Abstract
Cannabis sativa and related products are widely used, but their potential to cause significant clinical
interactions remains unclear, particularly for cannabinoid-enriched or otherwise concentrated
products. The pharmacokinetics of most cannabis products is not known. Where information
is known, there is wide variation. Extrapolation of limited clinical data is complicated
by the complexity and variability of cannabis products as well as their delivery through
various routes of administration. In vitro evidence shows that the major cannabinoids
are substrates for numerous metabolic enzymes, including the cytochrome P450 metabolizing
enzymes. Whereas many consumers consider cannabis products to be safe relative to
alternative prescription or narcotic drugs, clinical reports of cannabis-related drug
interactions and adverse events are increasing in frequency. Patients using these
products, whether for medical or nonmedical purposes, together with conventional therapeutic
agents may be at increased risk of adverse events, including therapeutic failure,
and require enhanced monitoring.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic and PersonalCorporate R&D ProfessionalsOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The American Journal of MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.Drug Metabol Rev. 2014; 46: 86-95
- Cannabinoids and cytochrome P450 interactions.Curr Drug Metab. 2016; 17: 206-226
- Information for Health Care Professionals. Cannabis (Marihuana, Marijuana) and the Cannabinoids.Health Canada, Ottawa, ON2018
- Human cannabinoid pharmacokinetics.Chem Biodivers. 2007; 4: 1770-1804
- Pharmacokinetics and pharmacodynamics of cannabinoids.Clin Pharmacokinet. 2003; 42: 327-360
- A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics.Cancer Chemother Pharmacol. 2017; 80: 441-449
- The pharmacokinetics and the pharmacodynamics of cannabinoids.Br J Clin Pharmacol. 2018; 84: 2477-2482
- Cannabis and anticancer drugs: societal usage and expected pharmacological interactions - a review.Fundam Clin Pharmacol. 2018; 32: 462-484
- Chemical constituents of marijuana: the complex mixture of natural cannabinoids.Life Sci. 2005; 78: 539-548
- Cannabis edibles: blood and oral fluidcannabinoid pharmacokinetics and evaluation of oral fluid screening devices for predicting Δ9-tetrahydrocannabinol in blood and oral fluid following cannabis brownie administration.Clin Chem. 2017; 63: 647-662
- Pharmacokinetics of cannabis in cancercachexia-anorexia syndrome.Clin Pharmacokinet. 2016; 55: 807-812
- Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy.Cannabis Cannabinoid Res. 2016; 1: 90-101
- Are THC levels in oral fluids and blood plasma comparable after oral ingestion of edibles containing cannabis or THC?.Clin Chem. 2017; 63: 629-631
- Phase I and II cannabinoid disposition in blood and plasma of occasional and frequent smokers following controlled smoked cannabis.Clin Chem. 2014; 60: 631-643
- Oxidation of the endogenous cannabinoid physiological and pharmacological implications.Pharmacol Rev. 2010; 62: 136-154
- Endocannabinoid metabolism by cytochrome P450 monooxygenases.Prostaglandins Other Lipid Mediat. 2015; 116-117: 112-123
- Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes.Life Sci. 2007; 80: 1415-1419
- Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2.J Inorg Biochem. 2018; 184: 88-99
- Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity.Drug Metab Pharmacokinet. 2012; 27: 294-300
- Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6.Drug Metab Dispos. 2011; 39: 2049-2056
- Characterization of the structural determinants required for potent mechanism-based inhibition of human cytochrome P450 1A1 by cannabidiol.Chem Biol Interact. 2014; 215: 62-68
- Interindividual variation in the pharmacokinetics of delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9.Clin Pharmacol Ther. 2009; 85: 273-276
- Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines.CNS Neurol Disord Drug Targets. 2017; 16: 554-566
- Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products.Clin Pharmacokinet. 2016; 55: 1353-1368
- Enhanced biotransformation of theophylline in marihuana and tobacco smokers.Clin Pharmacol Ther. 1978; 24: 405-410
- Effect of cannabinoids on the activity of monoamine oxidase in normal human platelets.Arch Int Physiol Biochim. 1982; 90: 15-20
- Cannabis extract, but not delta 1-tetrahydrocannabinol, inhibits human brain and liver monoamine oxidase.Gen Pharmacol. 1984; 15: 171-174
- Effects of acute cannabis use and short-term deprivation on plasma prolactin and dopamine-beta-hydroxylase in long-term users.Drug Alcohol Depend. 1982; 9: 251-255
- Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids.Drug Metab Dispos. 2009; 37: 1496-1504
- Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UD15-glucuronosyltransferases.Drug Metab Dispos. 2011; 39: 1967-1976
- Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse.Drug Metab Dispos. 2013; 41: 568-574
- Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents.Expert Opin Drug Saf. 2018; 17: 51-54
- Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana.J Pharmacol Exp Ther. 2006; 317: 850-857
- Cannabinoid type 1 receptor antagonists modulate transport activity of multidrug resistance-associated proteins MRP1, MRP2, MRP3, and MRP4.Drug Metab Dispos. 2011; 39: 1294-1302
- Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice.Clin Pharmacol Ther. 2007; 81: 495-502
- Interactions between cannabidiol and commonly used antiepileptic drugs.Epilepsia. 2017; 58: 1586-1592
- Prognosis of schizophrenia in persons with and without a history of cannabis use.Psychol Med. 2014; 44: 2513-2521
- The differential binding of antipsychotic drugs to the ABC transporter P-glycoprotein predicts cannabinoid-antipsychotic drug interactions.Neuropsychopharmacology. 2017; 42: 2222-2231
- Interaction between warfarin and cannabis.Basic Clin Pharmacol Toxicol. 2019; 124: 28-31
Epidiolex® prescribing information. Greenwich Biosciences, Inc.,August 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed October 2, 2019.
- Detection of in utero cannabis exposure by umbilical cord analysis.Drug Test Anal. 2018; 10: 636-643
Article Info
Publication History
Published online: May 29, 2019
Footnotes
Funding: No funding was received for the preparation of this review.
Conflict of Interest: None.
Authorship: All authors had access to the reviewed materials and contributed meaningfully to data synthesis and writing the manuscript.
Identification
Copyright
© 2019 Published by Elsevier Inc.
