The report is a product of the VA/HSR Evidence Synthesis Program.

Pharmacotherapy for the Treatment of Cannabis Use Disorder: A Systematic Review

Social, medical, and legal acceptance of cannabis has grown dramatically over the last 15 years, and cannabis use — for medical and recreational purposes — also has increased. From 2002 to 2012, the prevalence of daily cannabis use in the United States increased from 1.3 to 2.1%. Along with an increase in the acceptance and use of cannabis, the potency of cannabis available on the market has increased dramatically. Meanwhile, the proportion of the public that perceives important harms from cannabis use has decreased; however, among regular users, cannabis use can lead to physiologic dependence, with withdrawal symptoms similar to those of other substance use disorders. Between 2.5% and 6.3% of adults are estimated to have cannabis use disorder (CUD). Nearly half those adults have moderate or severe CUD, and the risk is greatest in young adults and socioeconomically disadvantaged groups. Cannabis use disorder also is a growing concern among Veterans.

This systematic review and meta-analysis examined the benefits and risks associated with the use of various pharmacotherapies for the promotion of cessation or reduction of cannabis use, abstinence and retention among individuals with cannabis use disorder (CUD). Investigators with VA's Evidence-based Synthesis Program (ESP) Coordinating Center in Portland, OR searched electronic databases, clinical trial registries, and reference lists through July 2018 for randomized controlled trials (RCTs) directly comparing pharmacological interventions against each other, placebo, usual care, or psychotherapy in individuals with CUD. After reviewing nearly 1,000 studies, 23 RCTs were included in the final analysis.

Findings
There is limited research examining the effectiveness of pharmacotherapies for CUD, and many of the existing studies are hampered by poor methodological quality or reporting. There is moderate strength evidence that antidepressants do not reduce cannabis use or improve treatment retention, and may be associated with lower rates of abstinence. There also is low to moderate strength of evidence that buspirone, and N-acetylcysteine do not improve outcomes. Although investigators found that cannabinoids do not improve retention, increase rates of abstinence, or reduce cannabis use, they did find low strength of evidence that they may reduce withdrawal symptoms. Two small studies of anticonvulsants (gabapentin, topiramate) show promise for improving treatment retention; however, the strength of evidence is low. Investigators found insufficient evidence to comment on effects of all other drug classes.

Given increasing access to and use of cannabis in the general population (including Veterans), along with the high prevalence of cannabis use disorder among current cannabis users, there is an urgent need for more research to identify effective pharmacologic treatments.

Implications
Findings will be used to help guide future HSR&D priorities. However, the current lack of effective pharmacotherapies leaves Veterans seeking treatment for CUD reliant on psychotherapeutic options that can be time-consuming, and less accessible for some (e.g.., Veterans living in rural areas). These factors may hinder treatment utilization and adherence, thus reinforcing the need to emphasize efforts that increase the accessibility of mental health services for Veterans. With the increased acceptance of cannabis use in the community, changes in its potency, and low rates for treatment seeking for CUD, it is especially important that clinicians be prepared to discuss potential risks of use with their patients and to assess for potential CUD.

Future Research
There are many areas ripe for further research in this field. As described above, further research on the effectiveness of certain potentially promising drug classes, such as anticonvulsants and cannabinoids (closely related compounds that include cannabinol and active elements of cannabis), is needed before these could be recommended for clinical practice. Given the change in the legal status of cannabis in many states, studies should assess outcomes beyond abstinence, use, withdrawal symptoms, and study retention, and include those related to function and changes in high-risk behaviors. Further, the treatment of withdrawal symptoms in those with cannabis use disorder should be further studied. In addition, the lack of reduction in depressive symptoms among those with comorbid CUD and Major Depressive Disorder (MDD) treated with antidepressants should be explored. Finally, the identification of subpopulations in which treatment retention might be higher, or in whom certain medications might be more effective, is needed.

Implications for VHA Policy/Practice
While there are psychosocial interventions that can promote recovery, their effectiveness is also limited. Primary prevention of cannabis use disorder by limiting exposure to cannabis, especially avoiding long-term, frequent use, and high potency THC (tetrahydrocannabinol) products should be promoted. The idea that cannabis is not harmful is common, false, and can hinder prevention efforts. The Marijuana Use Patient Discussion Tool (IB 10-927) from VA Pharmacy Benefits Management (PBM) Academic Detailing Service can aid in this effort.

Reference
Kondo K, Morasco BJ, Nugent S, Ayers C, O'Neil ME, Freeman M, Paynter R, and Kansagara D. Pharmacotherapy for the treatment of cannabis use disorder: a systematic review. VA ESP Project #05-225; 2019.

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