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Novel treatment approach shows promise in cannabis dependence
A novel fatty acid amide hydrolase inhibitor known as PF-04457845 reduced cannabis withdrawal symptoms and use among men with cannabis dependence or cannabis use disorder, according to data from a phase 2a trial published in The Lancet Psychiatry.
“In the U.S., 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. Currently, there are no medications approved to treat cannabis use disorder,” Deepak Cyril D’Souza, MD, professor of psychiatry at Yale University School of Medicine and director of the neuropsychiatry program at VA Connecticut Healthcare System, told Healio.com/Psychiatry.
“While many medications have been tested for cannabis, none have been consistently effective or well tolerated,” he continued. “One approach is to substitute cannabis with THC, the psychoactive compound in cannabis, similar to substituting tobacco smoking with the nicotine patch. While this approach has shown some promise in reducing withdrawal symptoms, it did not reduce cannabis use, and is limited by its psychoactive effects and abuse potential.”
An alternative approach may be to boost the brain’s own cannabis-like substance: anandamide, according to D’Souza. Prior research has demonstrated that increasing anandamide concentrations by fatty acid amide hydrolase (FAAH) inhibition, which potentiates endocannabinoid signaling, may have a therapeutic effect in cannabis use disorder. This double-blind, placebo-controlled, parallel group phase 2a trial reported the efficacy and safety of the FAAH inhibitor PF-04457845 in reducing cannabis withdrawal and use among adult men with cannabis dependence.
The investigators randomly assigned 70 men aged 18 to 55 years to receive 4 mg per day of PF-04457845 (n = 46) or placebo (n = 24). The men were admitted to the hospital for 5 days to achieve abstinence and quicken cannabis withdrawal symptoms, then were discharged to continue the remaining 3 weeks of treatment. Researchers assessed treatment-related differences in cannabis withdrawal symptoms during admission as well as self-reported cannabis use and urinary THC-COOH concentrations at week 4.
Most of the men (88%) adhered to study medication.
Compared with placebo, treatment with PF-04457845 was linked to decreased cannabis withdrawal symptoms on the first day of treatment (mean symptom score, 11 [95% CI, 7.78-15.57] vs. 6.04 [95% CI, 4.43-8.24]) and on the second day of treatment (mean symptom score, 11.74 [95% CI, 8.28–16·66] vs. 6.02 [95% CI, 4.28–8.47]). Treatment with PF-04457845 also was associated with reductions in related mood symptoms during the inpatient phase, the results showed.
“There was no evidence that people got ‘high’ from the drug, and the drug was very well tolerated,” D’Souza said.
Analysis also revealed that at week 4, treatment with PF-04457845 was linked to lower self-reported cannabis use (difference = 0.88; 95% CI, 0.29–1.46) and lower urinary THC-COOH concentrations (difference = 392.37; 95% CI, 17.55–767.18) compared with placebo. In addition, patients receiving PF-04457845 reported longer sleep times, deeper sleep and feeling more rested.
Treatment with the FAAH inhibitor was well-tolerated, with 17% of patients in both groups discontinuing treatment during the study period, according to the study. Overall, 43% of participants in the PF-04457845 group and 46% in the placebo group experienced an adverse event during the 4-week treatment phase. No serious adverse events occurred.
“With the growing legalization of cannabis globally, it is reasonable to expect that demand for effective treatments for cannabis use disorder will only grow,” D’Souza told Healio.com/Psychiatry.
“Cannabis withdrawal syndrome makes it difficult for people to quit using cannabis,” he continued. “We should expect that there will be an increasing demand for treatment of cannabis use disorder. While there are no approved medication treatments, there is a new approach in development that shows some promise. However, there is a need to replicate the findings of the current study in a larger study for this approach to become available in the clinic.”
Behavioral supports in both abstinence initiation and relapse-prevention designs should be used to develop FAAH inhibitors as possible pharmacotherapies for cannabis use disorder, Tony P. George, MD, of the department of psychiatry at the University of Toronto and Centre for Addiction and Mental Health, wrote in a related comment.
“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,” he wrote. – by Savannah Demko
Disclosures: D’Souza reports research support administered through Yale University School of Medicine from INSYS Therapeutics and Takeda. Please see the study for all other authors’ relevant financial disclosures.