Fatty acid amide hydrolase (FAAH) inhibition represents a novel therapeutic strategy to curb problematic cannabis use, new research suggests.
In a phase 2a study, treatment with the experimental FAAH inhibitor PF-04457845 reduced cannabis withdrawal symptoms, cannabis use, and sleep problems in men with cannabis dependence or cannabis use disorder (CUD) and was well tolerated.
"Cannabis use disorder affects around 13 million people worldwide. However, there are no FDA-approved treatments for CUD, and there are no other existing medications that clinicians have found to be consistently effective or safe in treating CUD," first author Deepak Cyril D'Souza, MD, psychiatry professor at Yale University School of Medicine in New Haven, Connecticut, told Medscape Medical News.
The study was published online December 6 in Lancet Psychiatry.
Viable Therapeutic Strategy
One approach is to potentiate endocannabinoid signaling by inhibiting FAAH, the enzyme that degrades the principal endocannabinoid anandamide.
In the double-blind, placebo-controlled, parallel group trial, 70 men with cannabis dependence according to DSM-IV criteria (equivalent to cannabis use disorder in DSM-5) were randomly allocated (2:1) to receive PF-04457845 (4 mg/day) or placebo, stratified by severity of cannabis use and desire to quit.
All participants were admitted to the hospital for 5 to 8 days to achieve abstinence and precipitate cannabis withdrawal. They were then discharged to continue the remaining 3 weeks of treatment as outpatients.
At baseline, the men smoked on average more than three cannabis joints a day. Admission to the hospital cut cannabis use to zero in both groups. During the inpatient phase, those receiving PF-04457845 reported fewer symptoms of cannabis withdrawal, including depression, irritability, and anxiety (as measured by the Marijuana Withdrawal Checklist) compared with those receiving placebo.
After 4 weeks of treatment, the PF-04457845 group reported less cannabis use compared to the placebo group (mean 0.40 vs 1.27 joints per day; P = .0003) as well as significantly lower urinary tetrahydrocannabinol carboxylic acid (THC-COOH) concentrations (mean 658 ng/mL vs 266 ng/mL; P = .009).
Treatment with the FAAH inhibitor also led to improvements in overall sleep (longer sleep times, deeper sleep, and feeling more rested).
"We were pleased that treatment with the FAAH inhibitor reduced cannabis use as measured by both self-reported use and also urine toxicology," D'Souza told Medscape Medical News.
"We were also very interested in the finding that treatment with the FAAH inhibitor restored stage 3 sleep. We believe that sleep disturbances might contribute to why regular users have difficulty quitting and why those who attempt to quit relapse. That we found improvements in self-reported sleep but also polysomnography gives us confidence in our findings on sleep," he added.
The next step, said D'Souza, is a multicenter trial funded by the National Institute on Drug Abuse (NIDA). This trial will include Yale, Columbia, Johns Hopkins and the Medical University of South Carolina. It will be longer — 8 weeks vs 4 weeks — and include women and men and will be conducted only on an outpatient basis.
If the results of this phase 2b trial replicate the findings of the phase 2a trial, then FAAH inhibitors may be used to reduce cannabis withdrawal symptoms and promote abstinence in patients who want to quit. However, the treatment will be used in combination with behavioral treatments, said D'Souza.
"One could envision getting the individual to first set a quit date. Then, leading up to the quit date, one could use behavioral interventions and also initiate treatment with a FAAH inhibitor prior to the quit date. The combined pharmacotherapy (FAAH inhibitor) and behavioral intervention would be continued for 8 weeks or so," he said.
In an accompanying editorial on this study, Tony George, MD, University of Toronto and the Centre for Addiction and Mental Health, Ontario, Canada, described the research as "very important, because it provides evidence that FAAH inhibition could be a viable therapeutic strategy to treat problematic cannabis use."
However, several questions remain to be answered about this approach, George says. The trial was short (4 weeks), whereas most clinical trials in the field have run 8 to 12 weeks. Also, there were no assessments of cannabis-related functional impairment and so the effect on functional outcomes achieved during this FAAH-inhibitor trial remain unclear.
"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 duration of FAAH inhibition needs to be rigorously tested with sufficient follow-up assessment periods (eg, 3–6 months after treatment)," writes George.
Echoing D'Souza, George notes the development of FAAH inhibitors as "putative pharmacotherapies for cannabis use disorder should therefore make use of behavioral supports in both abstinence initiation and relapse-prevention designs.
"In particular, the use of cognitive behavioral 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 study was funded by NIDA. The FAAH inhibitor and matching placebo were provided by Pfizer. Dr D'Souza receives research support administered through Yale University School of Medicine, currently from Takeda, and in the past 3 years from INSYS Therapeutics. Dr George has disclosed no relevant financial relationships.
Medscape Medical News © 2018
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