Cannabidiol and Abnormal Liver Chemistries in Healthy Adults: Results of a Phase I Clinical Trial

Abstract

Liver safety concerns were raised in randomized controlled trials of cannabidiol (CBD) in patients with Lennox-Gastaut and Dravet syndromes but the relevance of these concerns to healthy adults consuming CBD is unclear. The objective of this manuscript is to report on liver safety findings from healthy adults who received therapeutic daily doses of CBD for ~3.5 weeks and to investigate any correlation between transaminase elevations and baseline characteristics, pharmacogenetic, and pharmacokinetic data. Sixteen healthy adults were enrolled in a phase 1, open-label, fixed singlesequence drug-drug interaction trial to investigate the effect of repeated dose administration of CBD (1500 mg/day) on cytochrome P450 (CYP) 1A2 activity. Seven (44%) participants experienced peak serum alanine aminotransferase (ALT) values greater than the upper limit of normal (ULN). For 5 (31%) participants, the value exceeded 5× ULN, therefore meeting the international consensus criteria for drug-induced liver injury. There was no correlation between transaminase elevations and baseline characteristics, CYP2C19 genotype, or CBD plasma concentrations. All ALT elevations above the ULN began within 2-4 weeks of initial exposure to CBD. Among the 6 participants with ALT elevations who were discontinued from the protocol, some had symptoms consistent with hepatitis or hypersensitivity. We conclude that healthy adults consuming CBD may experience elevations in serum ALT consistent with drug-induced liver injury. Given the demonstrated inter-individual variation in susceptibility, clinicians should be alert to this potential effect from CBD, which is increasingly available in various non-prescription forms and doses to consumers.

A Phase 1 Open‐Label, Fixed‐Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects

“…The abnormal liver chemistry findings in this and other healthy volunteer and patient trials with CBD are described in more detail in a separate publication. 20 The authors of that publication concluded that healthy adults consuming CBD may experience elevations in serum ALT consistent with drug‐induced liver injury.…”

Practical Strategies Using Medical Cannabis to Reduce Harms Associated With Long Term Opioid Use in Chronic Pain

“…Studies have confirmed that at doses below 1500 mg of CBD, the drug does not produce hedonic effects or cognitive impairment (Birnbaum, 2019). Nevertheless, these high CBD doses may be associated with a few side effects; including gastrointestinal, sedation and -most importantly -there is increasing evidence that sustained high doses of CBD may result in transaminase elevations which may represent drug-induced liver injury (Brown and Winterstein, 2019;Watkins et al, 2020).…”

Cannabidiol and Cannabidiol Metabolites: Pharmacokinetics, Interaction with Food, and Influence on Liver Function

“…Finally, one area of significant controversy pertaining to the potential health benefits of CBD relates to the liver [ 23 ]. While some studies have suggested that CBD may promote favorable liver function, and may even be included in comprehensive treatments for liver diseases [ 24 ], others have suggested that CBD may harm the liver [ 25 ]. An additional goal of the current study was to determine the acute influence of a variety of different CBD formulations on circulating markers of liver function, and to determine if CBD availability (i.e., circulating concentration) predicts the magnitude and change of these circulating markers.…”