Ayahuasca: Problems and Prospects for

Clinical Study
Dennis J. McKenna, Ph.D.
Senior Lecturer
Mcen!"#$umn.edu
%hat is Ayahuasca&
Ayahausca is 'uechua for ()ine of the souls*
+t is a hallucino,enic be)era,e that forms an
important component of Ama-onian
shamanism and ethnomedicine
+t is the le,al (sacrament* for at least t.o
syncretic reli,ions in /rasil
+t has a reputation 0deser)ed or not1 as a
healin, medicine
Image of an
ayahuasca spirit
from the NW
Amazon
QuickTime and a
Photo CD Decompressor
are needed to use this picture
Left: preparation of ayahuasca by
Mestizo shamans in Peruvian
Amazon
Beo!: "#$ preparo in Manuas%
Brasi& 'he bre! is prepare( on an
in(ustria scae% an( it is not
uncommon for severa hun(re(
parishioners to consume it in group
ceremonies
)eremonia
ayahuasca
vesse from the
NW
Amazon
/otanical Sources of Ayahuasca
Banisteriopsis caapi
ayahuasca
*Mapighiaceae+
Psychotria viri(is
chacruna
*,ubiaceae+
#ipopterys cabrerana
chagro-ponga
*Mapighiaceae+
'ra(itionay% ayahuasca is a
(ecoction prepare( from the
stems of B& caapi an( the eaves
of either Psychotria viri(is or
#ipopterys cabrerana
Ayahuasca has a 2ni3ue Pharmacolo,y

+ts psychoacti)ity depends on a syner,y bet.een t.o

classes of acti)e constituents:

4he leaf admi5tures, Psychotria or Diplopterys species,

contain the potent hallucino,en, 6,67Dimethyltryptamine
0DM41

DM4 alone is not orally acti)e, due to inacti)ation by

peripheral Monoamine 85idase 0MA81 in the ,ut and li)er

DM4 can be ren(ere( orally acti)e by co7administration

.ith an MA8 inhibitor

/anisteriopsis contains harmine and other 97carboline

alaloids, .hich are potent, re)ersible MA8 inhibitors
Chemistry of Ayahuasca
NH
N
H
CH
3
O
CH
3
NH
N
H
CH
3
O
CH
3
NH
2
N
H
CH
3
O
CH
3
TETRAHYDROHARMINE
HARMAINE
HARMINE
N
N
H
CH
3
CH
3
N!N"dimeth#$tr#ptamine %DMT&
'he vine Banisteriopsis caapi
contains three .-carboines
as ma/or active constituents&
0armine an( harmaine are
potent% reversibe% seective
inhibitors of MA1-A&
'etrahy(roharmine is !ea2er
as an MA1I but reativey
potent as a serotonin upta2e
inhibitor&
'he eaf a(mi3tures% Psychotria
viri(is or #ipopterys cabrerana
contain the potent% short-acting
haucinogen% #M'&
#M' is oray inactive uness
ta2en in con/unction !ith an
MA1 inhibitor
:anomamo Snuffin, ;irola po.der
8ne .ay to ,et around the conundrum of oral inacti)ity is to in,est DM4 parenterally

Yanomamo Indians prepare

a snuff from the sap of
Virola species, another
DMT-containing plant

Drug abusers in the U.S.

smoke free base DMT in a
glass pipe or sprinkled on a
vegetable matrix
2bi3uity of DM4 and 97carbolines

/oth DM4 and 97carbolines are structurally simple indole

alaloids, biosynthetically deri)ed from tryptophan

DM4 and related tryptamine deri)ati)es, and 97carbolines are 3uite

.idespread in plants

Do-ens of species containin, them ha)e been identified

Many more remain unidentified

4hey are also .idespread in animals, includin, humans, and fun,i

DM4 is normally present in the human brain, cerebrospinal fluid, and

adrenal ,lands

4he pineal hormone, pinoline, is a 97carboline

Pinoine% a pinea hormone
*4-Me1-tetrahy(ro-.-
carboine+
NH
2
N
H
CH
3
O
Ayahuasca (Analo,s*

Due to their .ide7spread occurrence in plants, many

species could be used to prepare ayahuasca7lie bre.s

Many of them have been used in this manner

All that is needed is the ri,ht combination: a plant

containin, DM4 combined .ith a plant containin, 97
carbolines
'he (esert shrub on the eft%
Peganum harmaa% contains
.-carboines in the see(s% an( the
grass on the right% Phaaris
arun(inacea% contains #M'&
)ombinations of these an( many
other pants have been use( to
prepare ayahuasca anaogs
Le,al Status of Ayahuasca

DM4 is a schedule # controlled substance

97carbolines are not classified as controlled substances

4he la. is ambi,uous concernin, the le,al status of

plants containin, DM4

%hile DM4 itself is scheduled, none of the plants

containin, it ha)e been scheduled

DM4 and 97carboline containin, plants are freely bou,ht

and sold on the +nternet and else.here

<)en if desirable, it seems a practical impossibility to

control all of the do-ens or hundreds of plants containin,
DM4
2ni=o do ;e,etal Study

4he 2ni=o do ;e,etal 02D;1 is a /rasilian syncretic

reli,ion le,ally permitted to consume ayahuasca in
ceremonial settin,s

+n #>>", .e conducted a biomedical in)esti,ation on

lon,7term members of the 2D; in Manaus, /rasil

4he study looed at acute and lon,7term physiolo,ical

and psycholo,ical parameters in lon,7term members

C. S. Grob, D. J. McKenna, J. C. Callaway, et al. (1996) Human

pharmacology of hoasca, a plant hallucinogen used in ritual context in
Brasil: Journal of Nervous & Mental Disease. 184:86-94.
Key findin,s from the 2D; study

6o e)idence of acute to5icity

6o e)idence of neurolo,ical, co,niti)e, or personality

dysfunctions in lon,7term users

Most 2D; sub?ects performed sli,htly better than matched controls

on psycholo,ical measurements

Stron, e)idence of positi)e beha)ioral chan,es

Most members had histories of dru, abuse, alcoholism and domestic

)iolence before ?oinin, the 2D;

+nitial terrifyin, e5periences .ith ayahuasca helped them to chan,e

lifestyle in a more positi)e direction

<ffects of supporti)e conte5t are hard to separate from effects of

ayahuasca
2pre,ulaton of Serotonin 4ransporters

An une5pected findin, .as that lon,7term users had

si,nificantly eevate( densities 0/ma51 of serotonin
transporters in platelets compared to matched controls

@eceptor affinity 0Ki1 .as not si,nificantly different

bet.een ,roups

J. C. Callaway, M. M. Airaksinen, Dennis J. McKenna, Glacus S.

Brito, & Charles S. Grob (1994) Platelet serotonin uptake sites
increased in drinkers of ayahuasca. Psychopharmacology 116: 385-
387
#eficits of brain AB4 transporters and other
monoamine transporters
Ba)e been associated .ith:

Alcoholism

<arly onset alcoholism C )iolentDhomocidal beha)ior

Suicidal beha)iors

/in,e eatin,
Mantere T, Tupala E, et al. Serotonin transporter distribution and density in the
cerebral cortex of alcoholic and nonalcoholic comparison subjects: a whole-
hemisphere autoradiography study. m ! "sychiatry. #$$# pr%&'()*+:'((-,$,.
-alli.ainen T, Saito T, /achman -M, et al. ssociation between low acti0ity serotonin
transporter promoter genotype and early onset alcoholism with habitual impulsi0e
0iolent beha0ior. Mol "sychiatry. &((( !ul%*)*+:12'-2.
2nans.ered 3uestions:
Could lon,7term use of ayahuasca actually
re)erse these transporter deficits&
Could it therefore be used in the treatment of
alcoholism and other beha)ioral dysfunctions
associated .ith reduced transporter
e5pression&
Possible 4herapeutic 2ses of Ayahuasca

4reatment of alcoholism C substance abuse

4reatment of beha)ioralDpersonality disorders

Anecdotal reports e5ist:

Spontaneous remission of cancer

Accelerated healin, of physical in?uries

+n Ama-onian shamanism, ayahuasca is used for healin,

both physical disease and mental disease
Public Bealth C Safety Concerns

+ncreasin, popularity of ayahuasca raises public health

concerns

+ncreasin, e5perimentation .ith ayahuasca and ayahuasca

(analo,s* by e5perimental ethnopharmacolo,ists

+ncreasin, popularity of ayahuasca (tourism*

4he safety, or potential riss, of these practices are

unno.n

4here e5ists a need to collect more and better data on the

human pharmacolo,y of ayahuasca
@eli,iousDsacramental use of ayahuasca

@eli,ious use of ayahuasca has been le,ally sanctioned in

/rasil since the late #>E!Fs

+t is taen re,ularly by #!!!Fs of people in /rasil on a

.eely or bimonthly basis
G
At least three syncretic reli,ions 7 2D;, Santo Daime, and
/ar3uinha 7 are allo.ed to use it in reli,ious practices

4here is no e)idence that it is a public health or dru, abuse

problem

4here is e)idence that .ithin a ritual and reli,ions conte5t,

ayahuasca is a spiritual practice that may benefit members
of these churches
@eli,iousDsacramental use of ayahuasca in the 2.S.
may be permitte(
/ac,round: D<A raided a 2D; ceremony in 6e. Me5ico in
#>>> and sei-ed the (sacrament*

2D; sued the Justice Department for ri,ht to use ayahuasca as a

sacrament under the @eli,ious Hreedom @estoration Act

Jud,e James Parer of the 2.S. District Court of 6e. Me5ico

ruled in fa)or of the 2D;

Io)ernment could demonstrate no (compellin, interest* to restrict

reli,ious use

Io)ernment could not demonstrate that its use poses health riss

Io)ernment could not demonstrate that there .as a si,nificant ris of

di)ersion to ille,itimate use

4he 2D; is en?oined from resumin, their reli,ious use of

ayahuasca .hile the Justice Department is appealin, the decision
@ationale for Clinical Study

Multiple reasons e5ist to conduct .ell7desi,ned clinical

studies .ith ayahuasca in human sub?ects:

Possible therapeutic applications

G
Alcoholism, substance abuse, mental illness, cancer, etc.

Possible safety concerns

G
+s e5perimental or reli,ious use safe&

Possible public health concerns

G
2se is ,ro.in,, alon, .ith the potential for ad)erse
reactions
G
%e need to study ayahuasca in order to better understand its
use and misuse
Challen,es for Clinical @esearch

Clinical research in the 2.S. must be conducted under an

+6D protocol

Affiliation .ith a uni)ersity or other research institution

Appro)al by an +@/

HDA appro)ed +6D for phase + 0safety1 and phase ++

0efficacy1

Hor ayahuasca, D<A appro)al for research .ith a

controlled substance may be re3uired
+6D application for botanical dru,s

HDA has issued ,uidelines definin, criteria for appro)al

of +6D applications for botanical dru,s not pre)iously
mareted, or that may ha)e safety issues

+n)esti,ator must pro)ide details of the source,

composition, standardi-ation, and dosa,e formulation of
botanical dru,s that fit this definition

HDA ,uidelines did not co)er botanicals containin,

controlled substances

+t is unclear .hat restrictions may apply to botanicals

containin, DM4

DM4 is (controlled* but plants containin, it are not

Standardi-ation of Ayahuasca
B
"sing anaytica metho(s such as 0PL) an( functiona assays such as MA1 inhibition% a
stan(ar(ize(% repicabe (osage form of ayahuasca cou( easiy be ma(e:
G A reiabe source of fresh pant materia is nee(e(
G A yophiize(% encapsuate( e3tract containing 5uantifie( amounts of 2ey mar2er a2aoi(s
G If #6A permits are re5uire(% the !or2 must be (one in a 7MP ab !ith icensure for use of
#M' reference stan(ar(
Safety of Ayahuasca in Clinical 2se

Phase + +6D is to establish that ayahuasca is safe to use in

human sub?ects

Pre)ious studies indicate that occasional use is probably

safe

C86H<6 findin,s in /rasil

(Boasca study* .ith the 2D; in /rasil

@iba, et al. studies in Spain:

3iba !, 3odrigue4-5ornells , 6rbano 7, Morte , ntonijoan 3, Montero M,
8allaway !8, 9arbanoj M!. Subjecti0e effects and tolerability of the South merican
psychoacti0e be0erage yahuasca in healthy 0olunteers. "sychopharmacology )9erl+.
#$$& 5eb%&'*)&+:2'-('.
3iba !, :alle M, 6rbano 7, ;ritia M, Morte , 9arbanoj M!. -uman pharmacology of
ayahuasca: subjecti0e and cardio0ascular effects,
monoamine metabolite excretion, and pharmaco.inetics. ! "harmacol Exp Ther. #$$1
!ul%1$,)&+:<1-21.