchod ilator effect
notwithstand ing , A-9-THC does not appear to be su itable for tha t
therapeutic use , because of its psychotropic effects and poss ibly
othe r s ide-effects . However , othe r cannabinoid compounds such as
c annabinol and cannabid iol do not produce the central nervous system
effects of tachycard ia character i st ic of cannabis (Holli ster , 1973 )
and deserve fur ther invest igat ion for possible bronchod ilator
ac tivity .
ANTIANXIETY EFFECT
Users of cannabis have often reported that the drug produces feel ing s
of relaxat ion and calmness , and some have reported its use to reduce
anxiety . A problem with evaluating cannabi s as an ant ianx iety drug ,
however , i s that some subj ects report increased anx iety or pan ic
afte r using cannabis ( see Chapter 6 ) . FOr example , Regelson et al .
( 1976 ) found less tens ion and apprehension in cancer patients after
cannabi s use r but 6 of 50 subj ects rece iving A-9-THC reported such
s ide-effects as severe dizz iness , confused thinking , dissoc iat ion ,
and concer n over loss of sanity . In normals , Pillard et al . ( 1974 )
found no effects of cannabis on exper imentally induced anxiety .
Nabi lone , a synthetic cannabinoid , was found to reduce exper imentally
i nduced anx iety in normal volunteers but it was less effective than
diazepam (Nakano et al . , 19 7 8 ) . Nabi lone was found to be more
e ffective than placebo in pat ients with psychoneurot ic anxiety ( Fabre
et al. , 1978) .
There are very few stud ies of cannabis effects on anx iety .
There is no ind icat ion at th is t ime that cannabi s or nabi lone are

149
more effect ive or rel iable than cu r rently ava ilable ant ianx iety
med icat ion .
ANTIDEPRESSANT EFFECT
Regelson et al . ( 1976 ) repor ted a s ignif icant reduct ion in sel f
r ated depressive symptoms i n cancer pat ients t reated with 6 -9-TRC .
However , in a carefully controlled tr ial with four bipolar and four
unpolar depressed patients , Kot i n et al . ( 19 7 3 ) found no ant i
depressant act ivity .
ANALGESIC ACTION
Several animal models have been used to show analges ic effects o f
cannabis a nd its analogues ( for example , Grunfeld and Edery , 1969 J
Sof i a et al . , 19 7 3 ) .
Human stud ies have been conflicting . Milste i n
et al . ( 19 7 5 ) found increase in tole rance to exper imentally induced
pai n afte r smok ing cannabis , wh i le Hill et al . ( 19 74 ) were unable to
detect effects u s ing a d i fferent k ind of exper imental pa in .
Noyes et
al . ( 1976 ) found a reduct ion in pa in reports by cance r pat ients g iven
oral 6-9-THC J Regelson et a l . ( 19 7 6 ) also stud ied cancer pat ients
and found no s ignif icant changes in pain after 6-9-TBC .
Those subj ects who show analges ic effects of cannabi s also show
o ther pharmacolog ica l effects such as mental cloud ing .
The l i terature
does not ind icate a spec i f ic effect of cannabis on pa in pathways nor
does it suggest that cannabis is l i kely to be more effect ive than
cur rently ava ilable analge s ics .
ALCOHOLISM
cannabi s has been proposed as a t reatment for alcohol i sm ( Scher , 1971 )
based upon case repor ts and on the observat ion that cannabis and
A systemat ic evaluat ion
alcohol were generally not used together .
( Rosenberg et a l . , 1 9 7 8 ) failed to f ind cannabi s useful in a lcoholism .
Moreover , recent surveys ( see Chapter 2 ) ind icate that cur rently the
a buse of cannabis and alcohol are frequently combined .
OPIATE WITHDRAWAL
E a r ly clinical repor ts suggested that cannabis might be useful in
suppress ing the symptoms of opiate withdrawa l ( B i rch , 1889 J Thompson
a nd Proctor , 195 3 ) .
Recent ly a se r ies of animal stud ies ( Hine et
al. , 1 9 7 5a , b J Bhargava , 19 7 6 ) have found that 6-9-TBC suppresse s
many of the behaviora l mani festat ions of withdrawal prec ip itated by
naloxone in morph ine dependent rodents .
This effect is enhanced by
cannabid iol (CBD ) ( H ine et a l . , 1975a , b) , but CBD is not effective
alone .

150
There are no reports of systematic evaluat ions of cannabis as a
t reatment of opiate withdrawa l in human beings . The animal studies
do not present evidence that cannabi s is likely to be more effect ive
t han cur rently available treatments for opiate withdrawal .
ANTI TUMO R ACTION

The re is very l ittle informat ion about the effects of cannabis on
neoplasms .
In one study ( Har r i s et al . , 1976) , minor effects we r e
seen o n the Lewis Lung Tumor but not i n Ll210 leukemia . In anothe r
study (Wh ite et al . , 1976) , it was found that 6-9-TBC inhibited
tumor DNA replicat ion somewhat . I n that same study , cannabid iol
appeared to have a g rowth enhanc ing effect on the Lewi s Lung Tumo r .
These l imited stud ies do not support a view that 6-9-TBC has a
useful e ffect in inhibiting tumor g rowth .
SUMMARY
Cannabis and i ts der ivat ives have shown promise in the treatment of a
var iety of disorde r s . The evidence is most impress ive in g laucoma ,
where their mechanism of act ion appears to be different f rom the
standard drugs , in asthma , where they approach i soproterenol i n
e ffect iveness , and in the nausea and vomi t ing o f cancer chemotherapy ,
whe re they cOmpare favorably with phenoth iaz ine& . Smaller tr ials
have suggested cannabis might also be use ful in se i zu res , spast icity ,
and othe r nervous system di sorders . Effect ive doses usually produce
psychotropic and card iovascular effects and can be troublesome ,
particularly in older patient s .
Although mar i j uana has not been s hown unequivocally super ior to
any ex ist ing therapy for any of these condit ions , several important
a spects of its therapeut ic potent ial should be apprec iated . First ,
its mechanisms of act ion and its tox ic ity in several diseases are
d ifferent f rom those of drugs now being used to treat those
cond itions J thus , combined use with other drugs might allow greate r
t herapeut ic eff icacy without cumulat ive tox ic i ty . Second , the
d ifferences in act ion suggest new approaches to unde r stand ing bot h
the diseases and the drugs used to treat them . Last , the re may be an
opportunity to synthesize der ivatives of ma r i j uana that offer bette r
therapeut ic rat ios than mar i j uana itself .
The comm i ttee bel ieves that the therapeut ic potent ial of cannabis and
its de r ivat ives and synthet ic analogues warrant s further research
a long the l ines desc r ibed in this chapte r . The re also may be
s igni f icant heur ist ic benefits to be derived f rom the study of the
b iolog ical mechanisms by which these compounds act .

151
Some the r apeu t ic prom i se seems t o b e of fered by syn thet i c
cannabinoid a n a log ue s .
Th e comm i t tee r ecomme nds t ha t pa r t ic u l a r
atten t ion b e pa id to th e treatme n t of chemothe rapy-ind uced nau sea and

vom i t ing i n cance r pa t i ents because cu r r e n t man agemen t of th i s
impor tan t and w idespread problem i s inadequate and p r e l i m i n a r y
s tud i e s sugg e s t tha t c a n n a b i n o i d s may ha ve some spec i a l adva n tage .
Cannabinoids or the i r a n a log ues a l so may f ind a place
management of r e s i s ta n t g laucoma ,
in the
of seve re i n t rac table a s t hma ,
a nd
of cer ta in forms of se i z u r e s tha t a r e r e s i stan t to s tanda rd the rapy .

Co n t inued c a r e f u l ly con t rac ted c l i n ical t r i a l s i n these a reas s eem
wo r t hwh i l e at th i s t ime ,
can n a b i noids
in
as do s tud ies of the u sefulness of
the t r ea tme n t of musc le spa s t ic i ty .
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delta-9-tetrahydrocannabinol in pat ients rece iving cancer
chemotherapy . N . Engl . J . Med . 293 : 79 5-7 9 7 , 197 5 .
S allan , S . E . , Cronin , c . , Zelen , M . , and Z inberg , N . E . Ant iemetic&
in pat ients rece iving chemotherapy for cancer : A randomized
compar ison of delta-9-tetrahydrocannabinol and
prochlorperaz ine . N . Engl . J . Med . 302 : 1 3 5-138 , 1980 .

155
Scher , J .
Mar ij uana as a n agent in rehabil itat ing alcoholics .
J . Psychiatry 1 2 7 : 9 71- 972 , 1971 .

Shapiro , D .
The ocula r mainfestat ions of the cannabinols .
Qphthalmolog ica 1 6 8 : 3 6 6 - 3 6 9 , 1974 .
Shapiro , B . J . , Tashkin , D . P . , and Frank , I . M .
Mechanism of inc reased
spec i f ic a i rway conductance with mar ij uana smok ing in healthy
young men .
Ann . Int . Med .
78 : 8 3 2 -8 3 3 , 1 9 7 3 .
S of ia , R . D . , Solomon , T . A . , and Bar ry , B .
The ant iconvulsant
act ivity in delta-9-tetrahydrocannabinol in mice .
Pharmacolog ist 1 3 : 24 6 , 1971 .
Sof ia , R . D . , Nalepa , S . D . , Ba rakal , J . J . , and Vassar , B . B .
Anti-edema dna analges ic prope r t ies of 6 -9-tetrahyrocannabinol
( THC ) .
J. Pharmacol . Exp . Ther . 18 6 : 646-6 55 , 1 9 7 3 .
Tashk in , D . P . , Shap i ro , B . J . , and Frank , I . M .
Acute effects o f
smoked mar i j uana a nd oral delta-9-tet rahydrocannabinol on
spec i f ic ai rway conductance in asthmat ic subj ec t s .
Am . Rev .
Respir . Dis . 10 9 : 420-4 2 8 , 1 9 7 4 .
Tashk in , D . P . , Shapiro , B . J . , Lee , Y . E . , and Harpe r , C . E .
Effect s o f
smoked mar i j uana i n exper imentally induced asthma .
Am . Rev .
Resp i r . Dis . 112 : 377-38 6 , 197 5 .
Thompson , L . J . and Proctor , R . C .
The use of pyrahexyl i n the
treatment of alcoholic and drug w ithdrawal cond i t ions .
Med . J . 1 4 : 520-52 3 , 1 9 5 3 .
Tur kan i s , S . A . , Cely , w . , Olsen , D . M . , and Kar le r , R .
Ant iconvulsant
prope r t ie s of cannabid iol .
Res . Commu n . Chem . Pathol .
Pharmacol . 8 : 2 31-246 , 1 9 7 4 .
Tur kan i s , S . A . , Chiu , P . , Bory s , B . K . , and Kar ler , R .
Influence of
delta-9-tetrahydrocannabinol and cannabidiol on phot ically
evoked afte r-d i scharge potent ials .
PsychopharmacologY
52 : 2 0 7-212 , 1 9 7 7 .
Turkanis , S . A . , Smi ley , K . A . , Borys , B . K . , e t al .
An
e lectrophys iolog ical analy s i s of the ant iconvulsant action o f
pi lepsia
c annabidiol on l imbic se i zures i n consc ious rats .
2 0 : 3 51-36 3 , 197 9 .
Wada , J . A . , Sato , M . , and Corcoran , M . E .
Ant iepi lept ic prope r t ies of
delta-9-tetrahydrocannabinol .
Exp Neurol . 3 9 : 1 57-1 6 5 , 1973 .
White , A . C . , Munson , J . A . , Munson , A . E . , et al .
Effects of
de lta-9-tetrahydrocannabinol in Lewi s lung adenocarc inoma cell s
i n t i ssue culture .
J . Natl . Cancer I nst . 56 : 6 5 5-658 , 19 76 .

8
FEDERAL SUPpORT OF
RESEARCH ON MARIJUANA
PRESENT SOURCES AND AI)UNTS OF SUPpORT

I n this chapte r the comm i ttee has examined sources and amounts o f
federal support for research o n cannabis a nd the areas o f research
support . The comm i ttee has not analyzed the sc ient i f ic substance of
the work , nor has it examined the strategy of research support or
reviewed cur rent unpubli shed research .
The overall federal support for research on cannabis for the
f i scal year s 1977 , 1978 , and 1979 has averaged slightly more than $ 4
million pe r year i n real dollars ( Table 4 ) . Dur ing these years , 11
federal agenc ies allocated funds for this purpose . Of these , the
Nat ional Inst itute on Drug Abuse ( NIDA) has been the pr inc ipal agency ,
account ing for over four-f i fths of the total , therefore , our analys i s
will focus pr imar ily on this agency .
FOr f i scal year s 197 5 through 198 0 , NIDA ' s support of research on
c annabis amounted to $ 4 . 5 , $ 2 . 9 , $ 3 . 9 , $ 3 . 6 , $3 . 5 , and $ 3 . 8 million ,
respect ively , in real dollars , but in constant 1981 dollars , cor recte d
by the GNP deflator , the same f igures were $ 7 . 0 , $4 . 2 , $ 5 . 4 $ 4 . 6 ,
$4 . 2 , and $4 . 1 (Table 5 ) . Although the total research budget of th i s
agency for those years increased by approx imately $12 mill ion ( real
dollars) , the percent spent on cannabis declined f rom 14 . 2 to 8 . 2
( Table 5 ) . Dur ing the same per iod , the total numbe r of proj ects on
cannabi s supported by NIDA was reduced by approx imately SO percent r
however , the cost per proj ec t increased f rom $ 4 2 , 700 to $ 71 , 400 ( real
dollars) . This increased coat pe r proj ect is still somewhat lowe r
t han the mean coat o f all proj ects funded by the Nat ional Inst itutes
of Health in 1980 ( Leventhal , 1981) .
Table 6 shows the NIDA extramu ral research prog rams for f i scal
years 1975 through 1981 , allocated according to the type of drug being
s tud ied . In FY 1975 research on cannabi s was allocated only 13
percent of the total ext ramural budget , whe reas na rcot ics and
narcot ic antagonists rece ived more than 4 0 percent . The reafter , the
percentage devoted to cannabi s decl ined , to a low of 8 percent in FY
1 979 , but started to r ise again slightly in FY 1980 and FY 1981 . In
the last year , an est imated 1 1 pe rcent of the budget wa s spent on
cannabis research . The percent of the budget allocated to narcot ics
and narcotic antagon ists has declined stead ily , wh ile the percentage s
156

1 57
TABLE 4
dollars
Cannab is Research by Federal Agency : PY 1977-19 7 9 ( rea l

thousands )
in
Tota l ( 7 7 )
No . o f
g rants
Punds
Pe rcen t
Tota l ( 7 8)
No. of
g rants Punds
Pe rcen t
g rants
Pund s
Pe rcent
Total ( 7 9)
No. of
N IDA
75
3, 940
90
64
3 , 59 6
88
65
3, 536
84
NIMH
167
214
20 7
N IAAA
!.
85
1 22
91
80
85
NBI
68
36
N ICHD
13
!.
15
!.
N I RR
26
NIGMS
NIH
NC I
!.
25
!.
104
85
94
4 , 20 2
OTHER AGBNC I BS
VA
52
DOT
55
USDA
41
102
4 , 354
TOTAL
92
26
4 , 10 6
!.less than 1 percen t .
ADAMHA
DHHS
DOT
Alcohol , Dr ug Abuse a nd Men tal Health Adm in i s t r a t ion

Depa r tment of Hea lth and Human Se r v ice s
Depa r tment of Tr ansportat ion
NCI
NBI
Na t iona l Cance r I n s t i t u te
Nat ional Eye I n s t i tute
NIAAA
NICHD
NIDA
NIGMS
Nat iona l In s t i tute on Alcohol Abuse and Alcoho l i sm

Na t ional In s t i tute of Ch i ld Health a nd Human Deve lopmen t
Na t iona l Ins t i tute on Drug Abuse
NIH
Na t iona l In s t i t u te of General Med ica l Sc iences

Na t ion a l Inst itutes o f Hea lth
NIMH
Na t ional In s t i tute of Mental Health
NIRR
Nat iona l Ins t i tute of Research Resource s

Ve terans Adm in istrat ion
VA
USDA
Sou rce a
Depa r tmen t of Ag r iculture

Adapted f ra. in forma t ion prov ided by NIDA .

TABLE S
Tota l Re searc h and Research on can na b i s i n
l"Y
Tot a l N I DA research budget
'73
l"Y
' 74
l"Y
' 75
NIDA
py
Budg e t
'76
F lt
' 77
py
' 78
Flt
' 79
l!'i
' ci O
/!l{
' 8 J.
3l , 6 0 0
3 4 , 000
3 4 , 046
3 3 , 760
3 3 , 994
3 3 , 986
4 2 , 930
4 5 , !1 7 2
40, 400
58, 500
5 8 , 700
5 3 , 500
4 9 , 600
4 6 , 800
4 3 , 800
5 1 , 0UO
50 , 300
4 0 , 4 00
.!
.!
4 , 48 3
2,853
3, 940
3 , 596
3 , 536
3 , 7 11 11
.!
.!
7 , 043
4, 191
5, 4 21
4 , 636
4 , 201
4 , J. 4 4
.!.
Percen t canna b i s resea rch
.!
l4 . 2
9.1
ll . 6
10. 6
8.2
11 . 2
Tota l canna b i s proj ec t s
105
82
75
64
65
53
.!
4 2 . 70
34. 8
52. 5
56. 2
54 . 4
7 1 . 52
.!.
67 . 1
51 . 1
72 . 3
72 . 5
64 . 6
78 . 2
( r ea l dol la r s ,
thou.and s )
To t a l N I DA r esearch budget
( con s tant 1 9 8 1 dol lars ,
t housand s )
cannabis research budget
( r eal do l lars ,
thousand s )
Cannab i s r e se a r c h budget
( constant 1981 dol l a r s ,
thousand s )
( r ea l dol la r s ,
thousands )
Mean canna b i s project cos t

( r eal dolla r s ,
t housands )
Mean canna b i s p roj ec t coa t

( constant 1 9 8 1 dol la r s ,
t housands )
.!nata unava i lable a t present t i me .
9Mean
N I H Project Coat
( 1 980 )
was l O S .
Adapted fro in forma t ion prov ided by N IDA .
1-'
Ul
CD

TABLE
N I DA Ex t r amu r a l Research Prog r am , D i s t r ibut ion b y Dr ug
FY 1 9 7 5
Dr ug Class
AIIOu n t
FY 1 9 7 6
'
AIIOU n t
FY 1 9 7 7
'
AIIOUn t
FY 1 9 7 8
'
AIIO<J nt
( r e a l dol la r s i n thousand s )
FY 1 9 7 9
'
AIIOU n t
FY 1 9 8 0
'
AIIOu nt
lfY
.1.9 8 l.A
"--u nt:
Can nabi s
4 , 104
13
3 , 694
12
3, 532
11
3 , 114
10
3 , 26 3
3, 683
4 , 500
J..L
Depressants
1 , 642
1 , 527
1 , 9 76
1 , 557
1 , 123
1 , 495
1 , 00 0
316
729
1 , 57 2
1 , 51 5
2 , 358
2, 865
3 , 0 0il
Na rcot ics
9 , 787
31
1 1 , 298
36
1 1 , 766
37
9 . 341
30
8, 947
.H
1 0 , 667
2 !i
J. O , O O O
.I S.
Na r cot ic antagon i s ts
3 , 47 3
11
3 , 061
10
3 , 01 7
10
3 , 526
11
3 , 879
10
2 , 30 4
2 , 11 U O
S t iau1ants
1 , 926
2 , 360
2 ; 291
2 , 5 35
2 , 778
3, 277
II
4 , 0011
.1. 0
1 58
36 3
496
500
J.
Ha l l uc inogens
Vb1at i 1es/solvents
Tobacco
--
--
--
--
Endogenou s su bstances
--
--
--
--
110
--
556
294
:.1 7 8
9 34
1 . uo
2, 973
3 , 200
II
1 , 337
2, 717
2 , 607
3 , 400
tl
--
Po1ydrug ,
u nspec i f i ed ,
TOTAL
othe r
1 0 , 169
32
8 , 166
26
6 , 731
22
6, 723
22
1 2 , 286
32
l J. , 8 7 5
211
8 , 008
.10
31 , 5 7 5
100
31 , 198
100
31 , 4 9 1
100
31 , 1 38
100
38 , 1 7 5
100
42 , 024
100
4 0 , 408
J. O O
!Bst iJNte .
Sou rce
Adapted f r oa i n forJN t i on prov ided bY IIIDA .
....
Ul
10

160
devoted to halluc inogens , st imulants , and endogenou s substances
have i ncreased .
I n FY so , only $3 , 683 , 0 0 0 ( 9 percent) of the extramural budget
was devoted to cannabi s research . Almost as much was spent that yea r
by NIDA on st imulants and on tobacco . Por compar i son , the Nat ional
Cancer Inst itute ' s budget for its prog ram smok ing and Health wa s
$ 13 . 2 million in FY so , of which $ 3 . 9 million was allocated for
tobacco research ( Little , 1981) . The Nat ional Heart , Lung , and Blood
I nstitute allocated $8 . 2 mill ion to study the effects of c igarette
smok ing on the card iovascular repiratory system (Hurd , 1981) .
AREAS OP RESEARCH SUPPORT

Cannabi s research essentially began in the late 1960s with a Nat iona l
I nst itute of Mental Health progr am to produce ped ig reed cannabis
for research invest igator s . NIDA , which was created in 1972 , started
w i th an extramural budget of $ 2 9 . 6 million and an i ntramu ral budget
of $4 . 0 million for f i scal year 1973 ( Ludford , 1981) . In the ear ly
1 970s , NIDA ' s major thrusts were ( a ) supplying ( to researchers)
standard i zed mar i j uana of a known concentrat ion of 6-9-TRC and of
known genet ic stock , (b) fac i l itat ing administrative mechanisms , and
( c ) attempting to under stand the problem of drug abuse , e . g . , how
many people use the drug , what are the acute effects , and what are
it s impl ications (Peter sen , 1 9 8 1 ) .
Recently , NIDA ' s emphasis has shifted to study ing certain g roups ,
e . g . , children , adolescents , and pregnant women , espec ially with
r e spect to the long-term effects of cannabis on these g roups
( Petersen , 1981) . The NIDA prog r am plan for f i scal year 198 2
stresses that chronic and acute stud ies need to be conducted on the
effects of cannabi s and othe r drug s of abuse on women and adolescents ,
w ith a spec ial emphasis on :
( a ) i n-depth behavioral and b iolog ical
stud ies of the amot ivat ional syndrome ( burn-out ) , and ( b ) the
development of approaches to t reatment . Also spec i f ically targeted
are stud ies of the effects on brain funct ion and structure .
Table 7 presents the NIDA proj ects on cannabi s for f i scal years
1978 , 1979 , and 1980 stratif ied by research goal . These research
goals are def ined in the footnote to the table . POr f iscal years
197 8 , 1979 , and 198 0 , most of the money devoted to research on
cannabis ( approx imately $3 million annually) was spent in three areas :
( 1 ) hazard s of cannabi s use , ( 2 ) basic research , and ( 3 ) research
suppor t . Thi s last goal includes the g rowth , process ing , packag ing ,
and d istr ibut ion of cannabis , as well as the development of the
6- 9-TRC capsu le .
It is instruct ive to compare this d istr ibut ion of
cannabis funds with the d istr ibut ion of the total research funds of
NIDA .
In FY s o , research o n hazards took only 12 percent o f the
total NIDA research budget , basic research 42 percent , and research
suppor t 19 percent ( Pollin , 1981) .
The allocat ion of funds , by research topic , for f i scal years
1978 , 1979 , and 1980 is presented in Table 8 . The largest proportio n
o f the funds has been allocated t o two research topics :
( 1 ) drug

161
TABLE 7 NIDA Cannabis Proj ects by Research Goal :
( real dollars in thousands)
Goa ls
1.
FY
Epidemiology
2 . Et iology
3.
Prevent ion
4.
Hazards
5.
1978
FY
1979
FY 197 8-198 0
FY
1980
238
54
61
145
133
136
48
77
916
990
1 , 236
The rapeut ic uses o f canna b i s
43
49
50
6.
Treatment o f cannab is abuse
11
82
7.
Ba s i c research
972
1 , 29 5
1, 036
8.
General r esearch suppor t
1 , 194
1 , 013
1 , 139
3 , 596
3 , 536
3 , 788
TOTAL
1 . Epidemiology--to determine the inc idence , prevalence , trends ,

and d i str ibut ion of drug abuse by sex , race , geograph ic or ig in , and
other spec ial characteristics .
2 . Et iology--to determine the etiolog ic factors assoc iated with
drug abuse , inc lud ing those combinat ions of biolog ica l ,
psycholog ical , and soc ietal factors most assoc iated with increased
r isk for mi suse and/or abuse of drugs .
3 . Prevent ion--to develop and test new strateg ies and methods
which might decrease , postpone , or modify drug-abusing behavior
4 . Hazards--to determine the hazards of drug abuse to the
phys ical and mental health of the ind ividual and its adverse effect s
on soc iety .
s . Therapeutic uses--to study the e ffect iveness and safety of
cannabi s in the treatment of var ious med ical cond i t ions .
6 . Treatment--to determine the most effect ive therapeut ic
procedures for reduc ing drug abuse includ ing new and innovat ive
t reatment methods and development of more effect ive drug s to be used
in treatment .
7 . Basic research--to advance bas ic knowledge of the
pharmacology , biochemistry , and neurophysiology of drugs , the basi c
mechanisms involved in d rug tolerance , and dependence and the
underlying processes involved in add ict ive and/or habitual behavior s .
e.
Research support--to develop the methodolog ical and suppor t
resources requi red to further drug abuse research J to provide for the
publ icat ion and evaluat ion of research result s , the analysis and
supply of controlled substances , and the development of chemica l
methods to detect and assay drug s .
Source :
Adapted from informat ion provided by NIDA .

162
TABLE 8 NIDA Cannabinoid Proj ects by Research TOpic :
( real dollars in thousands)
FY
1978
FY
1 979
FY
197 8-198 0
FY
1980
Assay and models
482
30 2
268
Drug development , synthesis ,

and d i str ibution
706
756
950
54
76
16
Pe rformance (esp . dr iving )
193
111
76
Reproduct ion a nd development
491
864
849
Behavioral stud ies
124
62
15
O ther drug effects/tox ic ity
397
347
440
Metabolism and pharmacok inet ics
261
446
259
69
85
Psychophysiology
Immunology
64
97
67
58
103
Mechanism of tolerance and

d ependence
285
174
134
Cu ltural/ethnic
195
45
69
57
80
127
137
66
337
Drug interactions
Chemi stry
Patterns and lifesty le

C r ime/law
Abuse liability
TOTAL
48
76
3 , 594.!.
3 , 536
3 , 78 8
!Due to round ing o f numbers , the total value i s not exactly the
same as in Table 7 .
S ource :
Adapted from informat ion provided by NIDA .

163
development , synthe s i s , and d i str ibut ion , and
r eproduc t ion and development .
( 2 ) drug effects o n
Grants , Contracts , and Intramural Proj ect s

Tables 9 through 11 compa re the numbe r of g rants , contracts , and
intramu r a l projects on cannab i s , as well a s the fund s expended by
e ach agency for f iscal years 1 9 7 7 , 1978 , and 1 9 7 9 .
In each of these
year s , most of the extramural awards and most of the money involved
The rat io of g rant to
i nvestigator-init iated research g rants .
contrac t funds rose du r ing th i s pe r iod from approx imately 1 . 5 in FY
' 7 7 to a lmost 3 . 0 in FY ' 79 .
For NIDA a s a whole , that ratio has
cons i stently been much h igher 1 in FY ' 7 9 , for example , the fund ing o f
g rants was more than f ive t imes that o f contracts .
Suppor t of invest ig ator-init iated re search grants requires tha t
g rant appl icat ions be approved by a peer review comm i ttee .
In the
peer review process , each approved g r ant i s g iven a pr ior ity scor e
based o n sc ient i f ic mer i t of the proposal ( scaled from 1 0 0 to 500 ,
with 1 0 0 the h ig hest ) .
Thi s pr ior ity score dete rmine s the orde r i n
which ava i lable fund s a r e d isper sed .
The award r ate for all drug
research suppor ted by NIDA is shown in Table 12 .
The percentag e of
g rants r ecommended for approval has increased slightly over recent
yea r s , as has the total number of g r ant appl icat ions .
However , the
percent of approved g r ants that has been funded has gone down sharply ,
as shown in the table .
Por FY ' 8 1 it i s est imated that only 2 5
percent of all appl icants were u lt imately funded .
The pr ior ity score
at the 90th percent i le of funded appl icat ions has also been
d ec l i n ing , and in 1981 was e st imated at 190 .
These data suggest that
the re has been no decline in the qua l i ty of funded g r ants--i f
anything , the qual i ty has r i sen dur ing the past few year s .
The number o f invest igator-init iated proj ect s ha s dec rease d
s l ightly bu t still exceeds the number of contracts and intramural
proj ects .
Grants generally are for a per iod of 3 year s ( renewable o n
a year -to-year bas i s ) , with a max imum per iod of 5 years ( Peter sen ,
Contract proj ect s are funded on a year-to-yea r basis and a r e
1981) .
mainly concerned with the g rowth , processing , packag ing , and
d i st r ibut ion of cannab i s , as we l l as with the development of th e
6- 9-THC capsule . * A few stud ies a re conducted on tox icology and
pharmacok inet ics ( Peter sen , 1 9 8 1 ) .
For f iscal years 1 9 7 7 , 1 978 , and
1 9 7 9 , the number of contracts has declined :
16 , 1 4 , and 10 ,
r e spect ively .
However , the requests for proposals for f i scal years
1980 and 1981 have increased to 1 2 and 14 , respect ive ly ( Ludford ,
1 98 1 ) .
Intramural proj ec ts account for a small por t ion of the budget J
for fiscal year s 1 9 7 7 , 197 8 , and 1979 , they have been declining .
* NIDA has r equested that the NIH take over the cost and d istr ibut ion
of the drug s for clinical stud ies ( Snyde r , 1 9 8 1 ) .

164
TABLE 9 canna bi n oid Re se a rc h by Agency :
( real doll a r s i n thousands )
Grants
FY 1 9 7 7
Con tracts
I n t t aaura1
Total
No .
Fund s
75
3, 940
No .
Funds
No .
Funds
No .
N I DA
55
2, 267
16
1 , 6 29
NIMH
167
167
N IAAA
91
91
52
55
Funds
ADAMHA
44
N IH
NC I
NEI
NCHD
N I RR
NIGHS
OTHER AGENC I ES
VA
DOT
55
USDA
TOTAL
Source a
69
2 , 53 3
18
52
1 , 68 4
4l
4l
12
137
99
4 , 354
Adapted f roe i n format ion provided b y N IDA.
SUMMARY OP FINDINGS
Total federal suppor t for research on cannabis has been declining in
real dollars over the past 3 years . Most of that suppor t comes from
the NIDA research budg et , wh ich allocates approx imately 10 percent of
its resource s to this purpose . The current level of funding , under 4
m illion dollar s , supports only about 50 extramural proj ects and
represents only one-tenth of the total research prog ram of NIDA .
Th i s decl ine i n support has inexpl icably occur red dur ing a per iod
when the concern of the publ ic and of all levels of government seems
to be r ising . I t cannot be explained by lack of inte rest in the
f ie ld , for research grant applicat ions have r isen r ne ithe r can it be

165
cannabinoid Research By Agency :
( r eal dollars i n thousands )
TABLE 1 0
Grants
FY
1978
Con tracts
IntraJIUral
Total
No .
Pund s
No .
Punds
No .
Pund s
No .
N I DA
47
2 , 104
14
1 , 460
30
64
3 , 594
N IMH
1 58
56
214
N IAAA
85
85
NC I
80
80
NB I
68
68
NCHD
13
13
NIRR
26
26
26
Punds
ADAMilA
NIH
NIGHS
0'1'HBR AGENC I ES
6
VA
DOT
26
.!
.!
USDA
'l'O'l'AL
65
2, 534
15
.!Ind icates a f und ing leve l o f less than

Sou rce a
1 , 46 0
12
112
92
4 , 10 6
$1000.
Adapted f r oa inforaat ion p r ov id e d by NIDA .
attr ibuted to lack of sc ient i f ic opportunity r for every area we have

s tud ied , the comm i ttee has ident i f ied important quest ions that seem
amenable to new research effor ts .
(Many of these have been
e nuaerated in the preced ing chapter s . )
I n FY eo , NIDA spent a nearly equal a110u nt on st imulant d r ug s
a nd more than four t ime s as much on narcot ics and narcot ic antago
nists . Most of the cannabi s research is devoted to three areas i n
approx imately equal amounts :
( 1) g rowth , processing a nd d istr i bu t ion r
( 2 ) hazard s of cannabi s u se r and ( 3 ) bas ic research . Three quarter s
o f all the federal research money devoted to cannabis goes to

166
TABLE 1 1
ca n n a b i no i d Research by Ag en cy :
FY
1979
( r ea l dolla r s i n thousand s )
Gr a n t s
Con t r acts a
I n t r amu r a l
No .
No .
Funds
No .
N I DA
54
2, 6 08
10
N IMH
145
N I AAA
NC I
Fund s
Fu nds
Tota l
No .
Fu nds
ADAMHA
1
65
3, 536
62
207
122
1 22
85
85
NE I
36
36
N ICHD
15
15
25
925
NIH
NIRR
N I GHS
OTHER AGENC I ES
8
VA
25
DOT
104
104
USDA
85
85
13
1 , 11 4
94
4 , 224
TOTAL
69
!F Y 1 8 0 :
RFP 1 2
FY ' 81 :
RFP 1 4
source :
3, 020
12
90
Adapted f r om i n forma t ion prov ided by N I DA .
investigator-initiated extramural research grants , and most of the

r est to extramural contracts . There is relat ively little intramural
research . The fract ion of NIDA g rant s approved is about 60 percent ,
but the fraction funded is sl ightly more than half of that . The
total numbe r of cannabis research grants i s declining stead ily as
support ( in constant dollars) cont inues to fall and the average cost
of a proj ect ( in constant dolla r s ) goe s up .
The comm i ttee bel ieves that the magnitude of the problem , and the
extent and depth of public concer n about the consequences of
mar ij uana use warrant more support of research in this f ield .

167
TABLE 1 2
Drug Abuse Research Gr ant Award Rate s and Pr ior ity Score s
Appl icant s rece i ved
( numbe r )
Pe rcent r ecomme nded for approva l
1979
1980
1981
1982
Actua l
Actua l
Est imate
Est ima t e
359
369
382
360
59
62
63
62
63
57
40
27
37
35
25
20
244
230
190
170
Pe rcent funded o f those approved

d u r i ng y e a r
Pe rcent funded of a l l appl ican t s
9 0 pe rcent p r ior i ty score
Source :
Adapted from i nformat ion prov ided by NIDA .
Emphasis should be on stud ies of human be ings and other pr imates , and
investigator-initiated research g rants should continue to be the
p r imary vehicle of support .
RECOMMENDATIONS
I n view of the demonstrated h igh potent ial of r i sk to human health
that has been associated with the u se of cannabis , the ex isting fund s
a l located to such resea rch are not appropr iate . The comm i ttee ' s
recomme ndat ions to federal agenc ies regarding suppor t of
c annabis-related research a re :
More support of cannabis research is needed . Proper ly

allocated , it could pay large d ividends in new knowledge and could
help to d i spe l present ignorance in many c r i t ical areas . Withou t
this new informat ion , the pre sent level o f publ ic anxiety and
controversy over the use of mar ij uana is not li kely to be resolved i n
t he forseeable future . Furthermore , we are not l i kely to improve ou r
present slow prog ress in deve lop ing informat ion about possible
therapeut ic u ses of cannabis and its analogues without the stimulus
of increased research grant suppor t . At the end of each of the
c hapter s , we have pointed out opportunities or problems that are r ipe
at thi s t ime .
A larger proport ion of NIDA resou rces could j ust i f iably be

allocated to cannabis research . Without wishing to minimize the
value of any of the other drug research prog rams now supported by
N IDA , we believe that the magnitude and soc ial u rgency of the
mar ij uana problem war rant a h ighe r pr ior i ty for cannabis researc h

168
than it has apparently rece ived to date . A drug that is cur rently
u sed by about a third of all Amer ican high school sen ior s , and daily
by about one in eleven , dese rve s more study than we cur rently are
g iving it . No other i llicit drug is used as widely by our youth , and
yet NIDA spent only 9 percent of its research budget on it in FY so .
NIDA would be advised to cont inue its recent policy of

reducing the relat ive proport ion of contracts and emphas i z ing
g rants . Although we bel ieve that there is need for fede ral
i nit iat ives in st imulat ing work in neg lected areas of cur rent
conce r n , the bulk of research supor t should cont inue to go to
i nvestigator- init iated proj ects .
The durat ion for invest igator-initiated research should be

lengthened beyond the average 3-year per iod in order to attract and
hold good researcher s .
Other agenc ies should contr ibute funds for the product ion ,
processing , and d istr ibut ion of cannabis .
A sc ient i f ic advisory g roup should be formed to ass ist i n

provid ing sc ientif ic evidence and gu idance to the d irector o f NIDA .
An increased interagency effor t targeted toward spec i f ic

problems not read i ly add ressed by other approaches is required .
These would include , for example , human long-term stud ies , as well a s
stud ies i n epidemiology , prevent ion , and treatment . Funds should be
contr ibuted by all agenc ies .
Research on human be ing s and other pr imates should be

encouraged , par ticularly stud ies in the young . There i s a spec ial
need at th i s t ime for good epidemiolog ica l stud ies that follow
ident if iable cohorts of mar i j uana users over a per iod of t ime .
REFERENCES
Hurd , Susan . Nat ional Hear t , Lung , and Blood Inst itute . Bethesda ,
Md .
Per sonal commu n icat ion , 1981 .
L ittle , Franc ine . Nat ional Cancer Inst itute , Bethesda , Md . Pe r sonal
commun ication , 1981 .
L eventhal , Car l . Nat ional Inst itute of Arthr it is , Metabolism, and
Digestive Diseases , Bethesda , Md . Pe r sonal commu nicat ion , 1981 .
Ludford , Jacqueline . Nat ional Institute on Drug Abuse , Rockvi lle ,
MD .
Per sonal commu n icat ion , 1981 .
Peter sen , Rober t . Nat ional Inst itute on Drug Abuse , Rockvi lle , Md .
Per sonal commu nication , 1 98 1 .
Pollin , w . Statement on Drug Abuse Research before the Subcomm i ttee
on Alcoholism and Drug Abuse , Comm i ttee on Labor and Human
Resources . United States Senate , July 2 7 , 1 981 .
Snyder , Marvin . Nat ional Inst itute on Drug Abuse , Bethe sda , Md .
Personal commu nicat ion , 1981 .

Append ix
WORK OP TBB COMM I 'l'TBE
To conduct thi s study , the Institute o f Medic i ne estab l ished a

comm i ttee of exper ts drawn from relevant d i sc ipl ines , i nclud ing
c linical med ic i ne , epidemiology , pharmacology , psychiatry , and
tox icology . Th i s stee r i ng coa.i ttee ' s expert i se was augmented by
consultants , as wel l as by aany other per sons serving as panel
ll8Jibers . S ix panels , eac h cha i r ed by a comm i ttee meaber , were formed
to car ry out a detai led analy s i s of such spec ial i ssues a s the
effec t s of cannabis u se on behavioral and psychosoc ial development ,
on reproduc t ive and fetal b iology , on card iovascular and respiratory
systeJU , and to oons ide r neurobiolog ic , genet ic , oncogen ic , and
cytogenetic i ssues , and cell b iology , includ ing pharmacolog ic and
immunolog ic aspects . Du r ing the ear ly months of the study , the
panels met to apport ion wr i t i ng respons i b i l i t ies , and e stabl ished the
scope and focu s o f each panel s underta k i ng . The chronology of the
panel meet ings follows .
February 3 , 1981 : Pane l on Behavioral and Psychosoc ial I ssues met in
Washington
February 1 8 , 1981 : Pane l on Neurobiolog ical I ssues met in
Washington
February 2 6 , 1981 : Panel on Card iovascular and Respi ratory I ssues
met in New Yor k City
February 2 7 , 1981 : Panel on Genet ic/Oncogenic/Cytogene t ic I ssues
met i n Washington
Ma rch 1 1 , 1 981 : Panel on Reproduct ive and Petal I s sues met in
Boston
March 16 , 1 9 8 l a Subpane l on I ntrapersonal var iables and Social
Behavior of the Pane l on Behaviora l and Psychosoc ial Issues me t
i n Los Angeles
March 2 3 , 1981 : Panel on Cel l B iology/Pharmacolog ical and
IIIDUnolog ica l Issue s met in Boston
Apr i l 1 4 , 1981 : Panel on Behavioral and Psychosoc ial Issues met in
Washing ton
The steer ing comm i ttee , i n the meant ime , nominated add it ional
cand idate s for membership on the panel s and comm i ttee at its f ir s t
meeting o n December 1 , 1980 . Subsequently , four more meet ings were
169

170
held , o n Apr i l 1 5 , 1 9 8 1 , June 2-3 , 1 9 8 1 , Aug ust 31-Septembe r 1 , 1981 ,
and October 2 6 , 1 9 8 1 .
The f i r st two were held in Washington , the
t h i rd meeting was held in Wood s Hole , Massachusetts , and the f i nal
meet ing wa s held in Washing ton .
The comm i ttee made full use of research in other count r ies as
we l l as the Un ited S tates .
A spec ial effort wa s made to coord inate
activities with the staff of the Add ict ion Research Foundat ion/Wor ld
Health Organi zation Conference on Adverse Health and Behav ioral
Consequences of Cannabi s Use .
The g roup ' s draft report and work ing
The mandate of th i s
pape r s we r e made ava i lable to the IOM comm ittee .
g roup was to consider the sc ient i f ic , c l i n ical , and epidemiolog ical
informat ion about potent ial and actual ha zard s to health .
Because of widespread publ ic interest in the IOM study , a not ice
was placed in the February 2 4 , 1 9 8 1 , Federal Reg i ster to sol ic i t
i nformat ion f rom the publ ic and f rom profess ional g roups o n the
health-related effec t s of canna b i s use .
Approx imately 9 0 response s
were rece ived from professional organi zat ions , lawye r s , med ical
The response s
doctors , sc ient i sts , othe r profess ionals , and parents .
c an be d ivided into three categor ies :
1.
The dangers of mar ij uana .
The maj o r i ty of responses came
Many parents of
f rom people and g roups opposed to cannabi s u se .
cannabi s smoke r s ( and ex-cannabis smoke r s ) submitted statements abou t
t he i r per sonal exper iences and observat ions .
Included among the
g roups that responded are the Nat ional Federation of Parent s for Drug
Free Youth , Georg ia Cong ress of Parents and Teache r s , the Amer ican
Lung Assoc iat ion , Drug Informat ion Prog ram of the Crusade Against
C r ime , t he Comm i ttees of Cor respondence , Phoenix House Foundat ion ,
and Pr ide .
2.
The therapeut ic pgtent ial of mar ij uana .
Responses were
rece ived f rom med ical doctor s , a s well as individuals or the i r
parents , repor t ing that cannabis had allevi ated pa in f rom var ious
med ical problems-- rheumatoid arth r i t i s , mig raine headaches , mul t iple
scleros i s--and had in some cases lessened the s ide-ef fects of drug s
used i n chemothe r apy .
In most case s the mar ij uana had to be obtained
by unauthori zed means , mak ing many of the vict ims and the i r families
uncomfortable .
Seve ral respondents were f rom the State of Mich igan ,
where a cannabis the rapeutic research prog ram has recently been
author i zed by the state leg i s latu re .
Responses were also rece ived
f rom the Alliance for Cannabis The rapeut ics and the Ame r ican Med ical
Assoc iat ion .
3.
Suppor t of gene ral u se and legal i zat ion of mar i j uana .
Response s in this regard we r e r ece ived from lawyer s and othe r
i nd ividuals , as well as the followi ng organi zat ions :
the Eth iopian
Z ion Copt ic Chu rch , the Cannabis Inst itute of Amer ica , the Nat iona l
O rgan i zat ion for the Reform of Mar i j uana Laws , and the publ icat ion
One wr i te r contended that per haps more people would
H igh Times .
s ubmit statements i f the i r anonymity were assured .

Append ix
B
ACCESS '1'0 -9-THC AND MARIJUANA
FOR RESEARCH AND TREATMENT
The invest igat ional u se in human subj ects of -9-THC and ma r i j uana
are controlled by the Fede ral Food , Drug , and Cosmetic Act and the
Investigat iona l New Drug Regulat ions issued unde r that Act .
In
add i t ion , -9-THC and mar i j uana are controlled under the provis ions
of the Cont rolled Substances Act and cur rently are cont rolled in
Schedule I of the Cont rolled Substance s Act .
Schedu le I drug s ar e
t hose that have a
( 1 ) h igh potent ial for abuse , ( 2 ) no cur rently
accepted med ical use in treatment in the Un ited States , and ( 3 ) lac k
of accepted safety for use unde r med ical superv i s ion .
Basically two agenc ies wor k together for enforc ing the cont rol s
o f the Act a
the Food and Drug Administrat ion ( FDA) in the Department
of Health and Human Service s and the Drug Enforcement Administ rat ion
( DEA) in the Department of Just ice .
The Depar tment of Just ice was
pet it ioned to recons ider the re schedu ling of -9-THC and mar i j uana
in 1 9 7 2 , but to date there has been no change .
Howeve r , DEA and FDA
are now under court order to recons ide r thi s situat ion . An FDA
advi sory meet ing , held in June 1981 , cons idered the scheduling status
The
of the -9-TBC capsu le only (Federal Reg i ster , 1981 ) .
comm i ttee recomme nded that the -9-THC capsule be changed from
Schedule I to Schedule I I status when a new drug appl icat ion fo r
- 9-TBC i s approved by FDA . Schedule I I drug s a re those that
have :
( 1) a h igh potent ial for abuse , ( 2 ) a cur rently accepted
med ical use in treatment in the United State s or a cur rently accepted
med ical u se with seve re restr ict ions , and ( 3 ) abuse that may lead to
severe psycholog ical or phy s ical dependence .
COmpla ints and concerns were expressed to the study comm i ttee
abou t the supply and d i str ibut ion of mar i j uana and -9-TBC for
treat ing chemotherapy s ide-effects in cance r pat ients .
On the one
hand , phys ic ians said that there was poor cooperat ion f rom federal
agenc ies engaged in controlling and supply ing the drug (Koller , 1981 J
Monsma , 1981) , par t !cu larly with respect to ( 1 ) potency of -9-THC
rece ived ( concentrations we re too low to be effective ) , and ( 2 )
unce rtainty and irregular ity of the sh ipments of the drug .
On the
othe r hand , some cl inic ians felt that it was premature to release
A-9-TBC for use in cance r pat ient s (Moertel , 1981 J Cook , 1981)
because :
171

17 2
spec i f ic ind ications have not been established , in that the

way in which chemothe rapeut ic agents cause nausea and vomiting is not
known ,
spec i f ic populat ions of pat ients have not been establ ished ,
effect ive dose schedules have not been establ i shed r
safety of treatment at doses effect ive for ant iemet i c

purposes rema ins in quest ion r
r eported peer-rev iewed exper ience i s contrad ictory and st ill

fragmentary , and
c ontrolled , r andomi zed , prospect ive stud ies have not been
conducted .
Depend ing upon the use of the drug , two d i fferent agenc ies are in
charge of supply ing mar i j uana c igarettes and -9-THC capsules r the
Nat ional Institute on Drug Abuse (NIDA) controls the supply of
mar i j uana c igarettes and/or -9-THC capsules for basic research ,
and the Nat ional Cancer Inst itute (NCI ) controls the supply of
6-9-TBC capsules for cancer treatment . The processes of obtaining
supplies f rom each agency (or for each purpose ) d if fer .
OBTAINING 'l'HB MARIJUANA CIGARE'l"l'ES *

T o obta in mar i j uana c igarettes for basic research , t a n invest igator
must r eg i ster with DEA (apply for a l icense ) , f i le a Not ice of
Cla imed Investigat ion Exempt ion for a New Drug ( IND) t t with FDA ,
and submit an order for drug substance to NIDA . The agenc ies suggest
that all the paperwor k be f i led concu r rently in order not to
unnecessar i ly delay the process . FDA analyzes the sc ient i f ic
protocol and determines i f the proj ect has sc ient ific mer it , i f the
researcher is qualif ied , and i f IND requ i rements are sat isf ied . DBA
send s an agent to supply the orde r forms , to determine from local
pol ice records whether the invest igator has a d rug traff ick ing
record , and to see if the invest igator has provis ions for keeping the
d rug secure f rom theft . On not i f icat ion of approval by FDA and DEA ,
NIDA will supply the drug . The ent ire process i s supposed to take
f rom 3 0 days to 6 months , includ ing the visit from the DEA (TOcus ,
19 81) . However , some invest igator s have contended it can take longer .
To obtain mar ij uana c igarettes (or -9-THC capsules ) for
i nvestigat ional treatment of g laucoma , mult iple sclerosis , or
* Concentrat ions of -9-TBC r ange between o . s and 2 . 8 percent , the

mar i j uana c igarettes conta in other cannabinoids , as well as other
chemicals .
t DEA and FDA do not fund research . Federal agenc ies that have
supported cannabis research in FY 1979 ( in order of percent
cannabinoid research ) are : NIDA ( 8 4 ) , NIMH ( 5 ) , NIAA ( 3 ) , NCI ( 2 ) ,
DOT ( 2 ) , USDA ( 2 ) , NEI ( 1 ) , NICBG and NIGMS ( less than 1 ) .
t tTwelve state s hold the i r own IND as of September 19 81 .

173
anorex i a , the phy s ic ian aust g o through the bas ic r esearch route .
v iew o f the poss ible contaminant problems with asperg i llus and
salmone l la , it may be necessary to provide ste r i l i zed ma r i j uana
c igarettes to pat ients .
In
OBTAINING THE -9-TBC CAPSULES*

As a Schedule I drug , -9-TBC can only be used for investigat ional
purposes .
Howeve r , same cancer pat ients undergoing chemother apy
t reatment and resistant to standard ant iemetic drug s benefit f rom the
ant iemetic prope r t ie s of -9-TBC .
Ther e fore , a system has been
e stabli shed for the d i str ibut ion of -9-TBC capsules to
chemother apy pat ients within the guidelines of the Schedule I
r estr ict ions .
A psic ian who wants to dispense -9-TBC capsules to his
cance r patients does so under NC I Group c d i str ibut ion system (Group
The physic ian sends an FDA r eg i stration form to
C Gu ide l ines , 1 9 8 0 ) .
a DEA-approved hospital pharmacy .
The pharmacy forwards the
appl icat ion to NC I , wh ich ho lds its own I ND .
NCI evaluates the
c redent ials of the physic ian , and , i f approving , informs the pharmacy
Th i s process , under eme rgency si tuat ions ,
to supply the physician .
c an take as l ittle as 2 4 hou r s (Abraham , 1981 ) .
A physic ian aay also
obtai n mar ij uana c igarettes for cance r patients in an NCI-approved
More than 5 0 0 hospitals have been invited to
t reatment prog r am .
partic ipate (Abraham , 1 9 8 1 ) , and about 3 0 0 have clearance from DEA
( Gunby , 1981) . Shipments began late last fall ( Gunby , 1981) .
More
than 1 , 5 0 0 physic ians have applied , and 1 , 0 0 0 have been approved by
DEA ( Gunby , 1981) .
The doses ava i lable in capsule form are 2 . 5 and
5 mg .
At least one company has submitted a New Drug Appl icat ion ( NDA)
to the FDA for manufactu re of a synthetic -9-TBC capsule to trea t
cancer pat ients ( Federal Registe r , 1981 , TOcus , 198 1 ) .
I f an NDA for
9-TBC i s approved , a Schedule I statu s will no longer be
appropr i ate .
In fact , the Drug Abuse Advi sory Comm i ttee t
recomme nd ed that the -9-TBC capsule be changed from Schedule I to
a Schedule II status when an NDA is approved by FDA .
* Pur ity of -9-TBC capsules i s better than 9 6 percent ( 9 7-98

percent , c. Turne r , 1981 , and 1 0 0 percent , D . Abr aham , 1981) .
tTh e comm ittee advise s the Comm i ss ione r of Food and Drug s regard ing
the scient i f ic and medical evaluat ion of all informat ion gathered by
the Depar tment of Health and Human Services and the Depa rtment of
Just ice with regard to safety , eff icacy , and abuse potent ial of drugs
and othe r substance s and r ecomme nds action to be taken by the
Department of Health and Human Services with reg ard to the mar keting ,
investigat ion , and control of such drug s or othe r substances .

174
SUPPLIERS O F MARIJUANA C IGARETTE S AN D -9-THC CAPSULE S
Ma r i j uana c igarettes are suppl ied to NIDA by Research Tr iangle

Inst itute , wh ich stores and d i str i butes them (Davignon , 1 9 8 1 ) .
Many contractors are engaged in the synthesis , storage , and
d i st r i but ion of -9-TRC capsules to NCI .
Manu facture is done by
Aeroj et Propuls ion Labs ( large scale ) and Ar thur D . Little ( small
scale ) .
Stanford Research Institute assays -9-THC .
Banne r
Ge lat in encapsulates i t .
Flow Laborator ies stores and ships
9-THC to DEA-approved hospital pharmac ies .
REFERENCES
Abraham , Dav id .
Invest igat iona l Drug Br anch , Hea lth Sc ienc e
Administrat ion , Nat ional Cancer Inst itute , Bethesda , Md .
Per sona l commu n icat ion , 1981 .
Cook , D . A .
Pr ivate pract ice , Bay City , Mich .
Per sonal
commu n icat ion , 1981 .
Davignon , Paul .
Ch iei , Pha rmaceut ical Resou rces Branch , Nat ional
Cance r Inst i tute , Bethesda , Md .
Pe r sona l commu nicat ion , 1981 .
Study of
Federal Reg ister , Volume 4 6 , Number 3 1 , Februa ry 2 4 , 1981 .
the health-related effects of mar ij uana use , pp . 13816-13 818 ,
1981 .
G roup C Gu idelines for the use of -9-Tetrahydrocannabinol
NSC1 3 4 4 54 for nau sea and vomi t ing induced by ant ineoplast ic
Investigat iona l Drug Branch , Cance r The rapy
chemothe rapy .
Evaluat ion Prog r am , Div i s ion of Cancer Treatment , Nat ional Cancer
Inst itute , Bethesda , Md . , September , 19 8 0 .
JAMA
Gunby , P .
Many cancer pat ients rece iving TRC a s ant iemet ic .
2 4 5 : 1515-1518 , 198 1 .
K oller , C . A .
Ass i stant Professor o f Internal Med ic ine , Divis ion of
Un ivers ity of Mich igan , Ann Arbor ,
Hematology and Oncology .
M ich .
Per sonal commu nicat ion , 1981 .
Moe r tel , C . G .
Director , Mayo Comprehens ive Cance r Cente r 1 Professo r
of Oncology , Mayo Med ical School , Cha i rman , Depar tment of
Oncology , Mayo Clinic , Rocheste r , Minn .
Per sonal commun icat ion ,
1981 .
Senator , State Senate of Mich ig an , Lansing ,
Monama , Stephen v.
Mich .
Per sonal commu nicat ion , 19 8 1 .
Tocus , Edward c .
Chief , Drug Abuse Staff , Food and Drug
Administration , Rockville , Md .
Pe r sonal commu n icat ion , 1981 .
Turner , Car leton .
Di rector , Research Inst itute of Pha rmaceut ical
Per sona l
Sc iences , University of Miss i s s ippi , Oxford , Miss .
commu nicat ion , 1981 .

Append ix
LONGITUDINAL STUDIES
Append ix C i s a rev iew of prospective long itud inal stud ies of drug
use in normal populations listed by complet ion status , type of sample
( schoo l sample , commu nity sample ) , age of respondents , and year of
first contact . Some of the stud i e s are ongoing .
175

Characte r i s t ic s of Long itud inal Stud ie s of Drug Use in Normal Populat ions Listed by Completion
S tatus , Type of Sample , Age of Respondents , and Year of First Contact .
Part 1 .
Pr inc ipal
Inveat igator a
Population
Characte r i st ics
Calpleted Studiea a
Gcade/Age at
'1'1 of Sallp le
E l ig ible for
Panel
Schoo l Suplee
Year of
Fi rat
Contact
Year of
L.. t
Contact
lellaa
All ente r ing public

and parochial schoo l
f irst-g rade children
i n a black ni ty
i n Chicago with low
inco.e and high un
eI.oy.ent
Grade 1
1966
19751976
S.ith
Students froa g redea

c-12 i n 6 schoo l
ayateaa i n g reater
Boston a rea , pre
doai nantly wh ite and
iddle-claaa
Gredea
c-11
1969
1973
laplan
Seventh g rade students f roa 18 of 36

j unior high achoo l a
of the Houston
I ndependent Schoo l
Diatr ict
Grade 7
Jea110r and
Jea110r
High schoo l atudy a

Grades
randoa le of
7-9
students f roa g rades
7-12 of 3 junior and Grades
3 sen ior h igh schoo l s 10-11
i n a ... 11 c ity in
the Rocky Mountains ,
at all of Ang lo
r ican , idd leclaaa backg round
B U..- and
JoaephiiOn
Students f roa 5
Grades
7-10
j unior and 18 aen ior
high schoo l s purposefully aelected to
r epreaent va ried
r eg ions , nity
a i ae a , aoc ioac:onc-ic
leve l s , and racial
c011p0a l t lona but not
to r epreaent tha
Un ited State s
Total
llullbe r
of
Contacts
5
2-5
Interval
Betwee n
Con tecta
3 tiM
dur i ng
f i rst
g rede
2 years
7 yea r s
1 year
S he of
Sle '1'1
Bllg i ble
for Pane l
1 , 2U
12 , 000
(approx . )
S he of
Matched
Methode of Da ta
Collect!
Dr119a Inqu i red About
aa.e interv ieva 1

schoo l te sta ( IQ ,
achie-nt) and
g radea 1 ratings
by teacher , cli
nician , -the r
('1'1-'1'5 ) 1 pollee
recorda , quea
tlonna irea ( '1'5 )
Cigarette s , bee r or
vine , hard liquor ,
.. r i j uana , LSD,
othe r paycbade lica ,
upper s , downe r s ,
tranqu i l i aera , co
ca ine , heroin and
other opiate a, glue ,
cough syrup
Self-ini atered
quest ionnai res in
claaarooaa , achoo l
record a , peer s '
rat ings of atudents ' personalitiea
C igarette s , l iquor ,
.. r i j uana , ups ,
downs, psychedelics
op iates , inhalant s ,
nonpre scr iption
dr119 stor e products
Pane l
705
Var iable
1971
1973
1 year
7 , 6 20
3,U8
Self-ini atered
quest ionna ires in
claaaroo.a
Bee r or vine , liquor ,

.. r i j uana , na rcot ics
1969
1972
'
1 year
589
C83
1969
1972
2-3
1 yea r
26 2
Var i able
Belf-aCJ.in iatered
que stionna i re
outs ide of claaa ,
schoo l recorda
Bee r or vine , hard

li quor , .. r i j uana ,
hetaa inea , LSD ,
other paychede l ica ,
cocaine , and heroin
1971
1973
Belf-ini atered
questionna i res in
claaa roo.a
Cigarette s , bee r or
vine , hard liquor ,
.. r i j uana or hash ish,
uaphetaai nea , the
dr ine , barbiturates,
LSD , other payche
de llca , cocaine ,
hecoi n , i nha lants
2 years
18 , 363
8 , 136
....
....,
0\

Annie and
Wataon
Student of l public
high acboo l a i n a
northern Ontar io
city and dropouta
f raa .... claaHa
Grade 9
( 1 ) Mult i a tage rand aa aa.ple o f llaw

Yor k State public
aecondary acboo l
atudanta fraa 1 8
acboo la and data
f raa 110thara o r
fathara 1 beat acbool
fr iend in aubaa.pl a
of 5 acboo l a
Gradea
9-12
1971
1972
( 2 ) 1972 Senior
claaa ( Th i rd wave)
Grade 1 2
1971
1973
7-12
110nt:ha
Johnaton
Yout h in Trana i t ion

cohort--A national
rando. UIPle of
boya i n 8 7 publ ic
high acbool a in
cont inental Uni ted
Stataa i n 1966 1 drug
caaponenta added in
1970 and 1974
Grade 10
1966
197 4
2
l
1
4
B r itt and
Cupball
North Carol ina h igh

acboo 1 nniora who
axpraaaed an intant ion to attend
collage in fall
Grade 12
1961
1962
1 year
Gulaa and
Ung
Sen ior a at Dart.outb

Collage ..tcbad
retroapactive1y to
t he i r fraabaan year recorda
Collage
fraahMn
llot
Given
(pr ior
to 1976)
Rot
Givan
4 yaar a
90
Beagan
Collage j un ior at
Maalayan univer aity
aatchad ratroapact iva1y to the i r
f raahaan andaopra-yaar
record a
Collage
f raahaen
1965
1968
3 yean
70
Ga r f ield and
Ga r f ield
Randaa aa.pla at
large pr ivata auburban raa idential
waatarn univeraity
Collage
atudanta
19661967
19701971
1 year
Kandel
(llot
Givan)
(llot
Given)
ll 110ntha
6 110ntha
yeara
year
year
yeara
915
886
&elf-ad8iniatarld
Alcohol , aar i j uan ,
queationn i raa in
claaa1 intarviawa
witb dropouta
at T2
hallucinogana , barbiturata a , op iata a
tobacco , aolventa ,
C igaratta a , bear o r
wine , hard l iquor ,
.. r i j auna , haahiah ,
a.phatu inaa, Mthad r i ne , barbituraaa ,
tranqu i l i zara , LSD ,
other paychada lica ,
cocaine , heroin,
other narcot ica , inhalant a , cough ayrup
8 , 206
5 , 423
2 , 3 86
l r 635
&a lf-ad8in iatarad s ...

qua ationna i raa
(Tl , T2 ) 1 .. U ad
queat ionna i raa (T3 )
-2 , 2l 3
1 , 60 8
Interviawa (Tl ,
T2 , T4 1 1 aa lf-adaini aterad quaat ionna i raa (TlT4 ) 1 aa i lad
quaat ionna i raa
( T5 1 1 ability
teata (Tll
Cigaretta a , bear ,
wi ne , bard l iquor
aa r i j uana , a.phataainea , barbiturataa ,
ha llucinogana , Mthaqualona , coca i ne ,
heroin
2 , 300
1 , 420
Self-adainiatarad
queat ionna i rea ,
(unclear whether
in or out: of
claaa)
Alcohol
90
Ma i led quaationnai ra
Ma r i j uana , UIPhataainea , barbitu rataa ,

ha lluci nogen
70
&alf-adaini atarad
quaat ionna i raa 1
teat data on f i la
at Off ice of
Paycholog ical
Sar v i
'l'Obacco , alcohol ,
.. r i j uana , hallucinogena
Par aonally adainlaterad queationna i raa
Alcohol, ..r i j uana ,

haahiah , LSD, M aca-
300
T2 -100
T3201
T4-100
!.Tha aaaa Mtboda -r uaed in all wavea of data collection of a atudy , unlaaa apac i f ic t t.. a are i nd icated .
Se lf-ad8in i aterad
quaationn i rea in
claaaroaaa (adoleacanta ) . Ma i led
quaationna i raa
(parental
....
Una
....!
....!

Character istics of Long itud inal Studies of Drug Use in Normal Populat ion s Li sted by Complet ion Status ,
Type of Sample , Age of Respondents , and Year of First contact .
Par t 1 .
Princ ipal
In,..t igaton
Populat ion
Character iet ice
Grede/Age at
'1'1 of Suple
BU g ible for
ca.pleted Studiee a
Year of
Firat
Year of
La at
Contact
Contact
Panel
Grupp
Gold ate i n
Grovea
Randca auple of n
of etudente at
I l linoia State
Unive r s i ty not
reporting .. r t j uana
UH
Student enrolled
at Carnegie-Mellon
Univereity (claea
of 1972)
Full-tiee etudente
at predaa i nant1y
wbite nonapecie1i aed colleges with
projected enrollnt of over 1 , 000
( 1970 )
'rotal
IIUIIbe r
of
Con tecta
Schoo l Suaple e
Interval
Bet-n
Contecta
S he of
Suple '1'1
BUg ible
for Panel
College
1969
undergraduate
and g raduate
etudente
1973
2 years
127
1968
1 97 2
Appr ox a
9 11011 th8
16 11011 t he
20 11011 the
770
College
f reet.en
College
freet.en
1970
1971
1 year
7 , 948
She of
Matched
Panel
'1'2-120
'1'3-103
u7-
3 , 961
Methode of Data
Collection
Dr119 Inquired About
Pe nonal interMar i j uana

vi- at Tl , T2 r
.. t led quest ionna i ree for those
out of area at T2 ,
and for everyone
at T3
Se lf-ini etered
queet ionna i ree ,
outeide of cla
(.. 11 technique
preHrving enonytty)
Ma i led questionna i r
end
j uniors
Bee r , hard liquor ,

.. r i j uana ( inc l .
ha e h i e h ) ,
tranqu i l -
i aere and ber bituretea , uphateinee , hallucinogens ,

narcot ice , tobacc o
caffe i ne , alcohol ,
.. r i j uana , baeh i eh
thedr i ne , othe r
uphetu i nee , berbitu retee , aedetivee ,
trenqu i l i ae r e , LSD ,
other peychede l ice ,,
coca i ne , op i ue ,
he roi n , o t ha r nar cot ice , COIJ9 h eyrupe

llell inger
Jeeeor and
Jeeeor
(1) Probabi lity

auple of .. le
f reeheen of Univere ity of Cal ifornia at Be rkeley
in Fall 1970
College
freet.en
( 2 ) Probabil ity
euple of eenior
.. n in claaa of 1971
College
Hniore
1971
1973
2 1/2
year s
986
821
s-
College etudy--ran-
College
freehMn
1970
1973
1 year
276
226
Self-inietered
questionna ire
ecbool recorda
Bee r or wine , ha rd
liquor , .. r i j uana ,
doe eaeple of arts

and eo lence unlver-
1970
1973
2 1/2
year a
960
eity etudenta in a
834
Pereonal i nte rvi- and Hlfin ietered

for-. 1 acboo l
recorder .. ned
questionna ire
'I'Obacco ,
a lcohol ,
.. r i j uana or haahieh , uphetuinee ,
ber bitur etee , aedat i vee , peychede l ice ,

coca i ne , ha roin ,
op i ue , o t he r opiatee ,
inha lants
uphatM i ne e ,
LSD ,
other peychede lice ,
a .. ll Rocky Mountain
city
coca ine, heroin
....
......!
(I)

SciNck it
UIIPl ea of
incaa i ng f rean at a
( 1 ) Waab tngton Univaraity in S t . Louie
College
freat.. n
1970
1974
( 2 ) Univera ity of
California at San
Diego
College
frea'-tl
1971
1975
G inabarg and
Greenley
Student enrolled at
Un ivara ity of Wiaconain-Madi8on
1971-1974
College
freat.. n and
aoprea
1971
Sadava
( 1 ) College f rean
in an Bng l iab-lang uege Ra.an Catholic
college in province
of Quebec
College
frean
( 2 ) Undergreduatea
at a aaa l l Ontar io
univaraity i n introductory paychology
cou r a e
lt ay
Mooa
s-iatructured
interviawa a aa i lad
quaat ionna i rea to
nonrea identa
TObacco, alcoho l ,
aa r i j uana , baab i ah ,
uopha taine a , apeed ,
LSD , MIICaline ,
pai locyb i n , STP , MDA ,
opiatea , .ad ic inal
drug a
274
Ma iled queationnairea
Mar i j uana
358
319
Self-adaini aterad
queat ionna irea in
claaaroc.a
cannabi a , paychadel ica , uophatainea ,

a lcohol
6 .ontba
467
3n
self-adaini aterad
queat ionna i rea
Alcoho l , tobacco ,
.. r i j uana and othe r
i llicit druga
6 .antba a
1 30
1 24
ll2
68
85
98
Self-adaini aterad
queat ionnaire a ,
ad jective cbeck
liat , California
Paycholog ical
Inventory
Ma r i j uana
1 , 296
T2-886
TJ -567
&elf-adaini aterad
queat ionna i rea,
outa ide claaa
Alcohol
1 year
158
1 yea r
22 2
188
197 4
2 year
319
!lot
Givan
(prior
to 1973)
llot
G ivan
6 .antha
College
frea'-n and
aoprea
1972
1973
UIIP le o f
..le atudanta
ente r ing Labigb
univara ity
College
freat.. n
1971
1972
1973
Enter i ng claaaea of
two univaraitiea
College
fren
Not
Ghan
1974
1974
1974
llot
Ghen
--
--
--
3
2
1- '1'2 1
1 yeao
'1'2-T3 ,
T3-T4
9 11011 th a
3 yaara
Not
Givan
....
......!
10

Characteristics of Lonq itud ina l Stud ies of Drug Use in Norma l Populations Listed by Completion Status ,
Type of Sample , Age of Respondents , and Year of First contact .
Part 2 .
P r i nc ipal
Inveat igatora
Popu lation
Characta r i at ica
Lukoff and
Brook
Sa-plea of ghetto
co.aunity atrat ifiad
for athnicity, aocial
claaa , and cont iguity
witb davianca o
eo-plated Studiaa o
Grade/Age at
'1'1 of SUIPla
Elig i ble for
Panel
Year of
Firat
COntact
Year of
La at
COntact
( 1 ) Children
13-17 yra
1973
1 9 7 51976
CU..U n ity Sa-plea

Interval
Ban
Contacta
She of
SUIPle '1'1
llig ibla
for Panel
3 yean
403
183
28 4
183
664
Total
Rllllba r
of
Contacta
st .. of
Matched
Panel
llathoda of Data
Collection
Dr119a Inqu i red About
&ouaahold interviawa
Ma r i j uana , upa ,
downa , paychede l ica ,
heroin
536
Bouaahold interviawa
Alcoho l , -r i j uana ,
apha t-i nea, bar bi turata a , acid ,
coca i ne , heroin, g lue
( 2 ) Mothara
30-4 5 yra
B runawick
Rapraaantativa co..unity aaapl a of

Barl .. youth
16-17
yaar a old
19691970
19751976
6 yean
Sieber
19 year old conacr ipta born in

canton of Zur ich
who report alcohol/drug uaa
at i n i t ial contact
1 9 yean
1971
1974
3 year a
1 , 413
841
Self-adainiatarad Alcohol , tobacco ,

quaationna i rea 'I'l l -r i j uana
.. ilad quaationna i raa '1'2
Robina
( l l Viatnaa veterans 20 yaara

randca aaapla of a (-nl
anli atad .. laa wbo
retu r ned fraa Viatnaa
to the Un ited Stataa
in Sept.-bar 1971 ,
and a auppl...ntary
randaa aaap le f raa
1972
1974
1975
2 yean
605
571
Intar.iawa 1 urine
aaap laa 1 1 1 itary
and v.tarana ' Adini atration
recorda
to
r2
id
:Ill
raatr 1ctad to ..n

i nducted a ince 1 969
and fraa the 25 r
populou
lbte a
Cigarattea, a lcohol ,
.. r ij uana , a.phatainea , ha r biturataa ,
tranqu i l i za r a , hal 1uc inogana , cocaine,
narcot ics
....
Q)
0

-
Matched
to veteran
19741975
( 1 ) Nat ional probab i l i ty ..-ple of

Un ited State adult
population, ( )
a aJIPled f rc. reduced
Il target population
Nl , 810 , with abatainera and very
infrequent d r i nker
aubaaJIP led at a
leaHr rate
21 and
over
19641965
1967
( 2 ) National probab i l i ty ..-ple of

white .. lea aged 2159, with ove r...pUng of urban a rua
2 1-59
year a old
1969
1973
( 3 ) Probability
..-ple of wh i te
.. lea , aged 21-59,
in Sen Pranc iaco
21-59
yeua old
19671968
1972
( 2 ) Control group at
--..-ple of non-
302
284
2 year
1 810
1 , 359
4 yean
978
725
4 yeara
786
veteran ..tcbed on
Select ive Service
Boa rd , draft e l igib i l i ty , age , and
education
Cahalan
et a l .
615
Intervl ... l urine s..-plea 1 Select ive

Service Recorda
aou .. bold interviewa (Tl ) l .. il

queationna irea
Dr inking patterna ,
practicea , and
probl-
SaM
SaM
SaM
....
01)
....

Character ist ics of Long itud ina l Studies of Drug Use in Normal Popu lat ions Li sted by Complet ion Status ,
Type of SaJDple , Age of Respondents , and Year of First Contact .
Part J .
Pr incipal
Inveat lgaton
Buba and
Bentler
Populat ion
Charactar iat lca
Grade/Age at
'1'1 of Supla
BUg ibla for
Panal
Student in the
Grade a
greate r Loa Angel
7-9
area vitb over...pUng of lower aoc i oeconc.ic achoo l a
Lukoff
and Brook
Quota aa.pla fro. 6

atatea (Connec ticu t ,
Kanaa a , Nav Jeraey ,
Nav Yor k , Oh io , and
South Carolina)
App r oxiaataly equal
n Wibe n o f .. lea and
f ... lea , blacka and
vh i te a of iddle
soc iic atatua
Clayton
and Voaa
Nat ionally rapre .. n- 20-JO

tat iva aa.pla of .. n year old
born bat-n 1944 and
1 9 5 4 inclua i ve , vho
r eg iaterad vith
Select ive Serv ice
upon age 18
Grad
9-10
Ongoing Stud iea a
Contact
Year of
Laat
Contact
1976
1980!
Year of
Pint
1'otal
Hwlber
of
Contac:U
4
A--within Adolaacance , Adulthood

Interval
llat-n
Contact a
1 year
2 yean
1 year
Siaa of
Supla '1'1
BUg ibla
for Panel
1 , 6 34
Sba of
Matched
Panel
768
Method of Data
Collection
Druga Inquired About
Salf-a&.iniaterad
quaat lonna i raa
fro. the atudanta ,
paranu ( '1'1 , '1'4 1
and paa r a ( '1'1 , '1'2 1
C igarettea, bee r ,
vine , l i quor , .. r i juana , haahiah, cof fH , inor and .. jor
tranqu i l i aar a , barb i turate a , aadati vea ,
antldapraaaanta ,
upheta. ine a , non uphet .. inaa , uppe ra ,
LSD, other paycheda l i ca , an i f f ing
atu f f , aay l nitrate ,
nonpreacr ipt. ion
alHping pUla I
atbu lan ta, coug h
ic i ne , cold
ic i ne , coca ine ,
heroin, other na r cot ica , PCP , coca
paate
1979
19al
2 yean
932
Not yet
Se lf adaini aterad
co.platad quaatlonnairea
Alcoho l , c igarettea,
.. r i j uana , uphetainaa , barbi turatea ,
LSD , othe r paychedelic a , heroi n , other
narcot lc a , tranqu i l i aa r a , quaalude a ,
coca i ne , inhalant
19741975
1982
6-7
yea r
4 50
Pe r aonal inte rNot yet

co.platad viava
Cigar ettaa , alcohol ,

aa r i j uana , payche delica , at iulant a ,
aadatlve a , heroin ,
othe r op iata a , cocaine , tranqu l l i aera ,
inhalanu
....
Q)
...,

Pa r t 3.
Carpente r ,
Leater ,
Pand l na , and
Labouv le
Cohort-aequentlal
a) 12 yean
dea lgn-aan.s
b ) 15 yea n
IIAIIp lea of New Jeney c) 18 yean
edole-nta-a) 9 cohor ta born
1967-75
b) l cohorta born
1964-66
c ) l cohorta born
1961-63
d) 3 control g roupa
at T4
Ongoing Studt ..
1979
ongoing
s--PrOII Moleacence to Young Adulthood
14 tele
phone
8 ona i te
1 year
l yeara
unt il aqe
24 1 6
year a
after age
24
a ) l , l50
b)
4 50
c)
450
d)
150
NOt
ye t COII
pleted
Alcohol , c lgaret tea ,

aar l j uana , a.pheta
alnea , barb ituratea ,
LSD, other payche
de l i c a , heroin , other
narcot lca , tranqu 1 l i ae r a , quaaludea ,
ccca lne , inhalanta ,
pep, uoyl and butyl
n i t rate a , over -the
counte r paychothera
peutlc a , caffe i ne
On-a ite s
-pereanal inter
vi-
-Hlf-acblin1atered queat 1on
na 1rea
-behavioral teata
-blood aa.ple
-paycholoq lcal
teat
-..d lcal ex-
Te lephone
contact s
-.a jor l i fe event a
-alcohol and druq
ta k i ng oute011e a
E l l iott
Jeaeor ,
Jeaaor , and
Donovan
National Youth
Survey-Nat ional
probabi l i ty ault 1ataqe cluater aa.ple
o f dvelUnga
11-17 yeara
1976
1980
1 year
1 , 725
T2- 1655
Tl-1626
T4 -1 543
T5-1494
Pe r eanal at ruc
tured inter
vi-
Young adult followGradea

H igh achoo l
7-9
aaaple--randoa aa.ple
of atudenta froa
g radea 7-9 of l
j unior high achool a
i n a ...u city
in the Rocky
Mounta ina, alaoat
all of Ang loAaler ican , aiddle
c laaa bac kground
1969
198 1!
1
1
1
7
2
year
year
year
yean
yeara
432
Tl-T4 --Self -ad

NOt yet
coapleted alni atered quea
Uonna lrea in
achoo l ( h igh
achoo l aa.ple )
in ... u g roupa
(collaqe UJple )
Collaqe aa.ple-
randoa aa.ple of
f reahaan claaa arta
and ac ience
unive r a i ty atudenta
in a ... 11 Rocky
Mountain c i t y
1970
19n!
1
1
1
6
2
year
year
year
yeara
yea r a
205
'1'5 , T6-Mu lt
not yet
coapleted fol low-upa 1 aaUed
Hlf-adainia tered
quea tionna i rea
up.
Collaqe
f reahaan
ture contacta planned , if funda ava i lable .
wine ,
l iquor , aa r l j uana ,
ha lluc inoqena , co
ca i ne , he roin,
aed ical and non
aed lcal uae of
a.phe taainea , bar
b i tur ate s
Tobacco , bee r ,
Beer , w ine , hard

l iquor , aa r i j uana ,
LSD, aaphetaal ne a ,
cocaine ,
heroi n , tranqu i11aer a , barbitu
rate a , aorpb i ne
....
Q)
w

Character istics of Long i tud inal Studies of Drug Use in Normal Populations Listed by Completion Status ,
Type of Sample , Age o f Respondents , and Year of First Contact .
Par t 3.
PrlnClrpal
I nveat igato r a
Popula tion
Cbaractar i a t ica
Johnaton
and Bacn
K andel
Grade/A; at
Tl of Sa.pla
Elig i ble for
Panel
Ongoift9 Studieu
B--Fra. Mole8Cence to Youft9 Adulthood

Methode of Da ta
Collect ion
Year of
Fi r at
contact
Year of
Laat
Contact
Total
Nullbe r
of
Contact a
Interval
Between
Contacta
S i aa of
Saaple Tl
Elig i ble
for Pane l
She of
Matched
Panel
Mon i tOr ift9 tba

Grade 1 2
FUture--cohort
quantial dedgn.
Sueeeaaive nation
a l ly rapra ..ntat ive
cohorta of high
achoo l .. niora f ra.
1 1 5 publ ic and 1 5
p r ivate h igh achoo l a 1
repeated annua lly ,
entire aanior claa .. a
in aehool a w i t h 300
aenior a , and aub
aa.plea ( N-300 ) i n
larger aehoo l a
1975ongoin<J
Oft90lft9
11 for aaeh 1 year

for each
cohor t
coho rt
(2 yr a
for each
cohort
1/2
aa.pla)
2 , 4 00
( target
for each
cohor t ,
1 , 200 for
each co
hort l/2
aa.ple )
Tl--Se lf-adainia
NOt yet
ea.plated tered queation
na i rea i n claaa
roau T2, adult
fol low-upa -
Ma i led queat ion
na i rea
Gr ada a
Mul t i atage randa.
aaapla of adola8Centa 10-11
enrolled in New York
public aeeonda r y
schoo l .. leeted
f r- 18 achoo l a
a ) regular atudanta
b) ab .. ntaaa
1971
198
a) 1 , 321
330
b)
1 , 081
244
6 .antha
9 yaara
Tl , T2--Salf-a.S.inl aterad quaat ionnai raa in claaaroa.a

Tl--Mult follow
up- -Hou sehold
intarviwa
Druga Inqu ired About
Alcoho l , c igarettea,
.. r i juana , a.pheta
1ne a , barbi turatea ,
LSD, other payche
de l ica, heroin , othe r
nareot ica , t r anqu i
l i &er a , quaaludea ,
coca ine , inhalanta ,
PCP , .-y l a nd butyl
nitratea , over -the
counte r paychothe ra
peut ica , caffeine
Cigarette a , beer or
wine , hard liquor .
.. r i j uana , haah i ah ,
.. thedr ine , LSD ,
other payehedelic a ,
cocaine , heroin ,
other narcot ics , in
halanta , cough syrup ,
at iu lant a , aedat ivea
and tr anqu i l i zers
( ical and non
ical u .. )
co
..

Kaplan
Seventh g rade
Grade 7
1971
atudenta e n rolled i n
18
19811982
of 36 j u n ior h igh
1 yea r
1 year
9-11 yea ra
9 , 30 0
Not yet
Tl-T3--Se lf-
ca.pleted adaini atered

queationna i r e a
echoo l a of t ha
Ma r i j uana/haah i ah ,
ba r b iturate a ,
inha-
lanta , hal luc inogena ,

aJIPhe t-ine a ,
Houaton Independent
Schoo l Distr ict
T4 --Adu1t fol-
tr anqu i l i zers ,
lovup--House-
heroin , othe r na r -
ho l d interv i-a
cot ica , quaalude a ,

coca ine
Lauer and
Al l atudenta in 2
Akera
j un ior h igh achoo l a ,
7-12
1980
19 8 4
1 year
2 , 194
aanior h igh echoo l
in ... 11 IONA c i ty
C igare t te a , chewinq
Not yet
Se l f-adainiaterad
ccmplet-
queat ionna irea in
tobacco ,
ad
claaaroo.
c igar s/pipe
anu f f ,
Sal iva teat

Schlegel
Randoal aiiPle of
atudenta in
boarda
9 -12
1974
U8ill
echoo l
( urban ,
4 110ntha
1 , 781
91 8
4 110ntha
rural)
in aouthe rn Onta r io
(Tl-T4 ) Sel f-adiniaterad quae-
4 IIOfttha
Uonna l rea i n
1 year
claaaroo..
2 yeara
(T5-T7 ) Ma i led
sel f-adaini atered
year
saer , w i ne ,
l iquor ,
c igarette a ,
aJIPheta-
inea , barbiturate a ,
.. r i j uana , ha llucinogena , t ranqu i l i ze r s ,
he roin , g lue
que at ionnai rea

S. ith
Students and foraer

atudenta
in iddla-
1969
Grade a
8-10
1981
4-6
1 year
1 , 93 5
No t yet
Tl-'!'5--Self-ad-
Cigarette a , bear ,
w i ne ,
l iquor , .. r i-
year
leted iniatered quea-
c laaa preda.inant-
1 year
Uonna i r e a , pee r
j uana ,
haah i ah ,
ly wh ite schoo l
1 year
ratinga of per -
dooma ,
tr ipping
d i at r ict i n the
8 yaa ra
.ana l i ty ,
atu f f , cocaine ,
g reater Boston area
echool
recorda
upe ,
he roin and other

op iatea , d rug ator e
!luture contacts planned ,
if
funda available .
'!'6--Adult fol-
icine ,
l_..up - Ma i led
atuff , ca.bi nat ion
questionna i re
drug a
an i f f ing
....
(D
VI

Append ix
D
PARAQUAT ISSUE
Paraquat is a herbic ide that is used throughout the wor ld .

It is
avai lable in an aerosol form , granules , and a water-soluble
concentrate .
As a result of acc idental or suic idal swallowing of the
water -soluble concentr ate , more than 500 human fatal i t ies have
occur red ( Har ley et al . , 1 9 7 7 ) .
In contrast , ne ither i nhalat ion of
the spray nor ingest ion of pa raquat granu le s has been shown to be of
c linical impor tance ( Fairshter and Wilson , 1 9 7 5 ) .
About 60 percent of the mar ij uana consumed in the Un i ted State s
i s g rown in Mexico.
S ince 197 5 , in the attempt to reduce the i llegal
produc t ion of mar i j uana , the Mex ican gove rnment ha s been spraying
mar i j uana f ields from ai rplane s .
The herbic ide k i lls the treated
plants with i n 1 or 2 days . Mar i j uana producers have resor ted to
harvesting the plants soon after spraying , minimi z ing exposure to
sunshine , so that they are not destroyed .
The paraquat pe r s i sts on
the d r ied leaves .
Samples of mar i j uana conf i scated at the
u . s . -Mex ico border have d i sclosed that about 21 percent of the
conf iscated mar i j uana was contaminated with paraquat i n varying
concentrations .
Paraquat damages the lung s , hear t , k idneys , ad renal g lands ,
In
central nervous system , liver , ske letal musc le , and spleen .
The
g eneral , all effects but those on the lungs are trans i tory .
changes in the lung s of humans after ingestion appear to be
dose-related :
small amounts of the swal lowed chemical may cause
modest . and reve r sible lung damage r in contrast , larger quant itie s
c ause lethal pulmonary f ibros i s .
An impor tant element i n paraquat
tox i c i ty is the fact that it is concentrated in the lung s wher e i t
does part icular damage t o the alveolar l ining .
In many respects ,
probably includ ing the mechan ism by wh ich it damages the lung s , i t s
e ffec ts resemble those o f oxygen tox ic i ty but seem to be less
reve r s i ble ( Smith and Heath , 1976 ) .
With respect to mar ij uana , the use of paraquat as a her bic ide
enta ils the possibility of r i s k to two populat ions :
( 1 ) those who
spray the paraquat and the wor kers in the f ields who are exposed to
an envi ronment containing the par aquat spr ay , and ( 2 ) the mar i j uana
smoker .
To date , no tox ic effects attr ibutable to paraquat , per se ,
have been proved in e i the r populat ion .
However , the observat ions
thus far relate to the acute hazards of paraquat inhalat ion and do
186

18 7
not provide any assurance about the long-term effects . I ndeed ,
observat ions on other i nhaled tox ins suggest that exposure for many
year s may be prerequ i s ite for the development of clinical d i sabi l i ty .
An important quest ion with respect to the toxic effects of
paraquat on the lung s i s how much of the paraquat survives combustion
and i s transfer red in the smoke to the gas-exchang ing sur faces of the
lung s . Stud ies conducted by NIDA ind icate that a s much a s o . percent
of the paraquat in a mar ij uana c igarette appeared in a condensate of
smoke prepared unde r laboratory cond it ions . The results suggested
that a typical mar ij uana c igarette contam inated at approx imately 5 0 0
ppm--a reasonable degree o f contaminat ion--would produce smoke
containing up to 1 mg of paraquat . Thi s exper imental evidence has
led to the pred iction that a human smoker of five mar i j uana cigarette s
per day would expose the lung s to approx imately 5 mg of paraquat .
Laboratory ev idence der ived from hamste r s suggests the poss ibility o f
d amag ing the d i stal par t of the a i rways ( the bronchioles and the
prox imal alveolar ducts ) by this exposure . These expe r iments and
predict ions suggest that an i nd ividual who continued to smoke
paraquat-contaminated c igarette s would be a cand idate for ser iou s
lung inj ury . The prospect probably would be g reatly he ightened by
the tox ic effects of the combusted ma r i j uana .
There are only a few observat ions of exper imental animals that
bear d i rectly on the effects of inhaled paraquat (K imbroug h and
Ga ines , 1970 J Zavala and Rhodes , 197 8 ) . These suggest that similar
lesions are produced by ingested paraquat and by paraquat introduced
i nto the airways . For example , the introduction of minute quant ities
of paraquat d ichlor ide intrabronchially , in concentrations rang ing
f rom 10 mg to 100 mg , el ic ited focal pulmonary edema , hemorrhage , and
f ibros i s ( Zavala and Rhodes , 19 7 8 ) . The smaller doses are within the
r ange to which a smoker of mar i j uana contaminated by paraquat might
be exposed . However , the expe r imental evidence i s not ent i rely
r e levant on seve ral aocounts :
( 1 ) paraquat arr iving at the lung
surfaces by inhalation from contaminated a i r or afte r smok ing must be
carr ied in the form of smoke , gas , or small droplets , because larger
droplets , such as the aerosols used in ag r iculture , are apt to
prec ipitate out in prox imal a i rways , which are protected by cilia and
mucus , ( 2 ) the intrabronchial installation of paraquat in a solution
p rovides a d if ferent pattern of access to the gas-exchang ing sur faces
of the lung s than doe s inhalat ion of smoke , gas , or droplets J ( 3 )
because o f its water solubi l i ty , paraquat that escapes pyrolyzat ion
dur ing smoking would be expected to be taken up by the tracheal
b ronchial t ree and its branches before reaching the alveol i unless
car r ied i n the form of smoke , gas , or small droplets .
I n essence , the evidence concerning the inj ur ious e ffects of
paraquat inhaled after e ither spraying or smok ing i s too meager fo r
conclusions . The observat ions ava i lable since 197 5 have not proved
that paraquat , per se , i s harmfu l to the lung s . On the other hand ,
t he c l inical exper ience to date , coupled with the inc reas ing
understand ing of the biochemical basis for paraquat tox ic ity , rai se s
t he ser ious possibi l i ty that cont inued exposure to inhaled paraquat
is li kely to be harmfu l to the lungs , that the predominant effec t

188
will be d i f fuse interstitial f ibros i s , and that i f exposure i s
suff iciently intense over year s , respiratory insuffic iency ,
disabil i ty , and death may reasonably be expected to ensue .
REFEREICES
Fa irshter , R . D . and Wilson , A . F . Paraquat poi soning a Manifestation s
a nd therapy . Am . J . Med . 59 : 7 51-7 5 3 , 197 5 .
Barley , J . B . , Gr inspan , s . , and Root , R . K . Paraquat su ic ide in a
young woman : Results of therapy d irected against the superox ide
rad ical . Yale J . Biol . Med . 5 0 : 481-4 8 8 , 19 7 7 .
K imbrough , R . D . and Gaines , T . B . TOxicity o f paraquat to rats and
its effect on rat lung s . TOx icol . App l . Pharmacal . 17 : 679-69 0 ,
1970 .
Smith , P . and Heath , D . Paraquat . CRC Cr it . Rev . TOx icol .
4 : 411-44 5 , 197 6 .
Z avala , D . c . and Rhodes , M . L . An e ffect o f paraquat on the lung s of
rabbits . Chest 7 4 : 418-4 2 0 , 1978 .





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This PDF is available from The National Academies Press at http://www.nap.edu/catalog.php?record_id=18942

Marijuana and Health (1982)

Division of Health Sciences Policy; Institute of Medicine

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