Low-dose cannabidiol increases plasma concentrations of amitriptyline: A clinical drug-drug interaction study

Abstract

Aims: Cannabidiol (CBD), the main non-intoxicating compound from the cannabis plant, is regularly used by patients with chronic pain who also take analgesics. CBD has previously been shown to inhibit CYP-mediated drug metabolism. This study aimed to characterize the potential pharmacokinetic interaction of CBD with amitriptyline and tramadol, two commonly used analgesics.

Methods: This was an open-label, fixed-sequence, 2-way crossover study in 13 healthy participants. On Day 1, 25 mg amitriptyline and 50 mg tramadol were co-administered orally in a fasted condition, followed by a 7-day washout period. On Day 8, 30 mg CBD was administered orally 1 h prior to amitriptyline and tramadol. Pharmacokinetic sampling was performed for CBD, amitriptyline, tramadol and their respective active metabolites nortriptyline and O-desmethyltramadol for up to 24 h post-dose. The areas under the curve (AUCs) were compared between visits using a mixed effects model.

Results: Twelve participants (4M/8F) completed the study; one participant (M) dropped out for personal reasons. CBD significantly increased the AUC_0-24h (least square means [LSM] ratio 1.13, 95% CI: 1.01, 1.26, p = 0.033) and the C_max (LSM ratio 1.17, 95% CI: 1.01, 1.36, p = 0.041) of amitriptyline. CBD did not significantly change the AUC_0-24h and C_max of nortriptyline and tramadol, and the C_max of O-desmethyltramadol.

Conclusions: A single dose of 30 mg CBD significantly influenced the metabolism of amitriptyline in healthy volunteers. In patients, CBD-induced drug interactions may be more pronounced in chronic dosing and dependent upon prandial status.

Keywords: CBD; CYP2C19; DDI; amitriptyline; cannabidiol; interaction; tramadol.