Cannabidiol for the treatment of cannabis use disorder: Phase IIa double-blind placebo-controlled randomised adaptive Bayesian dose-finding trial

Abstract

Background

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.

Methods

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.

Outcomes

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.

Interpretation

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.

Trial registration

https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000361-36/GB