Review of: Tom P Freeman et al., “Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial,” The Lancet Psychiatry, July 28, 2020.

Review by: Stacey McKenna

After alcohol, cannabis is the most frequently used drug in the United States, and its popularity among adults is on the rise. According to the National Institute on Drug Abuse, roughly 30 percent of individuals who use cannabis experience dependence, tolerance and other indications of a cannabis use disorder. In fact, recent data suggest that about 4 million people in the United States and 22 million worldwide met diagnostic criteria for a cannabis use disorder, representing a marked increase in the past decade.

Despite all this, pharmacological treatments are rarely used for cannabis use disorder and a small body of research suggests that, thus far, many such therapies are not particularly or broadly effective. However, researchers are expressing growing interest in the therapeutic potential of cannabidiol (CBD). Early studies in animals and humans point to the potential of this non-intoxicating cannabinoid for treating addiction to a number of substances. However, there has been a dearth of clinical trials examining its dose-specific efficacy in the treatment of cannabis use disorder. To fill this void, Tom P. Freeman and colleagues conducted a phase 2a trial of CBD to identify the most effective doses and to rule out doses deemed ineffective in treating cannabis use disorder.

The team of United Kingdom-based researchers wanted to “identify which (if any) dose of cannabidiol was most efficacious at reducing cannabis use compared to placebo.” The trial, conducted at the Clinical Psychopharmacology Unit at the University College London, tested a placebo against three different doses of oral CBD—200 mg, 400 mg and 800 mg—administered daily over a period of four weeks. Follow-ups continued for an additional 20 weeks. Participants ranged in age from 16 to 60 years old, met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for moderate or more severe cannabis use disorder and claimed they voluntarily intended to quit using cannabis within the next month.

The trial and recruitment took place in two stages. During Stage 1 (May 2014 to August 2015), participants were randomly, but evenly, assigned to one of the three treatment groups or to the placebo group. Interim analysis was conducted to identify which doses showed promise and which did not. In Stage 2 (May 2016 to January 2017), as new participants joined, they were randomly assigned to the placebo group or to the doses that emerged as effective in Stage 1.

For the first four weeks of the study, participants took their assigned medication twice daily, and received reminders by text message to do so. In addition, psychologists conducted six separate, 30-minute motivational interview sessions—an established therapeutic approach shown to reduce cannabis use—with each participant. These took place at the screening visit, baseline visit and at site visits during weeks one through four of treatment. To ensure adherence to the CBD treatment protocol, participants were asked to return untaken capsules, self-report missed doses and submit to urine analyses during site visits. Additional follow-ups included a mix of telephone conversations and site visits, through week 24.

To evaluate whether the various doses of CBD were effective in reducing cannabis use disorder, Freeman et al. measured several outcomes, including:

  • Cannabis use—measured in urine and by self-report
  • Total score on the “Cannabis Withdrawal Scale”
  • Tobacco use—assessed in urine and by self-report
  • Alcohol use—assessed via self-report
  • Sleep quality—measured using the Pittsburgh Sleep Quality Index
  • Depression and anxiety

A total of 82 eligible individuals were enrolled in the study and randomly assigned to treatment or placebo groups. Forty-eight participants took part in Stage 1 and 34 in Stage 2. Ninety-four percent of enrolled participants—77 individuals—completed the treatment as intended.

All of the doses were well-tolerated by the participants, as indicated by very low numbers of “mild or moderate” adverse events that did not differ between placebo and any of the three treatment groups. When it came to efficacy, however, there was some variability. To identify the most effective dose, Freeman et al. used Bayesian inference, a statistical method that allowed them to make ongoing adjustments as new information emerged.

While the 200 mg dose was shown to be ineffective overall, daily doses of 400 mg and 800 mg of CBD decreased THC-indicators in urine and increased self-reported abstinence from cannabis use. These benefits were retained through the full 24 weeks of the study in the 400 mg group, but did not persist in the 800 mg group.

When it came to secondary outcomes, the study showed mixed results. For example, while the 400 mg dose of CBD led to a decrease in the number of cigarettes smoked compared to placebo, this group reported poorer sleep compared to the placebo group. Additionally, the 800 mg group experienced reductions in cannabis withdrawal symptoms and anxiety compared to placebo.

This study represents one of the first, if not the first, clinical trial to examine and compare the dose-specific effectiveness of oral CBD in the treatment of cannabis use disorder. Its value is not just in its novelty, however. The researchers’ flexible statistical methods, multi-stage approach and 20 weeks of follow-up are all strengths that support their findings. The primary limitation is that, as a phase 2a trial, this was a small study and as such, the authors note, not intended to evaluate the “magnitude of efficacy” of each dose. Additional research will be necessary to better understand how CBD can best be used in the treatment of cannabis use disorder.