A Systematic Review of the Efficacy of Cannabinoid Agonist Replacement Therapy for Cannabis Withdrawal Symptoms

About 30% of regular cannabis users report withdrawal symptoms on cessation of prolonged use, such as irritability, insomnia, decreased appetite, depressed mood, anxiety, and restlessness. However, among highly dependent and/or in-treatment users, the incidence of withdrawal can be even higher, reaching up to 50-95% of individuals. This syndrome was only recognized by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) as a diagnosis with specific criteria in 2013. The treatment options are poor, with high rates of relapse and non-responders. In this scenario, agonist replacement therapy with cannabinoids has demonstrated potential as a promising therapeutic intervention, with a series of studies having been carried out in recent years. This review sought to summarize trials with cannabinoid agonist replacement therapy for cannabis withdrawal symptoms with the aim of evaluating the efficacy of this pharmacological intervention. We entered the following search terms on the PubMed, Web of Science and PsycINFO databases: (marijuana OR marihuana OR cannabis OR THC OR tetrahydrocannabinol OR hashish OR pot) AND (treatment OR medication) AND (withdrawal OR abstinence) AND (dronabinol OR nabilone OR nabiximols OR sativex OR cesamet OR synthetic cannabinoid). The date of the most recent search was September 2017. Original trials, published in English, performed on humans and dealing with cannabis users who were treated for cannabis withdrawal symptoms using synthetic cannabinoids were all included in the present systematic review. Quality and risk of bias across studies were assessed using a Cochrane tool. The first, second, and last authors read the abstracts of all studies found in the search (n = 243). The inclusion and exclusion criteria were applied, and 233 articles were excluded. The first and second authors independently developed a data extraction sheet based on the included articles. The present review included ten original articles. Despite the limited number of studies and methodological differences, our findings demonstrate that the use of dronabinol, nabilone, or nabiximols, either alone or in combination with other drugs, shows promise in reducing cannabis withdrawal symptoms, probably with a dose-dependent effect. This has also been considered a safe group of medications with good tolerability and few adverse effects. No method of handling data and combining results of studies was carried out, representing a limitation of the review. Cannabinoids appear to be a promising group of drugs for the treatment of cannabis withdrawal symptoms. These medications may help decrease the rate of relapse in the treatment of cannabis dependence due to withdrawal symptoms occurring within the first few weeks of treatment. The protocol for this review has been registered in the PROSPERO International prospective register of systematic reviews (PROSPERO 2014:CRD42014014118).