CE: ; ADM/JAM-D-20-00267; Total nos of Pages: 2; JAM-D-20-00267 COMMENTARY Cannabinoids for the Treatment of Opioid Use Disorder: Where is the Evidence? Joji Suzuki, MD and Roger D. Weiss, MD The evidence cited for the potential benefits of cannabis With the growing public interest in the potential therapeutic benefits to treat OUD generally come from population-level research of cannabis and cannabinoids in the treatment of opioid use disorder 12/17/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= by http://journals.lww.com/journaladdictionmedicine from Downloaded showing an inverse association between enactment of medical Downloaded (OUD), some states have now either added or proposed to add OUD marijuana laws and opioid-related adverse outcomes.1–3 For as an indication for their state’s medical marijuana program. How- example, Bachhuber and colleagues found that states that from ever, these initiatives are based on weak evidence which at present do enacted medical marijuana laws from 1999 to 2010 experi- http://journals.lww.com/journaladdictionmedicine not support the listing of cannabis or cannabinoids as a treatment for enced fewer fatal opioid overdoses compared to states that did OUD. Nevertheless, studying the potential therapeutic applications not enact such laws.1 However, a subsequent study that of carefully chosen components of cannabis or cannabinoids to treat examined the same data used by Bachhuber and colleagues specific aspects of OUD is not without scientific merit. Given the further out to 2017 found that the association between medical high rates of treatment discontinuation among those taking medi- marijuana laws and opioid overdoses actually reversed in cations for OUD, interventions that further improve clinical out- direction.4 Indeed, there are other population-level studies comes are especially needed. The potential therapeutic applications that indicate cannabis use is associated with a higher risk of 5 by of cannabis and cannabinoids in the treatment of OUD are worthy of developing an OUD. As such, using population-level studies BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= further study, but it should be conducted with the same rigor that we as justification to place cannabis in the same category as expect of all pharmaceutical products. Until we have more research evidence-based treatments for OUD will give patients and to show their efficacy, policy makers and clinicians should refrain their families the false impression that cannabis and related from portraying cannabis and cannabinoids as evidence-based treat- products are indeed effective treatments for OUD. ments for OUD. A recent meta-analysis of 23 studies of patients in methadone maintenance treatment compared outcomes (reten- Key Words: cannabinoids, cannabis, opioid use disorder tion and nonprescribed opioid use) among those who did and 6 (J Addict Med 2020;xx: xxx–xxx) did not use cannabis. The authors noted that although the overall quality of the evidence was low and quite possibly here is a growing public interest in the potential thera- biased due to the observational nature of most studies, the T peutic benefits of cannabis and cannabinoids in the results suggested that cannabis use did not affect patient out- treatment of opioid use disorder (OUD). The interest has comes overall. A sub-group analysis of studies conducted in the grown to such an extent that some states have now either US showed an inverse relationship between cannabis use and added or proposed to add OUD as an indication for their treatment retention, whereas the association was in the opposite state’s medical marijuana program, giving an impression that direction for studies in Israel. Unfortunately, it remains difficult cannabis may be a suitable alternative to existing treatment to know how to interpret these findings. The included studies options for OUD. However, these initiatives are based on largely defined cannabis use through patient self-report or weak evidence and could encourage those with OUD to toxicology testing results. In evaluating the impact of cannabis eschew evidence-based and potentially life-saving treatments on OUD outcomes, however, additional pharmacologic infor- in favor of the hoped-for benefits of cannabis. mation would be needed. Given the complexity of the cannabis plant and its constituents, researchers would need to know not only the dosage used, but also the form of cannabis (flower vs on extract), constituents (% tetrahydrocannabinol and cannabidiol 12/17/2020 From the Department of Psychiatry, Brigham and Women’s Hospital, Boston, [CBD]), route of administration (oral vs smoked), frequency of MA (JS); Harvard Medical School, Boston, MA (JS, RDW); Division of use (daily vs intermittent), and indication for use (recreational Drug and Alcohol Abuse, McLean Hospital, Belmont, MA (RDW). vs medical). In addition, studies would need to account for Received for publication June 26, 2020; accepted June 27, 2020. existing clinic policies that explicitly or implicitly prohibit or This work was supported by National Institutes of Health [grant numbers K23DA042326 (JS), 2UG1DA015831 (RDW)]. permit the use of cannabis for patients being treated with Roger D. Weiss served as a consultant to Takeda Pharmaceuticals, Cerevel medications for OUD (MOUD). Therapeutics, Astellas Pharmaceuticals, and Analgesic Solutions. There have been no prospective clinical trials of canna- Send correspondence to Joji Suzuki, MD, Brigham and Women’s Hospital, 60 bis or cannabinoids for the treatment of OUD, nor trials that Fenwood Rd, Boston, MA 02115. E-mail: [email protected] compare such compounds to existing MOUD such as bupre- Copyright ß 2020 American Society of Addiction Medicine ISSN: 1932-0620/16/0000-0001 norphine. The potential for harm from both acute and chronic DOI: 10.1097/ADM.0000000000000711 use of cannabinoids has been well-described, yet is often J Addict Med Volume 00, Number 00, Month/Month 2020 1 Copyright © 2020 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited. CE: ; ADM/JAM-D-20-00267; Total nos of Pages: 2; JAM-D-20-00267 Suzuki and Weiss J Addict Med Volume 00, Number 00, Month/Month 2020 ignored or minimized in the current climate of permitting also be studied to facilitate difficult buprenorphine induc- greater access to cannabis.7,8 As clinicians and researchers, tions.15 Additionally, CB1 agonists could be studied as adjuncts we need to follow the science; there are no data at present to to ease opioid withdrawal for patients attempting to taper off support the listing by some states of cannabis or cannabinoids MOUD or patients with chronic pain who are tapering off of as a treatment for OUD, and we therefore strongly agree with opioid analgesics. It is also possible that adjunctive CBD may those who have argued against recommending cannabis or aid in preventing relapse to opioid use by attenuating the cannabinoids as a substitute to existing MOUD options.9 response to environmental cues and stressors among individu- Nevertheless, studying the potential therapeutic applica- als already taking MOUD. Given the high rates of treatment tions of carefully chosen components of cannabis or cannabinoids discontinuation of MOUD, pharmacologic treatments that help to treat specific aspects of OUD are not without scientific merit. patients to initiate MOUD, remain in treatment for longer Although only a few controlled studies utilizing pharmaceutical durations, and prevent relapse are especially needed. cannabinoids in humans with OUD have been conducted, results In the context of the growing opioid crisis, research to of these trials have been informative. Two placebo-controlled improve treatment outcomes among those already taking randomized clinical trials of the synthetic tetrahydrocannabinol MOUD is critically needed. The potential therapeutic appli- dronabinol have shown modest reduction in opioid withdrawal cations of cannabis and cannabinoids in the treatment of OUD symptoms compared to placebo among individuals with is worthy of further study, but it should be conducted with the OUD.10,11 In the study by Lofwall and colleagues, after abrupt same rigor that we expect of all pharmaceutical products. cessation of an opioid, dronabinol 20 mg and 30 mg provided Until we have more research to show their efficacy, policy modest suppression of opioid withdrawal compared to placebo, makers and clinicians should refrain from portraying cannabis although it was accompanied by adverse effects including tachy- and cannabinoids as evidence-based treatments for OUD. cardia and subjective highs. Bisaga and colleagues compared dronabinol 30 mg to placebo in individuals with OUD undergoing REFERENCES a rapid buprenorphine detoxification; those receiving dronabinol 1. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical canna- experienced significantly less opioid withdrawal symptomatology bis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668–1673. than those given placebo. Furthermore, after study participants 2. Wen H, Hockenberry JM. Association of medical and adult-use marijuana were successfully initiated on extended-release naltrexone, par- laws with opioid prescribing for Medicaid enrollees. JAMA Intern Med. ticipants who intermittently smoked cannabis were significantly 2018;178(5):673–679.