NEW FRONTIERS
Pot Is Hot — What You Need to Know
Cannabinoid-Pharmaceutical Interactions
nceractions beeween
medications arevery
common, especially
in elderly populacions that
‘medicare for pain, diabe-
tes and high cholesterol
“The geriatric population
is also che fastese-growing
group of medical anna-
bis users, Cannabis has
demonstrated efficacy
in ereating pain, and
Adrian Devitt-Lee, MS
‘This review wil describe
potential cannabinoid-
drug interactions in
the context of treat
ing pain (with opiates
and non-steroidal ant
inflammatory drugs)
and metabolic disorders
(using insulin, warfarin
and stating). Owing tothe
highly complicated role of
‘annabinoidsin thecardio-
some phyrocannabi- Cannabis samaes being prepped at Sonoma LabWorksforanalisof «vascular system-—with at
roids (pCBs) have been
suggested for various
metabolic conditions!" Thus eis impor-
rant tounderseand how eannabinoids ean
interact with common pharmaceuticals,
boeh to predice and preven negatveinterae
tions, while taking advantage of situations
where cannabis and pharmaceuticals act
synergistically
Drug interactions can be both useful
and dangerous. A drug that potentiates
an opiate, for example, may increase che
painkillingeffect, but could also increase
the likelihood of overdose, Ora second
analgesic couldllow the dose ofan opiace
tobe reduced, which would slow tolerance
and decrease other side effets.
Bucunderstanding al,
‘the convergenc iological
pathways oftwo rugsis
sifficult, Examining the
‘metabolic interactions
‘cannabinols ferpenes pesticides andresidul solvents.
between drugs is one way to generically
prediet drug interactions: sinee more
than half of all pharmaceuticals are
metabolized bya family of enzymes called
‘eytochrome P4S0 (CYP), knowing how
‘cannabinoids affect CYPs provides good
First approximation to pCB-drug inter
actions. In general, inhibiting the CYPs
that metabolize a pharmaceutical will
increase its blood concentration, leading
toan increase in both effects and toxicity,
But for prodrugs-which are metabolized
inco the active compound-inhibition of
metabolism will deeraie both the desired
and adveseeffers, And the interaction can
‘change from inhibition to activation with
dlifferenc drugs “Due co complications like
these, itis much easier to predice whecher
druginteractions arelikely than to predice
ther exact effect.
least four cannabinoid-like
receptorsinitating changes
in the vasculature, multiple phases to the
«effects, and opposing effeetsundee normal,
stressed and pathological condicions—
‘cannabinoid ineeraetions with drags used
to trear hypertension are beyond the scope
of this article
‘The Endocannabinoid
‘The endocannabinoid syseem comprises
the ewo known cannabinoid receptors—
CBI and CB2—as wellas their endogenous
lipid agonists, che enzymes tharbreak down
these agonist and che cransporemolecules
that shutele them through the cell, CBL
is che most prevalent G-protein-coupled
receptor in the brain ts primary function
isco inhibic GABAergicand glutamarergic
neurons aftr they release ther respective
neurotransmitters, Neural CBI reduces
pain and is required for extinguishing
‘arian Devit-Lee sa chemist and mathematician who has been involved in cannabinoid research for the pasts years.
‘He wes regulary for Project CBD, a nonpromt dedcated to cannabis education and cannabinad science. Me Is currertly
‘employed by CannaCraf Inc, a medical cannabis producer and distributor.
FAuL2017 33fearful memories. CBI is also broadly
inured in the body, particularly the
liver and adipose tissue, where ie generally
‘promotes the synthesis of fat, The CB2
‘receptors primarily expressed on immune
cells where it inhibits the inflammatory
response. In disease, overactive endocan-
nabinoid signaling can contribute to
fibrosis and insulin resistance. Endocan-
nabinoid deficiencies have been associated
with bromyalgiaand autoimmune disor-
ders, among others,
Cytochrome PASO
Cytochrome P450 (CYP) are nonspecific
cnaymesthat oxidize avariery of molecules,
making the molecules
‘more water-soluble and
‘easier for che kidneys to
filter. CYPs are generally
concentrated in the liver.
Cannabidiol (CBD), a
‘non-euphoric cannabis,
‘component, inhibits C¥PS
TAL, 2B6, 209, 2C19, 3A4
and 3AS with submicro-
‘molar potency, and can
increase the activity of
CYPs 2810 and 2813."
‘which indicates that THC and CBD could
decrease the metabolism of NSAIDs and
increase their side effects,
But inceractions within the endocan-
nabinoid system are likely more impor-
tant. Both THC and CBD can increase the
synaptic concentration of anandamide,a
‘major endocannabinoid." Since COX2 is
‘membrane-bound, this could increase the
role of COX2 in metabolizing endocannab-
inoids.In combination, phytocannabinoids
and NSAIDsmay lead toa superadditive or
“synergistic effect on cannabinoid signal-
ing. The subsequene activation of CB1 and
(CB2 receptors confers analgesicand anti-
inflammatory effects. In shore, canna
Opiates: Opiates are very powerful
analgesics but are complicated by toler-
ance dependence and withdraal They act
primarily on p-opioid receptors (ORs) in
the spinal cord, brain and brainstem. The
laters responsible for resprarorydepres-
sion during overdose. Generally, opiates
are metabolized by CYPs 344 and 2D6."
High doses of CBD could interact with
opiates via CYP344,bucthis has not been
seen clinically. Oral CBD (400-800 mg)
administered with ineravenous Feneanyl
noc increase adverse effete” The same
lacko effect harbeen shown for morphine
when THC tich cannabis is vaporized.”
Endogenously, cannabinoids and
opioids modulate each
other. CBI and HOR
feceptors can dimer-
ize to convey analgesic
signals” Thelack of CBI
receprrsin te brainstem
suggests the possibility
of porentiating opiate
analgesia without influ.
éncing che lethal thresh-
odin other words, CBL
agonists (euch as THC)
can widen the cherapeutie
‘Tetrahydrocannabinol window of opiates." CBL
(THC; the main psychoac- agonism can also poten-
tive component of canna- slate the addictive nature
bis) is an equally potent of opiates, according to
inhibitor of CYP2C9, some research.” Burrecent
and weakly inhibits other ‘Gas chromatography i usedto analyze terpenes and residual solvents epidemiological data have
(CYPs. Drugs metabolized
bychese CYPenzymesmay
shave aleered plasma concentrations, and
‘hie should be monitored closely. Burcini-
cally relevant changes in drug metabolisen
due eo CBD are usually seen wich high
doses of pure CBD.” Interactions are
_more likely ro occur because of convergent
biological pathways.
Pain Medications
‘NSAIDs: Nonsteroidal anti-inflamma-
sory drugs work primarily by inhibiting.
cyclooxygenase 2(COX2), COX? produces
prostaglandins~a type of inflamma.
tory lipid-from arachidonic acid and
endocannabinoids, By inhibiting COX2,
[NSAIDs reduce inflammation and promote
activity at cannabinoid receptors, which
appears to be one oftheir mechanisms of
action. This stimulatory influence on the
endocannabinoid system suggests poten-
tial interactions wich cannabis. NSAIDs
are metabolized primarily by CYP2C9,
34 raLL2017
incannabis extracts.
‘noids are likely to synergize with NSAIDs,
potentiatinghe analgesia while minimally
‘impacting the gastric side effects.
Ibuprofen appears to modify endocan-
‘nabinoid signaling even more directly In
addicion co inhibiting COX2, ibuprofen
‘or its metabolites inhibic fay acid amide
‘nyrolase (FAH) the main enzyme respon-
sible for breaking down anandamide.*
‘The increase in cannabinoid signaling
by these three mechanisms is unlikely to
‘exacerbate the side effects of ibuprofen —
‘which arelargly due to COX! inhibition —
but it should potentiate their anti
inflammatory and painkilling effects.
‘Unfortunately thisinteraction has nor been
studied in detail—to che author'sknowledge
ro studies have examined simultaneous
use of phytocannabinoids and NSAIDs
for analgesia, But promising studies have
shown synergy when anandamide is ad-
‘ministered with NSAIDs."
lessened this concern:
prescription opiace use
and overdose deaths have significantly
decreased in stares wich medical canna:
bis laws?"
‘The most promising cannabinoid.
opiate interactions appear to be
between CBD and opiates. CBD reduces
cue-induced heroin-seeking, likely
‘through its modulation of dopamine and
serotonin. CBD-and toa lesser extent
‘THC™are negative allosteric modulators
ofp and d-opioid receptors, meaning they
decrease the activiy of opiates at chese
receptors." Both THC and CBD can
reduce opiate wichdrawal in animals.
(Other ways of either antagonizing ot
augmenting the endocannabinoid system
have also shown promise in reducing
opiate withdrawal and tolerance."
(Our understanding of the interplay
berween cannabinoids and opiates is stil
developing, but the clinical data demon-
strate significant synergy between the 0,with minimal changes in opiate metabo-
lismand eoicity: THC appearsco synergize
most with the painkilling effect of opiates,
“while CBD is most promising for reducing
‘withdrawal and dependence. Hence, canna
binoids are likely to potentiate opiates,
decreasing pain while minimizing risks
associated with tolerance, dependence
‘and overdose. Nota interactions will be
positive, but che potential is there, and
‘dramatic problems appear unlikely.
Metabolic Syndromes
Inculin: There is strong preclinical
evidence that cannabinoids influence
_lucoseand insulin sensitive, which could
shave a serious impace on
patients with eype 1 or
type 2 diabetes, though
the effece will depend on
which cannabinoids are
caken.**Tnsulin sensiciv-
ity will likely be impaired
by paychoactive consticu:
‘ents of cannabis like THC,
ing CBD and tetrabydro-
‘cannabivarin (THCV)
ray increase sensitivity
to insulin, CBI activa:
tions part of a feedback
mechanism that reduces
the body's response to
glucose and insulin 252
production of cholesterol by the liver:
This effect isnot necessarily specific
lowsdensity lipoprotiens. The metabolism.
‘ofstatins sess general than for other drugs
mentioned here. Statinsare metabolized by
CYPs 3A4/5, 2C8/9/19 and 206, indicar-
ing char phytocannabinoids could change
statin metabolism. Prodrugs like simvas-
tatin and lovastatin require metabolism
to become active. The more hydrophilic
statins eg, pravastatin) are excreted bythe
kidneys with minimal metabolism by CYP,
10 these statins are unlikely tobe affected
by cannabinoids. Cannabinoids are known
to be involved in cholesterol metabolism,
hear disease and mitochondrial function,
which activation of CBI is important).
Bur ifthe former effect of cholesterol
inhibiting CBI is dominane, then statins
may amplify the effeet of cannabinoids,
resulting in increased side effects like
anxiety These changes wil beparticulasly
relevant in patients taking THC, which
directly activates CBI receptors. Canna
binoids also exere effects through changes
in membrane fluidity and permeability,
which willereainly be altered ifcholesterol
levels are decreased, Patients taking eanna-
binoids who begin trearmene with statins
should be warned thatthe effective dose
of cannabinoids wil likely change. (Note
tha chereis no established “normal” dose
of cannabinoids. Doses of
‘THC range from roughly 1
to 50 mg, and are depen-
ent on a patient's condi-
‘ion, tolerance, experience
and comfort wich the
psychoactivity of THC.
fa patient has found an
effective dose of eanna-
binoids, statins could
shife this dose in either
2 Warfarin is
one of the most widely
used blood thinners and
is primarily inactivaced
by CYP2C9. Common
murations in CYP2C9
‘Some studies, although {Gel aps being formulated wit specifi concentrtions of THC and CBD reduce its activity to less
Fewer, chow theopposite”
One CBI antagonist,
Rimonabant, was briefly approved in.
Europe for treating obesity, but severe
psychiatric complications (depression and
‘suicidal behavior) forced its removal from
the market.
Epidemiological daa, however, compli-
‘ates the picture. Cannabis use is associ-
ated with an overall decrease of metabolic
‘syndromes! Moreover, while there is an
increased prevalence of prediabetes among
‘cannabis users, there is no change ora
lower incidence of diabetes compared to
the general population Irisnotclear if this
‘due to uncontrolled confounding factors
cor if the effect of CBI activation changes
‘becween healthy and insulin insensitive
individuals. Tei possible thar the endocan-
nnabinoid system buffers insulin senstivicy
rather chan stretly inbibiting ie
Statins: Statins reduce the synthesis
of cholesterol by blocking HMG-CoA
reductase,an important early step in the
SONOMA MEDICINE
fom COertracted cannabis ol
which raises the possibility of interactions
with statins by non-metabolic means."
CBI activation may even inhibit HMG-CoA
reductase although this was only shown.
incancer cells"
“The ajorinteractions beoween statins
‘and phycocannabinoids will likely be on
‘cannabinoid function. Cholesterol levels
are intimately involved in CBI receptor
function. CBI has multiple binding sites for
cholesterol, which influences mary aspects
ofits signaling *** The cholesterol precur-
‘sor pregnenalone decreases CBI actvity**
Cholesterol similarly inhibits CBI, bueie
also directs CBI to ies proper location
in neurons.*™*"* If the latter effect is.
more dominant, cannabinoids—especilly
psychoactive cannabinoids—could become
less effective in patients taking statins.
‘This would be relevant for the treatment
‘of multiple sclerosis, pain, cachexia and
«epilepsy, among others (.e, conditions for
than halfoF normal, which
may contribute to the
dificalty of dosing warfarin; over third
ofall patients who take warfarin end up
dn the emergency room before an optimal
doseis ound, aeconding toa 2008 report.”
‘THC and CBD can both inhibit CYP2C9,
and hence amplify warfarin’ effecs. This
hasbeen demonstrated ina case scudy as
well as preclinical work: Doctors should
be cautious about mixing cannabinoids
with warfarin, alehough reducing the dose
of warfarin should be enough to prevent
adverse effets.
Cannabinoid-Cannabinoid
Interactions
Te would be inappropriate to address
cannabinoid-drug interactions without
mentioning the influence of many canna-
binoid and cerpenoid compounds on
each othe, sometimes called the “entou-
sage” effect * Cannabis isa plant, nota
drug, Different varietal ie, strain) and
aut2017 35_growing practices lead to plants with very
different compositionsand effets Studies
hhaveshown that THCand CBD potentiate
‘many ofeach other’ medical effets while
‘mitigating others °
‘CBD isolates have narrower therapeutic
windows and gnealy equrehigher doses
than whole-plane preparations. For
example, GW Pharmaceutieals Epidiolee
isa pure CBD sublingual rnceure thathas
been eested in clinical er
is for certain
forms of epilepsy. While ic has been effec.
tive in many patients ie requires doses of |
5-50 mg/kg/day, whichis up co 1.2 grams
‘oF CBD fora $0-pound child With such
‘enormous doses drug interactions become
very likey.
By comparison, artisanal cannabis,
preparations usually require 1-100 mg
of cannabinoids.***"In many ways, the
entourage effect is a microcosm of drug.
interactions on che whole. Without a
derailed understanding of the medicine
being used, che variety of chemicals can
lead to inconsistent results and may
reduce medical efficacy or potentiate side
effects. Orinteractions berween drugscan,
beexploited to mitigate each other's side
effects while synergistically improving a
patient's quality of ife.
Emait: adrianeprojecteba.org
References
1
‘Navona Academies of Sciences, Engineeting
and Medicine, “The Health Efe of Canna
bis and Cannabinoids The Curren State of
Evidence and Recommendations fo Research?
‘Te Nesnal cade re (2017
tod iid parsers in pant with pe?
‘Eee arene dbl plato
‘once paral group poe sy Deny
Gare 3810)177786 (208
argent ET, aly "The cannabinoid (9)-
‘eraiocannaivarin (THCY) arose
Jnvlin esti in wo mote model of
bes er Ds 388 013
el Cea Priciv modes of PDAS
ecto avin vowing aed
Fisrmacopbor modeling”) Parma ap
J, 31268392657 2008)
YamioniS "Pen nhiion ohman
{rocreme PSO ah rms bycnmabii
‘eof pena yay goupin theresa
cole” ps8 1617905201)
Sorina -Chaaenason ofan
Intact
‘Bec arma 4503299119).
Sear oh Soneronl aparen e
36 FALL 2017
poten direction ofhuman rochrome
450 1A by eanabidiok role of pearyesor
incl nie” Paro Bal 36(71197-208
(202),
4 JangReca *Cannaitiolisapownrinibioe
ofthe catalyi activ of eytochrome PASO
2C18; Dng Meta Pharmacoines 243328
(01),
9, Yamaor,e¢al, "Comparison in he in vio
inky ic of ego toca
sd polygeic somatic bydeoatbons con
‘ained in marijuana smoke on cytochrome
‘450209 activity” Drag Metib Pharma,
27(9:294-300 2012,
10, Abrams Dj, eta, “Cennabinid-opoi inter-
section in conic pain” Clin Phrmacal Ter,
so(6:844-s1 201),
1M. Getty AL cal, "Drugdrg intercon betwen
slobazam and annabiil in children with
Sacro pep” pis (12461 2019,
12. Gaseon TE, eta teractions berweencanabic
dilandcommoniy wed aniepptic dus”
"pips Epub aad of rine DOL 101111/
epil3as2 207)
13, Sila LG, etl, “Participation of cannabi-
noid recor in peripheral nociception in-
dled by sme NSAIDS" Ere J Met Bol Rs,
's(22:1240:3(2012,
14. Deutsch DG, "A Pesonl Rerospectv: Fleva=
‘ing Anandsmide (AEA) by Targeting Fay Acid
Amide yrolase(FAAH) and che Paty cid
Binding Proteins (FABPS)” Fron: Pbarmaco
7370 @016).
15. Dogan KC eal (Profi ae substrate selec
heirs of endcannabinld
by CON" Nar Chm Bo 711) 805 9 (201)
16. Guindon Jel, "Synergistic antinociceptive
\ffecrs of enandamide, an endocannabinoid,
‘nd nonseroidal ant infammatory dg in
petipheral desuesaroleforendogenous sy
4d ethanolamides?, Eur J Pharmacol, S50
(1-3,68-77 006)
17. Guinden J el “Locl interactions between
‘naadamid, an endocannabinoid, and bu-
rod armenia enfin,
Enacue and inflammatory pain” Pat, 121
(-2.85-93 2006)
18, Smith HS, "Opioid metabolism,” Mayo Cis
ro 847613242009).
19 Manni AF eal “Sefey ane pharmacokinetics
fora cansbidiolwhen admins concon-
‘zany wich inavencas encanyin humans”
J Adis Mad 98)204-10 2015.
20. Hojo M, el, "*mu-Opiid receptor forms a
functional berroimer with cannabinoid CBL
receptor elecropiysiologialand FRET assy
analysis” J Pharmac S,10(3)308-19 (208),
21, Cooper D eral "Oxqcodone’ effets on can
‘abis-induced analgesia and subjective drug
ratings” presented atthe 2016 Intemasional
CCennabinoi Research Soe,
22.Spano MS ets “Cannabinci- opioid interac
‘toting dco anlar
‘ratiorefic of maternal posmatal aolseent
and adue exposure wo the drugs,” Grr Drag
Tarts 1(8)45061 2010).
23.Bradiond AC, Bradford WD, “Medial Marijuana
Laws Reduce Prescription Medication Use In
‘Medicare Pare D Huth af 357123062016).
24 Conon Mea, "Canabiesranubainetor
resenponcrugs~aerosssetonal study")
‘ais es, 10989-598 2017,
25.Rea Yet, "Cannabidial, a nonpsychotropic
‘component of cannabis hibits ev induced
heroin seeking and normalize sree me-
solimbic neuronal disturbances,"J Nero,
2947)147649 (2009).
26, Katsidont Va “Cannabiiel inhibit the
revanfciaring ee of morphine invaie-
‘mantofSHITIA reeeptarsin the dorsal raphe
mules," Adi Bi, 182).28696 (201).
27 Kathmann M, ea "Cannabcl san alos
‘iemodulator ar mu and deles-opind ep
tor” Naty Schmidber: Arc Pharma
‘72(5)35%61 2006)
28.Vayse ) cay" Modlacon ofa brain opi
receptors by cannabinoids") Pharmacel Exp
The, 241(2)534-9 (1987)
Biche Bebe, 23(1)13- (1985).
230.Hund YL, ea, Eay phase inthe derlopment
‘of eammabidiel ava treatment for nico:
‘poe cep taal center tge” Mar
rsberspes,12(8)807-15 2015).
2. WilsKL athe LA, Efe of pharmacological
‘modulation ofthe endocannabinoid eyremon,
‘opiate withdrawal a review ofthe preclinical
‘animal literate" Fon Porc, 71872016)
82, KI, eta ‘Doabledisocaion cf moncac-
yore ipseinibidon and CB] ancora
in che cena amyl, basolateral amyl,
and he imerocepiveinsular corcexontheaf
feeveproperiescfacutenalomne precpitated
_merphine withdrawal nats" Narepnebphar
acl, (71868-73015).
33.Wils HE eal "CBI sncagonisn inerfeence
with affective properties of acute naloxone
precipitated morphine withdrawal in rats”
Prypbarmaclg, 231(2)429-300 (2019.
$4. Arguta DS, DiDatiio NV, “eripheral endo-
‘courabineldsieatng controls bypespagia
‘neste derinduced ebesiy” Phys Beha,
1713239 2017}
35, Lindborg KA, etal, “Efecs of in vitro an-
ragonsm of endcesnnabincd receptors
the glucose anspor ystem in normal nd
{nslin-resican ca sell muscle” Dabs
(bes Met 12(8)722-30 (2010,
36.AraioR, eal "Modulation of glucose peake
ina human chriocarcinoma cll line eo)
‘by dietary bioactive compounds and drugs of
abuse? J Bice, 14(2)177-86 (208).
37. Miederer |, etal “Efecs of tetrahydeocan-
‘abinal on ghicoee upeae in the a bean,”
‘Newopharmacly, 17273281 (2017),
38.12U BK, etal, "Endocannabinoid modulation
of omcutti and aon homeasate
‘rity’ Nownpharmaclgy, 12438 1 (2017,
39.Lipnaetal“Micochoer:aposiblenerus
Reterences continue on page 48
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48 FALL 2017
References, continued trom page 6
fovthe relation of emegyhomeosasishy he
endocannabinoid sytem?” Phyl Endo
ern! Mash, 2071)1-13 2914.
40, Rimmerman N, etal "The now paycoatve
plant canabined annabiil ates choles:
terol metabelismelated genes in microglial
cel" Cl Ma Nobo, 31(6:921-30 2012).
4 Lama al "inhibin of yoy meh
viguar-crnzyme Areduceseactviyand of
Ras farnesplation mediaeanicumor effects
of anandamide inhuman beast cance cls"
Endo Relat Cancer, 172495508 (2010).
42. Oddi Seca "Paimitolain of iene 15 of
(CB repre aes gan atimdatdinernal-
inuion snd wot interaction with menbrane
holeeroland caveolin Bich Bp
1862(5}523-532 2017
48, Ode § eal “Functional characeiation of
pura cholesterol binding equence(CRAC)
Eikemnen perl ermine regen? Me
roe, 16(5)858-65 201).
44, Vale etl "Pregnenolone cn protect che
brain from cannabis intoxication," Scene,
336168) 348 2014),
45 StoaiuoloM ea “Endogrous scopes
tlle odlatrsin GPCRe a dopa ar
‘Suting CEL among dffieat membrane mi-
Groenitonment" Sep 515453 (2018).
‘4 Hering Heap afin tbe matenane of
synapses den spines ae surice AMPA re
epee sabi” New 28326271 (2003),
4, Cason B,"Deciarng war on warfacin misdos
ing? Blnlay Hata, S(}S4-55 (2008).
48 Yarreudeenong Wetal Probable interaction
beweenwarfarinan marjuan smoking” Amn
Pharmac 437} 1347-3 209)
1, uso, “Taming THC Portal ansatis sy
rgyan phyocetabinsdaerpenoid entourage
tfc” Br] Pharma, 1647134464 (2011).
50. Russo E Guy GW, "A ale of wo canrabinid
‘Thetheapeuticracoealeforcombaning reat
roenmabinolandcannsbiil” Mod pas
62}23446 (2005)
St Bich $C eel, "Cannabiio!9eahydrocane
‘hina recta norte peta doeares
toe att” Dg Alea Depend 175187-197
(2017.
2 Texel Sta neracons betwen canal
and STHColoving acute and pete oxng
‘nkound iypeaciy sensorimerr ging
pipes ed neti changes the
‘eb pattem” Br Nera
27aya32-145 201.
58. Gallly Kel “Overcoming the bell-shaped
dovereponsefeanmabtal byusng cannabis
‘rac enticed in canabiinl” Pharmaiogy
hermary, 675-85 2015)
S54. De Peroni etal, "Eeasofcanrabinide
and canabinoenrichedanmableenracton,
‘TWP hunneland endocamabinoid merabaic
temgnes' Br) Pharmac 167)147994 2011),
58, Golden, Bonn, Came Real: How te
‘old inde pl bang eying,
om crank pin pe, Golden 16.
56, Sulak Dera "he curren status of arsanal
‘cannabis force treatment of eppoy in the
nied aes ie Beha 7028.33 (2017,
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