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