Novel approach for the treatment of cannabis use disorder shows promise in phase 2 trial

Experimental drug reduced cannabis use and withdrawal symptoms compared with placebo

Results of a phase 2 randomised trial of 70 men suggest that an experimental drug that boosts the brain's own cannabis-like chemical may help reduce withdrawal symptoms and cannabis use in men with cannabis dependence or cannabis use disorder.

The findings published in The Lancet Psychiatry journal, show for the first time that men with cannabis dependence or cannabis use disorder treated with the fatty acid amide hydrolase (FAAH) inhibitor 'PF-04457845' used less cannabis and experienced fewer withdrawal symptoms--such as sleep disturbance--at 4-week follow-up compared to those given placebo, and there were no safety concerns.

PF-04457845 works by blocking FAAH, an enzyme that breaks down a principal natural endocannabinoid chemical in the brain called anandamide (that acts on brain cannabinoid receptors like cannabis does). Less FAAH means higher anandamide levels, which may potentially improve mood and reduce anxiety.

"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. 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", says Professor Deepak Cyril D'Souza from Yale University School of Medicine, USA, who led the research.

"PF-04457845 was well tolerated. However, more research is needed to demonstrate that PF-04457845 is safe and effective in a larger sample of treatment-seeking individuals, particularly women, and in other outpatient settings over the long-term." [1]

Cannabis use disorder is characterised by a continued problematic pattern of use despite negative consequences such as social and functional impairment, risky use, tolerance, and withdrawal symptoms. Cannabis withdrawal symptoms include craving for cannabis, irritability, anger, depression, sleep disturbances, and decrease in appetite and weight, that make it difficult to quit. Cannabis use disorder affects around 13 million people worldwide [2]. In the USA, around a third of all current cannabis users meet diagnostic criteria for cannabis use disorder, and more than 250,000 people were admitted for cannabis abuse treatment in 2016 [3]. Long-term recovery is achieved by only a few of those who seek treatment with behavioural interventions like cognitive behavioural therapy and motivational enhancement therapy.

Currently, there are no approved pharmacological treatments for problematic cannabis use. Almost every class of psychotropic drug has been tested for cannabis withdrawal or dependence, but none has been consistently effective or well tolerated. Substitution therapy with THC, the psychoactive compound in cannabis, has shown some promise in reducing withdrawal symptoms but does not prevent relapse and is limited by its psychoactive effects and abuse potential. In mice dependent on THC, blocking the FAAH enzyme reduced cannabis withdrawal syndrome.

In the study, 70 men (aged 18-55 years) with cannabis use disorder were randomised to receive the FAAH inhibitor, PF-04457845, (4mg daily; 46 men) or matching placebo (24 men) for 4 weeks. All participants were admitted to hospital for about one week of the treatment phase to achieve abstinence and cannabis withdrawal. Participants were then discharged to continue the remaining 3 weeks of treatment as outpatients.

Adherence to medication was confirmed by video-calling and pill count, and corroborated by weekly blood concentration of the PF-04457845 and anandamide. Cannabis use was assessed by self-report and urine screening for levels of the THC metabolite THC-COOH. Sleep problems, that feature prominently in cannabis withdrawal, were assessed using questionnaires and polysomnography (a test that records brain waves, blood oxygen level, heart rate, breathing, and eye and leg movements overnight).

At the start of the study, participants were smoking on average more than three cannabis joints a day. Admission to hospital reduced cannabis use to zero in both groups. During the inpatient phase (week 1), men treated with PF-04457845 reported fewer symptoms of cannabis withdrawal including depression, irritability, and anxiety compared with those given placebo (table 2).

At the end of treatment (4 weeks), the PF-04457845 group reported less cannabis use compared to the placebo group (average 0.40 vs 1.27 joints per day), and also had lower levels of THC-COOH in their urine (average concentrations of THC-COOH 266ng/mL vs 658 ng/mL).

Additionally, improvements in overall sleep (longer sleep times, deeper sleep, and feeling more rested) were noted compared with placebo. In contrast, reductions in the time spent in deep sleep occurred immediately following abstinence in the placebo group, consistent with the evidence of sleep disturbances in cannabis withdrawal syndrome.

The authors note that withdrawal-induced deep sleep disturbances could play a key role in relapse, and treatment via FAAH inhibition might be useful in correcting it, which in turn could facilitate maintenance of abstinence from cannabis.

Adherence to the study medication was 88%, and urinary THC-COOH concentrations correlated with self-reported cannabis use over time. PF-04457845 was well tolerated, and adverse events were mild and similar in both groups (20 [43%] of 46 participants in the PF-04457845 group vs 11 [46%] of 24 participants in the placebo group had an adverse event during the 4-week treatment phase). No serious adverse events were reported. Drop-out rates were similar between the PF-04457845 (8 [17%] of 46 men) and placebo groups (4 [17%] of 24 men).

The authors note some limitations, including that the study did not include women because of a lack of safety and toxicity data at the time, and did not fully assess motivation to quit cannabis use or the functional consequences of problematic cannabis use. In the future, studies will be needed to compare the advantages and disadvantages of direct agonists like THC with FAAH inhibitors.

Writing in a linked Comment, Dr Tony George from the University of Toronto and Centre for Addiction and Mental Health, Ontario, Canada, says FAAH might prove to be a safe and effective treatment approach but several questions remain to be answered: "No assessments of cannabis related functional impairment...were done, and thus the effect on functional outcomes achieved during this FAAH inhibitor trial is not clear...The population studied seemed not to include adults with psychiatric comorbidity, but it will be important to include these patients in future studies as they seem to be at much higher risk for the initiation and maintenance of cannabis use disorder. Finally, the endurability of FAAH inhibition needs to be rigorously tested with sufficient follow-up assessment periods (eg, 3-6 months after treatment)."

He concludes: "Most pharmacotherapy trials in addiction have sought to develop medications as adjuncts to behavioural interventions. The development of FAAH inhibitors as putative pharmacotherapies for cannabis use disorder should therefore make use of behavioural supports in both abstinence initiation and relapse-prevention designs. In particular, the use of cognitive-behavioural therapy in combination with contingency management could be the optimal approach to testing of putative cannabis pharmacotherapies, because they are most effective in achieving initial abstinence, facilitating the study of relapse-prevention efficacy, which might be the most sensitive test for medications development."

The Lancet