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

Lack of evidence for the effectiveness or safety of over-the-counter cannabidiol products

“…CBD has been assessed in randomized controlled clinical trials in rare childhood epilepsies, 20,66–68 schizophrenia, 18,69 type II diabetes, 70 fatty liver disease, 71 Crohn’s disease, 72 Parkinson’s disease, 73 Huntington’s disease, 74 and cannabis dependence. 19 The results from the trials in childhood epilepsy have led to its licensing as a treatment for Lennox–Gastaut syndrome and Dravet syndrome. The only other licensed medicine that contains CBD is the oromucosal spray nabiximols (Sativex), which contains similar quantities of Δ 9 -THC and CBD, and is approved as a treatment for spasticity in multiple sclerosis.…”

“…9,10 Neuroimaging studies have shown that it has effects on brain activity, 11,12 and can modulate both the endocannabinoid and other neurotransmitter function in both volunteers and patients. 13–15 Moreover, data from experimental medicine studies and clinical trials suggest that pharmaceutical grade CBD can reduce anxiety 16,17 and psychotic symptoms, 18 and has beneficial effects in addiction 19 and childhood epilepsy. 20 Endocannabinoid signalling also has a role in regulating the immune system, and CBD also has potential as an anti-inflammatory agent.…”

The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers

“…Furthermore, long-term daily administration of CBD, as delivered in clinical trials (Freeman et al, 2020; Leweke et al, 2012; McGuire et al, 2018), could produce different effects on the neural correlates of reward anticipation and feedback. We only delivered a single oral 600 mg dose in healthy volunteers.…”

“…Moreover, behavioural evidence from human studies suggests that CBD can reduce the salience of drug-related cues in those with cannabis (Morgan et al, 2010) and nicotine (Hindocha et al, 2018) dependencies, and reduce drug cue-induced cravings in those addicted to heroin (Hurd et al, 2019). Additionally, a four-week treatment of CBD dose-dependently decreased cannabis use in a clinical trial of people with cannabis use disorder (Freeman et al, 2020). In all of these studies, CBD attenuated atypical reward-related behaviours conferred by addiction, suggesting a restorative effect.…”

“…Human research has shown that CBD can acutely alter neural, behavioural and psychological processes relating to reward, including effort sensitivity (Lawn et al, 2016), attentional bias to drug pictures (Hindocha et al, 2018; Morgan et al, 2010), drug consumption (Freeman et al, 2020; Morgan et al, 2013), neural response to music reward (Freeman et al, 2018) and levels of stress-induced social anxiety (Bergamaschi et al, 2011; Zuardi et al, 1993), without producing reinforcing or unpleasant side-effects (Haney et al, 2016). However, it is not known if CBD specifically acts on the human brain’s reward circuitry, or acts by another mechanism.…”