A marijuana-drug interaction primer: Precipitants, pharmacology, and pharmacokinetics

Abstract

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 highlights the relative absence of safety, pharmacokinetic, and drug interaction data for marijuana and its constituents, most notably the cannabinoids. This review articulates current issues surrounding marijuana terminology, taxonomy, and dosing; summarizes cannabinoid pharmacology and pharmacokinetics; and assesses the drug interaction risks associated with co-consuming marijuana with conventional medications. Existing pharmacokinetic data are currently insufficient to fully characterize potential drug interactions precipitated by marijuana 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 potential marijuana-drug interactions and inform health care providers and consumers about the possible risks of co-consuming marijuana products with conventional medications.

Keywords: Cannabinoid; Drug interaction; Marijuana; Natural product; Pharmacokinetics.

Figure 1:. Structures of THC, CBD, CBN, and their major metabolites

(A) Structures of THC, CBD, and CBN. (B) CYP2C9 catalyzes formation of the primary active THC metabolite, 11-OH-THC, which is subsequently oxidized to the inactive THC-COOH, whereas CYP3A4 catalyzes formation of a second primary, but inactive metabolite, 8β-OH-THC. (C) Primary metabolites of CBD are formed by CYP2C19 (7-OH-CBD) and CYP3A4 (6β-OH-CBD and 6α-OH-CBD). (D) Relative efficiency of glucuronide conjugation of THC and its metabolites, CBN, and CBD by various UGT enzymes, calculated as a percent of UGT1A9 V_max/K_m (Mazur et al., 2009). ^a not determined due to lack of UGT activity against THC. ^b not determined due to very low UGT activity toward CBD.

Figure 2:. Effects of cannabinoid ligands on the central nervous system and peripheral nervous system

Activation of the cannabinoid 1 receptor (CB₁) and cannabinoid 2 receptor (CB₂) by cannabinoid ligands inhibits production of adenylate cyclase via activation of a coupled G_i/G₀ G-protein subunit. CB_1/2 activation also promotes exocytosis of a variety of neurotransmitters, which act broadly on the central and peripheral nervous system (CNS and PNS), perhaps by modulation of calcium and potassium transport.

Figure 3:. Effect of route of administration on dose-normalized C_max of THC, 11-OH-THC, COOH-THC, CBD, and CBN.

Dose-normalized C_max after administration of parent cannabinoid (THC, CBD, or CBN). 11-OH-THC and COOH-THC were measured after administration of THC via various routes; metabolite C_max was normalized to the administered THC dose. Symbols represent mean values from individual studies (see Supplementary Table). Horizontal and vertical lines represent geometric means and corresponding 95% confidence intervals, respectively. Data were not available for CBN administered via oral mucosal spray.

Figure 4:. Effect of route of administration on dose-normalized AUC of THC, 11-OH-THC, COOH-THC, CBD, and CBN.

Dose-normalized AUC after administration of parent cannabinoid (THC, CBD, or CBN). 11-OH-THC and COOH-THC were measured after administration of THC via various routes; metabolite AUC was normalized to the administered THC dose. Symbols represent mean values from individual studies (see Supplementary Table). Horizontal and vertical lines represent geometric means and corresponding 95% confidence intervals, respectively. Data were not available for COOH-THC following intravenous administration of THC nor for CBN administered orally and via oral mucosal spray.s