New Drug Reduces Cannabis-Withdrawal Symptoms

December 12, 2018

By Will Boggs MD 

NEW YORK—The fatty acid amide hydrolase (FAAH) inhibitor PF-04457845 reduces cannabis withdrawal symptoms and cannabis use in men with cannabis dependence, according to results of a phase 2 trial.

"In the USA, around a third of all current cannabis users meet diagnostic criteria for cannabis-use disorder (CUD), and more than 250,000 people were admitted for cannabis-abuse treatment in 2016," said Dr. Deepak Cyril D'Souza from VA Connecticut Healthcare System, in West Haven, and Yale University School of Medicine, in New Haven, Connecticut.

"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," he told Reuters Health by email.

FAAH degrades anandamide, one of the two principal endocannabinoids, and FAAH inhibitors have been shown to reduce withdrawal precipitated by type 1 cannabinoid receptor antagonists in tetrahydrocannabinol (THC)-dependent animals.

Dr. D'Souza and colleagues investigated whether four weeks of treatment with the potent, selective FAAH inhibitor PF-04457845, supplied by Pfizer, reduced cannabis-withdrawal syndrome (including abnormalities of sleep architecture) and cannabis use during a week of enforced abstinence (inpatient) and during the following three weeks, in 70 men with cannabis dependence (46 assigned to PF-04457845 and 24 assigned to placebo).

Withdrawal symptoms, as assessed by the Marijuana Withdrawal Symptom Checklist, were significantly lower in the PF-04457845 group than in the placebo group on days 0 (mean, 6.04 vs. 11.00, respectively) and one (mean, 6.02 vs. 11.74) of enforced withdrawal.

The PF-04457845 group had significantly lower depression, anxiety and irritability subscores on day 0, compared with the placebo group, and on average the PF-04457845 group reported better overall sleep and showed significantly more time in stage N3 sleep.

At the end of the four-week study, reported cannabis use was significantly lower in the PF-04457845 group than in the placebo group, and urine concentrations of THC-COOH were significantly lower in the PF-04457845 group than in the placebo group.

Dropout rates did not differ between the two groups, the researchers report in The Lancet Psychiatry, online December 6.

Adverse events were mild and did not differ between the groups, and there were no serious adverse events.

"If the results of a soon-to-begin larger multicenter completely outpatient trial replicate the findings of the published study, then FAAH-inhibitors might be used to reduce cannabis withdrawal symptoms and to promote abstinence in patients contemplating quitting, in combination with behavioral treatments," Dr. D'Souza said.

"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.

"Regular use of cannabis is associated with measurable changes in brain endocannabinoid function; i.e., repeated exposure is associated with downregulation of brain cannabinoid receptors and the enzyme that degrades anandamide," he explained. "This is the biological basis of tolerance, dependence, and cannabis withdrawal."

"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," writes Dr. Tony P. George of the University of Toronto and Center for Addiction and Mental Health, also in Toronto, Canada, in a linked editorial.

The "endurability of FAAH inhibition needs to be rigorously tested with sufficient follow-up assessment periods (e.g., 3-6 months after treatment)."

"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 concludes.

Pfizer Inc. supplied the FAAH inhibitor and its matching placebo, but had no other role in this study.


Lancet Psychiatry 2018.

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