Drug-drug interactions as a result of coadministering Δ9-THC and CBD with other psychotropic agents, Carola Rong et al., 2018

Drug-drug interactions as a result of coadministering Δ9-THC and CBD with other psychotropic agents

Carola Rong, Nicole E. Carmona, Yena L. Lee, Renee-Marie Ragguett, Zihang Pan, Joshua D. Rosenblat, Mehala Subramaniapillai, Margarita Shekotikhina, Fahad Almatham, Asem Alageel, Rodrigo Mansur, Roger C. Ho & Roger S. McIntyre

Expert Opinion on Drug Safety, 2018, 17:1, 51-54.

Doi : 10.1080/14740338.2017.1397128



Introduction : To determine, via narrative, non-systematic review of pre-clinical and clinical studies,
whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in
clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents. Areas covered: A non-systematic literature search was conducted using the following databases : PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper.

Expert opinion : Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

KEYWORDS :  THC; CBD; medical marijuana; cannabidiol; drug interactions


1. Introduction

Marijuana is one of the most widely used recreational drugs in the world [1]. In its natural plant-derived form, marijuana contains over 70 cannabinoids, which are structurally diverse compounds capable of exerting pharmacologic effects. The most abundant of the cannabinoids (i.e. depending on strain) are Δ9- tetrahydrocannabinol (Δ9-THC), the principal euphoriant compound, and cannabidiol (CBD), the non-euphoriant-active moiety with putative beneficial effects on brain function [2].

In the United States, marijuana use has more than doubled in the past decade, increasing from approximately 4% in 2001–2002 to 9% (and higher) in 2012–2013 [4]. The increased utilization of marijuana is likely due, in part, to the increasing number of states increasing access (via legalization /decriminalization policies) to medical and recreational use of marijuana. Individuals who utilize marijuana often cite the alleviation of psychiatric symptoms as a reason for use (i.e. depression, anxiety) [5,6].

Psychotropic agents, including antidepressants and anxiolytics, are among the most commonly prescribed medications in the United States for mood-based disorders. For example, approximately 10% of adults in the United States are receiving a prescription for antidepressant medication [4,7]. Moreover, the percentage of individuals in the general population who are prescribed for these agents is increasing, with longer duration of exposure and polypharmacy [8]. Polypharmacy, the use of multiple different psychiatric agents simultaneously, poses a hazard due to possible adverse drug–drug interactions (DDIs). For example, it is estimated that approximately 10% of all emergency room visits are a direct consequence of DDIs [9]. The increasing rates of utilization of psychiatric medications in conjunction with the increasing use of marijuana provide the impetus for understanding potential DDIs relevant to patient outcome and safety.

Some examples of cannabinoid-containing pharmaceutical products include: dronabinol, which is synthetic Δ9-THC for the treatment of anorexia in AIDS patients; nabilone, an antiemetic; and Sativex® (GW Pharmaceuticals), a mixed compound consisting of a 1:1 ratio of Δ9-THC and CBD indicated
for the treatment of spasticity in multiple sclerosis [3,10]. Thus, the growing development of cannabis-based pharmacotherapies, increased use of medical marijuana by way of inhalation or ingestion, and the possibility of DDIs with other prescribed medications have led to a greater discussion among patients, practitioners, and policymakers about safety, tolerability, and efficacy/inefficacy on the individual medications.

Article highlights

● Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents
● Potential for clinically meaningful elevations in Δ9-THC exposure in individuals with diminished CYP2C9 and/or CYP3A4 function, and in CBD exposure in individuals with diminished CYP2C19 and/or CYP3A4 function
● Patients should be informed that the consumption of Δ9-THC and/or CBD may result in DDIs that are of consequence to the expected probability of efficacy, tolerability, and/or safety of their treatment. This box summarizes key points contained in the article.

In our previous paper from our group, we comprehensively reviewed the pharmacodynamics of cannabis [11]. Here, we aim to extend this further by focusing on its pharmacokinetics. The aim of the review herein was to summarize the extant literature that broadly sought to evaluate the effect of marijuana on hepatic biotransformation pathways relevant to the clearance of commonly prescribed psychiatric medications. Of specific interest was whether consumption of marijuana, via its active cannabinoids Δ9-THC and CBD, could alter clearance and bioavailability of psychiatric medications with implications for safety and tolerability.