Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial

Abstract

There is a substantial and unmet clinical need for pharmacological treatment of cannabis use disorders. Cannabidiol (CBD) could offer a novel treatment but it is unclear which doses might be effective or safe. Participants meeting DSM-5 cannabis use disorder criteria were allocated to four-week treatment with oral CBD at 200mg, 400mg, 800mg or placebo during a cessation attempt using a double-blinded block randomisation sequence. All received a brief psychological intervention of motivational interviewing. An adaptive Bayesian dose-finding design was used to identify effective/ineffective doses at a priori interim and final analysis stages. The primary objective was to identify the Most Effective Dose (MED) of CBD for reducing cannabis use. The primary endpoint was lower urinary THC-COOH:creatinine concentrations and/or increased days per week abstinent from cannabis during treatment, evidenced by posterior probabilities exceeding Pr=0.9 for CBD versus placebo. All analyses were intention-to-treat. Participants were initially randomised to placebo, 200mg, 400mg and 800mg CBD (n=48; 1:1:1:1). At interim analysis 200mg CBD was eliminated from the trial as an ineffective dose. Randomisation continued to 400mg CBD, 800mg CBD, and placebo (n=34; 1:1:1). At final analysis, both 400mg CBD and 800mg CBD exceeded primary endpoint criteria (Pr=0.9) for both primary outcomes: urinary THC-COOH:creatinine (Pr (400mg=MED | Data) =0.9995; Pr (800mg=MED | Data) =0.9965), days per week abstinent from cannabis (Pr (400mg=MED | Data) =0.9966; Pr (800mg=MED | Data) =0.9247). Compared to placebo, 400mg CBD decreased THC-COOH:creatinine concentrations by -94.21 ng/ml (95% Interval Estimate= -161.83, -35.56) and increased abstinence from cannabis by 0.48 days per week (95% Interval Estimate=0.15, 0.82). Compared to placebo, 800mg CBD decreased THC-COOH:creatinine concentrations by -72.02 ng/ml (95% Interval Estimate= -135.47, -19.52) and increased abstinence from cannabis by 0.27 days per week (95% Interval Estimate= -0.09, 0.64). CBD was well tolerated with no severe adverse events and 94% completed treatment. In the first randomised clinical trial of CBD for cannabis use disorder, 400mg and 800mg CBD were safe and more effective than placebo at reducing cannabis use. https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000361-36/GB