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An investigational cannabis withdrawal treatment succeeded in a phase IIa trial, researchers reported.

Meeting the 4-week trial's primary endpoints, daily treatment with the long-acting fatty acid amide hydrolase (FAAH) inhibitor PF-04457845 led to fewer cannabis withdrawal symptoms and less cannabis use in men compared with placebo, Deepak Cyril D'Souza, MD, of the VA Connecticut Healthcare System in West Haven, and colleagues wrote in

The initial 5-8 days of treatment occurred in an in-patient hospital setting, followed by a 3-week outpatient continuation on the treatment. During the first two in-patient treatment days, men taking PF-04457845 experienced significantly less severe symptoms of withdrawal, measured by the Marijuana Withdrawal Symptoms Checklist, vs placebo, as follows:

• 1st treatment day: 6.04 vs 11.00; mean difference 4.96 (95% CI 0.71-9.21, P=0.048)
• 2nd treatment day: 6.02 vs 11.74; mean difference 5.73 (95% CI 1.13-10.32, P=0.035)

After 4 weeks of treatment, men on PF-04457845 self-reported significantly less use of cannabis compared with men on placebo (P=0.0003):

• PF-04457845: mean 0.40 joints/day (95% CI 0.25-0.62)
• Placebo: 1.27 joints/day (95% CI 0.82-1.97)

This finding was also supported by significantly lower urinary tetrahydrocannabinol carboxylic acid (THC-COOH) concentrations among those on the novel treatment vs placebo at week 4 (658 ng/mL vs 266 ng/mL; mean difference 392.37 ng/mL, 95% CI 17.55-767.18, P=0.009).

"A lot of other drugs have been tested for their ability to reduce cannabis use and withdrawal, but until now none have been consistently shown to work against both withdrawal symptoms and relapse," D'Souza explained in a statement. "Furthermore, unlike cannabis or its principal active constituent delta-9 tetrahydrocannabinol (THC), FAAH inhibitors do not appear to have psychoactive or rewarding effects, and are therefore not likely to be abused."

The trial included 70 adult men with cannabis dependence according to DSM-IV criteria, which is the same as the criteria for cannabis use disorder in the DSM-V. These criteria included smoking 30 or more cannabis joints in the past 30 days or 180 joints in the past 6 months, a minimum of 2 years of regular use, a prior attempt to quit that resulted in withdrawal symptoms, and a repeated positive urine drug screen.

A total of 46 men were stratified based on their severity of cannabis use and desire to quit and blindly randomized to receive 4 mg of once daily PF-04457845 treatment, while 24 men received placebo. No women were included in the study -- a limitation of the trial, the researchers noted.

In a post-hoc analysis, patients receiving the active drug also reported significantly better overall sleep on the first day of treatment (mean score 41 vs 60; difference -18.82, 95% CI -30.42 to -7.22, P=0.004).

Throughout the study, no serious adverse events occurred, and other adverse events were generally mild and did not differ between the groups.

In an , Tony George, MD, of the University of Toronto and Centre for Addiction and Mental Health, called the study "very important" and said the evidence suggests that FAAH inhibition "could be a viable therapeutic strategy to treat problematic cannabis use."

However, George also pointed out that there are still several lingering questions about FAAH inhibition that have yet to be answered, noting that the 4-week length of the trial was notably shorter than the more usual length of 8 to 12 weeks. In addition, he said, the motivation behind participants wanting to quit cannabis varied widely; most trials use a standardized baseline for motivation to quit. Other safety concerns linger as well, George said, suggesting that a follow-up of 3 to 6 months is needed in these participants as well as an assessment of cannabis-related functional impairment.

"Nonetheless, if these questions are resolved satisfactorily, FAAH inhibition might prove to be a safe and effective treatment approach to address an important public health problem in the era of cannabis legalization," he concluded.