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 33fearful 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