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Is cannabinoid agonist treatment, in combination with psychosocial services, a safe and efficacious approach to reducing illicit cannabis use in patients with cannabis dependence who are seeking treatment?
In this randomized clinical trial of 128 participants, a 12-week course of nabiximols, a combination of tetrahydrocannabinol and cannabidiol, resulted in significantly fewer days of illicit cannabis use compared with placebo, and was well tolerated by participants.
The use of cannabinoid agonist medication appears to be a promising addition to the treatment of patients with cannabis dependence.
There are no effective medications for treating dependence on cannabis.
To examine the safety and efficacy of nabiximols in the treatment of patients with cannabis dependence.
Design, Setting, and Participants
This parallel double-blind randomized clinical trial comparing nabiximols with placebo in a 12-week, multisite outpatient study recruited participants from February 3, 2016, to June 14, 2017, at 4 outpatient specialist alcohol and drug treatment services in New South Wales, Australia. Participants had cannabis dependence (as defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and were seeking treatment, were nonresponsive to prior treatment attempts, were 18 to 64 years of age, had no other substance use disorder, had no severe medical or psychiatric conditions, were not pregnant, were not mandated by a court to undergo treatment, and provided informed consent. Results for primary efficacy measures and all secondary outcomes were obtained using a modified intention-to-treat data set.
Participants received 12-week treatment involving weekly clinical reviews, structured counseling, and flexible medication doses—up to 32 sprays daily (tetrahydrocannabinol, 86.4 mg, and cannabidiol, 80 mg), dispensed weekly.
Main Outcomes and Measures
Primary outcome was self-reported number of days using illicit cannabis during the 12-week period. Other outcomes included alternate cannabis use parameters (periods of abstinence, withdrawal, cravings, and problems), safety parameters (adverse events and aberrant medication use), health status, other substance use, and treatment retention.
A total of 128 participants (30 women and 98 men; mean [SD] age, 35.0 [10.9] years) were randomized and received at least 1 dose of study medication. Participants had used a mean (SD) of 2.3 (2.1) g of cannabis on a mean (SD) of 25.7 (4.5) days in the past 28 days. Treatment retention was comparable for the 2 groups (placebo, 30 of 67 participants [44.8%]; nabiximols, 30 of 61 participants [49.2%]), and both groups used similar mean (SD) doses (placebo, 18.5 [9.5] sprays daily; nabiximols, 17.6 [9.5] sprays daily, equivalent to a mean [SD] of 47.5 [25.7] mg of tetrahydrocannabinol and 44.0 [23.8] mg of cannabidiol). For the primary end point, the placebo group reported significantly more days using cannabis during the 12 weeks (mean [SD], 53.1 [33.0] days) than the nabiximols group (mean [SD], 35.0 [32.4] days; estimated difference, 18.6 days; 95% CI, 3.5-33.7 days; P = .02). Both groups showed comparable improvements in health status, with no substantial changes in other substance use. Medication was well tolerated with few adverse events.
Conclusions and Relevance
This study demonstrates that cannabinoid agonist treatment, in this case using nabiximols, in combination with psychosocial interventions is a safe approach for reducing cannabis use among individuals with cannabis dependence who are seeking treatment.
anzctr.org.au Identifier: ACTRN12616000103460
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: April 22, 2019.
Corresponding Author: Nicholas Lintzeris, MBBS, PhD, Drug and Alcohol Services, South East Sydney Local Health District, 591 S Dowling St, Surry Hills, New South Wales, Australia 2010 (email@example.com).
Published Online: July 15, 2019. doi:10.1001/jamainternmed.2019.1993
Author Contributions: Drs Lintzeris and Mills had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lintzeris, Dunlop, Copeland, McGregor, Bruno, Phung, Montebello, Hall, Jefferies, Shanahan, Allsop.
Acquisition, analysis, or interpretation of data: Lintzeris, Bhardwaj, Mills, Copeland, McGregor, Bruno, Gugusheff, Phung, Montebello, Chan, Kirby, Jefferies, Luksza, Shanahan, Kevin, Allsop.
Drafting of the manuscript: Lintzeris, Mills, Dunlop, Phung, Montebello, Kirby, Jefferies, Kevin, Allsop.
Critical revision of the manuscript for important intellectual content: Lintzeris, Bhardwaj, Mills, Dunlop, Copeland, McGregor, Bruno, Gugusheff, Phung, Montebello, Chan, Kirby, Hall, Jefferies, Luksza, Shanahan, Kevin.
Statistical analysis: Lintzeris, Bhardwaj, Mills, Bruno, Phung, Kirby.
Obtained funding: Lintzeris, Dunlop, Copeland, McGregor, Phung, Montebello, Shanahan, Allsop.
Administrative, technical, or material support: Lintzeris, Bhardwaj, Mills, Dunlop, McGregor, Bruno, Gugusheff, Phung, Montebello, Chan, Hall, Jefferies, Luksza, Shanahan, Allsop.
Supervision: Lintzeris, Copeland, Phung, Allsop.
Conflict of Interest Disclosures: Dr Lintzeris reported receiving grants from National Health and Medical Research Council of Australia during the conduct of the study; grants from Camurus, personal fees from Indivior and Mundipharma outside the submitted work; and being the Clinical Director of the Lambert Initiative in Cannabinoid Therapeutics at University of Sydney from 2015-2017, involved in a number of studies of medical cannabis, unrelated to this study. Dr McGregor reported receiving grants from National Health and Medical Research Council of Australia and from Lambert Initiative for Cannabinoid Therapeutics during the conduct of the study; having patents to WO2018107216A1, WO2017004674A1, and WO2011038451A1 issued and licensed; and having patents to AU2017904438, AU2017904072, and AU2018901971 pending. No other disclosures were reported.
Funding/Support: The study was an investigator-led trial with the University of Sydney as the study sponsor. National Health and Medical Research Council project grant 1088902 supported research costs, health services were predominantly funded by the participating New South Wales health services, and study medications were provided free by GW Pharmaceuticals.
Role of the Funder/Sponsor: The sponsor and funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Group Information: The Agonist Replacement for Cannabis Dependence (ARCD) study group members are Raelene Dojcinovic, Betty Jago, Lynsey McKendrick, Consuelo Rivas, Ricardo Schwanz, Abigail Yang, and Zachary Zavareh, all from South Eastern Sydney Local Health District; Susan Hazelwood, Josephine Hindson, Melissa Jackson, Julian Keats, Craig Sadler, and Anthony Winmill, all from Hunter New England Local Health District; Angelo Barbaro, Kerin Black, Pip Bowden, Jonathon Coreas, Tim Ho, Shyam Nagubandi, Mahsa Shahidi, Catherine Silsbury, Lisa Snell, and Matthew Wijanto, all from Western Sydney Local Health District.
Data Sharing Statement: See Supplement 3.
Additional Contributions: The Agonist Replacement for Cannabis Dependence (ARCD) study group members all contributed by participating in data collection and the delivery of study interventions. New South Wales Health Pathology Royal Prince Alfred Hospital assisted with the urinalysis for this study.
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