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A Marijuana-Drug Interaction Primer: Precipitants, Pharmacology, and Pharmacokinetics

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A Marijuana-Drug Interaction Primer: Precipitants, Pharmacology, and Pharmacokinetics Pharmacology & Therapeutics 201 (2019) 25–38 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera A marijuana-drug interaction primer: Precipitants, pharmacology, and pharmacokinetics Emily J. Cox a,NehaMaharaob, Gabriela Patilea-Vrana b,JashvantD.Unadkatb,e, Allan E. Rettie c,e, Jeannine S. McCune d,e, Mary F. Paine a,e,⁎ a Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, United States of America b Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, United States of America c Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, United States of America d Department of Population Science, City of Hope, Duarte, CA, United States of America e Center of Excellence for Natural Product-Drug Interaction Research, United States of America article info abstract Available online 7 May 2019 In the United States, the evolving landscape of state-legal marijuana use for recreational and/or medical purposes has given rise to flourishing markets for marijuana and derivative products. The popularity of these products Keywords: highlights the relative absence of safety, pharmacokinetic, and drug interaction data for marijuana and its constit- Cannabinoid uents, most notably the cannabinoids. This review articulates current issues surrounding marijuana terminology, Drug interaction taxonomy, and dosing; summarizes cannabinoid pharmacology and pharmacokinetics; and assesses the drug Marijuana interaction risks associated with co-consuming marijuana with conventional medications. Existing pharmacoki- Natural product netic data are currently insufficient to fully characterize potential drug interactions precipitated by marijuana Pharmacokinetics constituents. As such, increasing awareness among researchers, clinicians, and federal agencies regarding the need to conduct well-designed in vitro and clinical studies is imperative. Mechanisms that help researchers navigate the legal and regulatory barriers to conducting these studies would promote rigorous evaluation of po- tential marijuana-drug interactions and inform health care providers and consumers about the possible risks of co-consuming marijuana products with conventional medications. © 2019 Elsevier Inc. All rights reserved. Contents 1. Introduction............................................... 26 2. Marijuanaproductsandconsumption................................... 26 3. Majorconstituents............................................ 26 4. Pharmacology.............................................. 27 5. Pharmacokinetics............................................ 29 6. Druginteractions............................................ 31 7. Conclusions............................................... 34 Conflictofintereststatement......................................... 36 Acknowledgments.............................................. 36 AppendixA. Supplementarydata...................................... 36 References.................................................. 36 Abbreviations: AUC, Area under the plasma concentration-time curve; CBD, Cannabidiol; CB1, Cannabinoid receptor 1; CB2, Cannabinoid receptor 2; CBN, Cannabinol; Cmax, Maximum plasma concentration; CYP, Cytochrome P450; IC50, Half-maximal inhibitory concentration; Ki, Inhibitory constant; THC, (−)Δ9-trans-(6aR,10aR)-tetrahydrocannabinol; Δ8-THC, (−)- Δ8-trans-tetrahydrocannabinol; UGT, uridine 5′-diphospho-glucuronosyltransferase. ⁎ Corresponding author at: Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, PBS 341, PO Box 1495, Washington State University, Spokane, WA 99210-1495, United States of America. E-mail address: [email protected] (M.F. Paine). https://doi.org/10.1016/j.pharmthera.2019.05.001 0163-7258/© 2019 Elsevier Inc. All rights reserved. 26 E.J. Cox et al. / Pharmacology & Therapeutics 201 (2019) 25–38 1. Introduction are primarily a function of the relative content of two dibenzopyran cannabinoids produced by Cannabis varieties: [(−)Δ9-trans-(6aR, Marijuana, or cannabis, is the most commonly consumed scheduled 10aR)-tetrahydrocannabinol] (THC), the primary psychoactive constit- or illicit substance worldwide (Degenhardt et al., 2013; Vergara et al., uent, and cannabidiol (CBD), the primary non-psychoactive constituent 2017). State restrictions on access to marijuana and derivative products (Fig. 1A) (Grotenhermen, 2016). THC and CBD are the major cannabi- in the United States have been relaxing since 1996, fostering the appear- noids in 11C. sativa and C. indica strains (Fischedick, Hazekamp, ance of state-legal dispensaries and an increasingly diverse market of Erkelens, Choi, & Verpoorte, 2010). As such, cannabinoid studies in commercially available products (Jikomes & Zoorob, 2018; Maxwell & humans have focused largely on THC and CBD, and to some extent on Mendelson, 2016; Vergara et al., 2017). Patterns of consumer use are cannabinol (CBN), an aromatized monoterpenoid derivative of THC similarly in flux. In 2013, there were an estimated 181.8 million recrea- present in marijuana smoke condensate (ElSohly & ElSohly, 2007). tional users aged 15 to 64 years (WHO, 2016). By 2016, the percentage Although there is extreme inter-strain variability in THC:CBD ratios, in of individuals aged 12 years or older who were current marijuana users general, C. indica dominant strains, which are short and wide-leafed, was higher than that from 2002 to 2015. This increase was due largely to tend to produce more CBD relative to THC; the taller and more increased consumption by young adults aged 26 years or older, whose narrow-leafed C. sativa dominant strains tend to produce more THC rel- use has increased more than that of young adults aged 18 to 25 years. ative to CBD (Dufresnes et al., 2017; Hillig & Mahlberg, 2004). Given these changes, the absence of definitive data regarding con- Routes of administration for marijuana and derivative preparations stituent composition, pharmacokinetics, safety, and efficacy of mari- (e.g., wax, oils, and resins) include inhalation (smoking), oral consump- juana products is increasingly conspicuous. These gaps in scientific tion, or topical application. The increasing popularity of vaporizing knowledge about marijuana products are compounded by the lack of instruments has produced a market for water-soluble emulsions or so- definitive information regarding the risk of co-consuming marijuana lutions of cannabinoids for inhalation. Oral forms (edibles) are often products with conventional drugs (both prescription and over-the- prepared by solubilizing constituents of the whole plant in lipids, incor- counter). The shifting legal landscape affords an unprecedented oppor- porating into food products, and cooking to de-carboxylate cannabinoid tunity to study the drug interaction liability of marijuana amidst a constituents. wealth of information regarding constituents, consumption patterns, Dosing recommendations for marijuana remain nascent, albeit some and safety data from both prescription and illicit synthetic derivatives. states have defined a standard dose of THC per serving of edible product As with most natural products, evaluating the drug interaction risk (e.g., 10 mg in Washington, California, and Colorado; 5 mg in Oregon). of marijuana and constituents (e.g., cannabinoids) is difficult due to Precise dosing is complicated by inaccurate labeling, a problem inherent the complex phytochemistry of the plant and the abundance of deriva- to the natural product market (Ekor, 2014; Raynor, Dickinson, Knapp, tive products on the commercial market. However, marijuana is unique Long, & Nicolson, 2011). For example, among marijuana products pur- among natural products in that its constituent composition has been a chased online, 26% contained less CBD than indicated on the label subject of forensic examination for decades. Additionally, synthetic (Bonn-Miller et al., 2017). Cannabinoid content of marijuana also has cannabinoids have been approved for prescription use by regulatory increased substantially over the last two decades such that the THC con- agencies in multiple countries. To facilitate increasing research on the centration of confiscated marijuana reportedly increased by 103% be- pharmacokinetics and drug interaction risk of marijuana products, this tween 1998 and 2008 (ElSohly et al., 2016; Niesink, Rigter, Koeter, & review summarizes cannabinoid constituents, pharmacology, and phar- Brunt, 2015). Recommended medical dosing with whole plant products macokinetics in humans, as well as probable marijuana-drug interac- is to “start low, go slow, and stay low,” titrating slowly over approxi- tions precipitated by concomitant consumption of marijuana products mately two-week increments (MacCallum & Russo, 2018). Prescription with conventional drugs. cannabinoids in the United States are labeled with low initial doses for twice-daily administration (e.g., 2.5 mg dronabinol, 1 mg nabilone, 2. Marijuana products and consumption 2.5 mg CBD) (Valeant Pharmaceuticals International, 2006; Greenwich Biosciences, Inc., 2018; AbbVie, Inc., 2017). According to United States law, the Schedule I substance Cannabis Adverse events reportedly ensuing from medical marijuana sativa (C. sativa) encompasses all non-fibrous components of any mari- consumption appear to pertain primarily to THC content; thus, juana strain (21 USC 802). Pragmatically, the botanical
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