Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain, Marta Vázquez et al., 2020,

Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain

Marta Vázquez, Natalia Guevara, Cecilia Maldonado, Paulo Cáceres Guido, and Paula Schaiquevich

Hindawi, BioMed Research International, 2020, Article ID 3902740, 9 pages

Doi : 10.1155/2020/3902740

Choosing an appropriate treatment for chronic pain remains problematic, and despite the available medication for its treatment, still, many patients complain about pain and appeal to the use of cannabis derivatives for pain control. However, few data have been provided to clinicians about the pharmacokinetic drug-drug interactions of cannabinoids with other concomitant administered medications. Therefore, the aim of this brief review is to assess the interactions between cannabinoids and pain medication through drug transporters (ATP-binding cassette superfamily members) and/or metabolizing enzymes (cytochromes P450 and glucuronyl transferases).


1. Introduction

A drug-drug interaction (DDI) occurs when one drug alters the clinical effect of another. Drug interactions occur on pharmacodynamic and pharmacokinetic levels. In the first case, one drug may alter the sensitivity or responsiveness to another drug. Pharmacokinetic DDIs occur when a drug alters the absorption or disposition (distribution and elimination) of a concomitantly administered drug. This change can lead to an altered quantity of drug at the site of action affecting the magnitude and duration of the effect. In this scenario, a drug is a perpetrator referring to the one that causes an effect on the substrate drug, for example, by inducing or inhibiting drug-metabolizing enzymes. Although DDIs are often associated with toxicity or therapeutic failure [1], sometimes they can produce beneficial effects to the patient (i.e., improving the bioavailability of a drug and producing additive or synergistic effects) [2]. In any case, clinicians must be familiar with DDIs in order to improve prescribing tools.

During the last 5 years, a dramatic rise in the use of cannabis led to an increased number of patients taking it simultaneously with their previous medication. This situation could result in several problems as cannabinoids may be classified as either perpetrators or substrates depending on the concomitant drugs leading to altered exposure, adverse events, and/or lack of clinical efficacy. However, scarce evidence is available about cannabis drug interactions with potential implications in clinical efficacy and safety.

The endocannabinoid system has been recognized as a potential therapeutic target. Either highly purified cannabidiol (such as Epidiolex recently approved in the United States for use in Lennox–Gastaut or Dravet syndrome) or formulations with different Δ9-tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios (such as Sativex, an oromucosal spray for the treatment of multiple sclerosis-associated spasticity) are being investigated for other disease states. Although the use of cannabinoids for the treatment of pain is supported by some controlled clinical trials [3–5], currently and according to  systematic reviews and meta-analysis [6–8], there is onlymoderate evidence to support the use of cannabinoids in treating chronic pain and larger and higher quality clinical trials are needed. Despite this fact, chronic pain relief is by far the most common condition cited by patients using cannabis for medical purposes and very little is known about potential pharmacokinetic interactions with common medication prescribed for chronic pain.

Nowadays, even cannabinol (CBN), a byproduct of THC degradation, is being studied for its analgesic effect [9].

CBD, THC, and CBN are extensively metabolized in the liver and in the intestine. Mainly CYP2C19 and, to a lesser extent, CYP3A4 are implicated in CBD biotransformation [10, 11]. CBD can also undergo direct conjugations via UDP-glucuronosyltransferase (UGT) enzymes, such as UGT1A9, UGT2B7, and UGT2B17 [12, 13]. THC biotransformation is primarily dependent on CYP2C9 and CYP3A4 isoenzymes [14], but UGT enzymes play a critical role in metabolizing THC metabolites (THC-OH, THC-COOH) as well [12]. CBN is metabolized by CYP2C9 and CYP3A4 and can also undergo direct glucuronidation by hepatic UGT1A9 and the extrahepatic UGT1A7, UGT1A8, and UGT1A10 [12, 14].

CBD is not only a substrate but also an inhibitor of CYP450 enzymes and UGTs. In addition, some isoenzymes of the cytochrome P450 system or UGTs are also subjected to inhibition by THC and CBN [11, 15–25]. Regarding the inducing activity of cannabinoids, smoked cannabis may increase the clearance of drugs metabolized by CYP1A2 [24, 25], resulting in lower concentrations of these drugs and perhaps in therapeutic failure.

Furthermore, in vitro and animal studies have shown that CBD, THC, and CBN interact in some way with ATPbinding cassette superfamily: breast cancer-resistant protein (Bcrp) and glycoprotein P (Pgp). Thus, a significant impact on the absorption and disposition of other coadministered drugs that are also substrates of these transporters may be expected. According to some preclinical studies [26–29], CBD inhibits Pgp and Bcrp. Even though inhibitors are often substrates, different in vitro and animal studies show that CBD is not a Pgp substrate [30, 31] and it acts provoking a downregulation in Pgp expression. THC and CBN could also deregulate Pgp, Bcrp, and multidrug-resistant protein (MRP) 1-4 expression [15]. An overview of the effect of cannabinoids on CYP450 isoenzymes, UGTs, and efflux transporters is summarized in Table 1.

As cannabinoids are often used as add-on therapy, the occurrence of DDIs seems more plausible. Therefore, their use in the therapy could interfere with the disposition of other drugs that undergo the same metabolic pathways. Nonetheless, few studies in humans have been carried out and reported in the literature about DDIs of cannabinoids with other prescribed medications [32–34] and some of them are only case reports [35–37].

Although in vitro or animal studies about DDIs should not be extrapolated to human beings, healthcare providers should be aware of clinically important DDIs leading in some cases to therapeutic improvement or in other cases to therapeutic failure or toxicity. Therefore, this review addresses a comprehensive overview of potential pharmacokinetic interactions affecting drug metabolism enzymes such as cytochrome P450 or UGTs and membrane efflux transporters between cannabinoids and drugs used for chronic pain.