[Skip to Content]
[Skip to Content Landing]

Nabiximols for the Treatment of Cannabis DependenceA Randomized Clinical Trial

Educational Objective Understand how to respond to the following clinical question: 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.
1 Credit CME
Key Points

Question  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?

Findings  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.

Meaning  The use of cannabinoid agonist medication appears to be a promising addition to the treatment of patients with cannabis dependence.


Importance  There are no effective medications for treating dependence on cannabis.

Objective  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.

Interventions  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.

Results  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.

Trial Registration  anzctr.org.au Identifier: ACTRN12616000103460

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

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.

Article Information

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 (nicholas.lintzeris@health.nsw.gov.au).

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.

UN Office on Drugs and Crime.  World Drug Report 2013. Vienna, Austria: UN Office on Drugs and Crime; 2013.
UN Office on Drugs and Crime.  World Drug Report 2015. Vienna, Austria: UN Office on Drugs and Crime; 2015.
Australian Institute of Health and Welfare.  2016 National Drug Strategy Household Survey: Preliminary Findings. Canberra, Australia: Australian Institute of Health and Welfare; 2017.
Hall  W, Degenhardt  L.  Adverse health effects of non-medical cannabis use.  Lancet. 2009;374(9698):1383-1391. doi:10.1016/S0140-6736(09)61037-0PubMedGoogle ScholarCrossref
World Health Organization.  The Health and Social Effects of Nonmedical Cannabis Use. Geneva, Switzerland: World Health Organization; 2016.
Roffman  RA, Stephens  RS.  Cannabis Dependence: Its Nature, Consequences, and Treatment. Cambridge, UK: Cambridge University Press; 2006. doi:10.1017/CBO9780511544248
Allsop  DJ, Copeland  J, Lintzeris  N,  et al.  Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial.  JAMA Psychiatry. 2014;71(3):281-291. doi:10.1001/jamapsychiatry.2013.3947PubMedGoogle ScholarCrossref
Johnston  J, Lintzeris  N, McGregor  I, Allsop  DJ, Helliwell  D, Winstock  A.  A double blind, randomised, placebo controlled trial of lithium carbonate for the management of cannabis withdrawal: paper 220.  Drug Alcohol Rev. 2013;32:43.Google Scholar
Gates  PJ, Sabioni  P, Copeland  J, Le Foll  B, Gowing  L.  Psychosocial interventions for cannabis use disorder.  Cochrane Database Syst Rev. 2016;(5):CD005336. doi:10.1002/14651858.CD005336.pub4PubMedGoogle Scholar
Danovitch  I, Gorelick  DA.  State of the art treatments for cannabis dependence.  Psychiatr Clin North Am. 2012;35(2):309-326. doi:10.1016/j.psc.2012.03.003PubMedGoogle ScholarCrossref
Vandrey  R, Haney  M.  Pharmacotherapy for cannabis dependence: how close are we?  CNS Drugs. 2009;23(7):543-553. doi:10.2165/00023210-200923070-00001PubMedGoogle ScholarCrossref
Darke  S, Farrell  M.  Would legalizing illicit opioids reduce overdose fatalities? implications from a natural experiment.  Addiction. 2014;109(8):1237-1242. doi:10.1111/add.12456PubMedGoogle ScholarCrossref
Haney  M, Hart  CL, Vosburg  SK, Comer  SD, Reed  SC, Foltin  RW.  Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse.  Psychopharmacology (Berl). 2008;197(1):157-168. doi:10.1007/s00213-007-1020-8PubMedGoogle ScholarCrossref
Huestis  MA, Sampson  AH, Holicky  BJ, Henningfield  JE, Cone  EJ.  Characterization of the absorption phase of marijuana smoking.  Clin Pharmacol Ther. 1992;52(1):31-41. doi:10.1038/clpt.1992.100PubMedGoogle ScholarCrossref
Karschner  EL, Darwin  WD, Goodwin  RS, Wright  S, Huestis  MA.  Plasma cannabinoid pharmacokinetics following controlled oral Δ9-tetrahydrocannabinol and oromucosal cannabis extract administration.  Clin Chem. 2011;57(1):66-75. doi:10.1373/clinchem.2010.152439PubMedGoogle ScholarCrossref
Levin  FR, Mariani  JJ, Brooks  DJ, Pavlicova  M, Cheng  W, Nunes  EV.  Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial.  Drug Alcohol Depend. 2011;116(1-3):142-150. doi:10.1016/j.drugalcdep.2010.12.010PubMedGoogle ScholarCrossref
Trigo  JM, Soliman  A, Quilty  LC,  et al.  Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: a pilot randomized clinical trial.  PLoS One. 2018;13(1):e0190768. doi:10.1371/journal.pone.0190768PubMedGoogle ScholarCrossref
Bhardwaj  AK, Allsop  DJ, Copeland  J,  et al; Agonist Replacement for Cannabis Dependence (ARCD) study group.  Randomised controlled trial (RCT) of cannabinoid replacement therapy (nabiximols) for the management of treatment-resistant cannabis dependent patients: a study protocol.  BMC Psychiatry. 2018;18(1):140. doi:10.1186/s12888-018-1682-2PubMedGoogle ScholarCrossref
World Health Organization.  International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). 2nd ed. Geneva, Switzerland: World Health Organization; 2005.
Copeland  J.  Marijuana Brief Intervention: An SBIRT Approach. Center City, MN: Hazelden Publishing; 2017.
Sobell  LC, Sobell  MB. Timeline follow-back: a technique for assessing self-reported alcohol consumption. In: Litten RZ, Allen JP, eds.  Measuring Alcohol Consumption: Psychosocial and Biochemical Methods. Totowa, NJ: Humana Press Inc; 1992:41-72. doi:10.1007/978-1-4612-0357-5_3
Suraev  A, Lintzeris  N, Stuart  J,  et al.  Composition and use of cannabis extracts for childhood epilepsy in the Australian community.  Sci Rep. 2018;8(1):10154. doi:10.1038/s41598-018-28127-0PubMedGoogle ScholarCrossref
Kevin  RC, Allsop  DJ, Lintzeris  N, Dunlop  AJ, Booth  J, McGregor  IS.  Urinary cannabinoid levels during nabiximols (Sativex)-medicated inpatient cannabis withdrawal.  Forensic Toxicol. 2017;35(1):33-44. doi:10.1007/s11419-016-0330-0PubMedGoogle ScholarCrossref
Overall  JE, Gorham  DR.  The Brief Psychiatric Rating Scale.  Psychol Rep. 1962;10(3):799-812. doi:10.2466/pr0.1962.10.3.799Google ScholarCrossref
Larance  B, Bruno  R, Lintzeris  N,  et al.  Development of a brief tool for monitoring aberrant behaviours among patients receiving long-term opioid therapy: the Opioid-Related Behaviours In Treatment (ORBIT) scale.  Drug Alcohol Depend. 2016;159:42-52. doi:10.1016/j.drugalcdep.2015.11.026PubMedGoogle ScholarCrossref
Allsop  DJ, Norberg  MM, Copeland  J, Fu  S, Budney  AJ.  The Cannabis Withdrawal Scale development: patterns and predictors of cannabis withdrawal and distress.  Drug Alcohol Depend. 2011;119(1-2):123-129. doi:10.1016/j.drugalcdep.2011.06.003PubMedGoogle ScholarCrossref
Heishman  SJ, Singleton  EG, Liguori  A.  Marijuana Craving Questionnaire: development and initial validation of a self-report instrument.  Addiction. 2001;96(7):1023-1034. doi:10.1046/j.1360-0443.2001.967102312.xPubMedGoogle ScholarCrossref
Copeland  J, Gilmour  S, Gates  P, Swift  W.  The Cannabis Problems Questionnaire: factor structure, reliability, and validity.  Drug Alcohol Depend. 2005;80(3):313-319. doi:10.1016/j.drugalcdep.2005.04.009PubMedGoogle ScholarCrossref
Saunders  JB, Aasland  OG, Babor  TF, de la Fuente  JR, Grant  M.  Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption—II.  Addiction. 1993;88(6):791-804. doi:10.1111/j.1360-0443.1993.tb02093.xPubMedGoogle ScholarCrossref
Heatherton  TF, Kozlowski  LT, Frecker  RC, Fagerström  KO.  The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire.  Br J Addict. 1991;86(9):1119-1127. doi:10.1111/j.1360-0443.1991.tb01879.xPubMedGoogle ScholarCrossref
Ware  JE  Jr, Sherbourne  CD.  The MOS 36-item short-form health survey (SF-36), I: conceptual framework and item selection.  Med Care. 1992;30(6):473-483. doi:10.1097/00005650-199206000-00002PubMedGoogle ScholarCrossref
Darke  S, Hall  W, Wodak  A, Heather  N, Ward  J.  Development and validation of a multi-dimensional instrument for assessing outcome of treatment among opiate users: the Opiate Treatment Index.  Br J Addict. 1992;87(5):733-742. doi:10.1111/j.1360-0443.1992.tb02719.xPubMedGoogle ScholarCrossref
Benjamini  Y, Hochberg  Y.  Controlling the false discovery rate: a practical and powerful approach to multiple testing.  J R Stat Soc Series B Stat Methodol. 1995;57(1):289-300.Google Scholar
Baker  NL, Gray  KM, Sherman  BJ,  et al.  Biological correlates of self-reported new and continued abstinence in cannabis cessation treatment clinical trials.  Drug Alcohol Depend. 2018;187:270-277. doi:10.1016/j.drugalcdep.2018.03.017PubMedGoogle ScholarCrossref
R: a language and environment for statistical computing [computer program]. Vienna, Austria: R Foundation for Statistical Computing; 2016.
Bates  D, Mächler  M, Bolker  B, Steve  W.  Fitting linear mixed-effects models using lme4.  J Stat Softw. 2015;67(1):1-48. doi:10.18637/jss.v067.i01Google ScholarCrossref
Wickham  H. tidyverse: Easily install and load the ’tidyverse.’ R package version 1.2.1. https://cran.r-project.org/web/packages/tidyverse/index.html. Accessed March 12, 2018.
Therneau  TM, Grambsch  PM.  Modeling Survival Data: Extending the Cox Model. New York, NY: Springer Science & Business Media; 2013.
Van Buuren  S, Groothuis-Oudshoorn  K.  mice: Multivariate imputation by chained equations in R.  J Stat Softw. 2011;45(3):1-67. doi:10.18637/jss.v045.i03Google Scholar
Teruya  C, Schwartz  RP, Mitchell  SG,  et al.  Patient perspectives on buprenorphine/naloxone: a qualitative study of retention during the Starting Treatment With Agonist Replacement Therapies (START) Study.  J Psychoactive Drugs. 2014;46(5):412-426. doi:10.1080/02791072.2014.921743PubMedGoogle ScholarCrossref
Morgan  CJ, Freeman  TP, Schafer  GL, Curran  HV.  Cannabidiol attenuates the appetitive effects of Δ 9-tetrahydrocannabinol in humans smoking their chosen cannabis.  Neuropsychopharmacology. 2010;35(9):1879-1885. doi:10.1038/npp.2010.58PubMedGoogle ScholarCrossref
Crippa  JAS, Hallak  JEC, Machado-de-Sousa  JP,  et al.  Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report.  J Clin Pharm Ther. 2013;38(2):162-164. doi:10.1111/jcpt.12018PubMedGoogle ScholarCrossref
Hermann  D, Sartorius  A, Welzel  H,  et al.  Dorsolateral prefrontal cortex N-acetylaspartate/total creatine (NAA/tCr) loss in male recreational cannabis users.  Biol Psychiatry. 2007;61(11):1281-1289. doi:10.1016/j.biopsych.2006.08.027PubMedGoogle ScholarCrossref
Hermann  D, Schneider  M.  Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: a critical review.  Curr Pharm Des. 2012;18(32):4897-4905. doi:10.2174/138161212802884825PubMedGoogle ScholarCrossref
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.


My Saved Courses

You currently have no courses saved.