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Original Investigation |

Nabiximols as an Agonist Replacement Therapy During Cannabis Withdrawal:  A Randomized Clinical Trial

David J. Allsop, PhD1,2; Jan Copeland, PhD1; Nicholas Lintzeris, PhD3,4; Adrian J. Dunlop, PhD5,6; Mark Montebello, FAChAM3; Craig Sadler, FAChAM5; Gonzalo R. Rivas, BNurs3; Rohan M. Holland, BNurs5; Peter Muhleisen, BPharm, MPSA5; Melissa M. Norberg, PhD1,7; Jessica Booth, BSc (Hons)8; Iain S. McGregor, PhD8
[+] Author Affiliations
1National Cannabis Prevention and Information Centre, National Drug and Alcohol Research Centre, Faculty of Medicine, University of New South Wales, Sydney, Australia
2now with the School of Psychology, University of Sydney, Sydney, Australia
3Drug and Alcohol Services, South Eastern Sydney Local Health District New South Wales Ministry of Health, Sydney, Australia
4Addiction Medicine, Central Clinical School, Faculty of Medicine, University of Sydney, Sydney, Australia
5Drug and Alcohol Clinical Services, Hunter New England Local Health District, New South Wales Ministry of Health, Newcastle, Australia
6School of Medicine and Public Health, Faculty of Health, University of Newcastle, Newcastle, Australia
7Department of Psychology, Macquarie University, Sydney, Australia
8School of Psychology, University of Sydney, Sydney, Australia
JAMA Psychiatry. 2014;71(3):281-291. doi:10.1001/jamapsychiatry.2013.3947.
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Importance  There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal.

Objective  To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal.

Design, Setting, and Participants  A 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers.

Interventions  A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission.

Main Outcomes and Measures  Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes.

Results  Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F8,377.97 = 2.39; P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37]; P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ21 = 0.79; P = .67), and those receiving nabiximols did not report greater intoxication (F1,6 = 0.22; P = .97). The number (F1,50 = 0.3; P = .59) and severity (F1,50 = 2.69; P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F1,48 = 0.29; P = .75), cannabis-related problems (F1,49 = 2.33; P = .14), or cannabis dependence (F1,50 < 0.01; P = .89).

Conclusions and Relevance  In a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations.

Trial Registration  anzctr.org.au Identifier: ACTRN12611000398909

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Figure 1.
Study Flow

Diagram shows the number of participants at each stage of the study.

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Figure 2.
Mean Change From Baseline in Withdrawal Score for Overall Withdrawal Scores and for Symptoms That Were Significantly Suppressed by Nabiximols

The adjusted model graphs show the mean values across all 5 multiply imputed data sets. Effect sizes (Hedges g) for change in withdrawal scores each day relative to baseline are reported. Sample sizes in each treatment arm before multiple imputation are also shown. Significance was based on the unadjusted mixed models for repeated measures (MMRM) post hoc pairwise comparisons between groups on each day, adjusted for multiple comparisons using Bonferroni adjustment. Treatment × time interactions shown: Omnibus type II test of fixed effects from adjusted MMRM. Error bars indicate standard error.aP ≤ .01.bP ≤ .05.

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Figure 3.
Retention in Withdrawal Treatment

The 2 hazard ratios (HRs) determined from the Cox regression marked on the graph show retention estimates at 2 time points: The day 6 HR (4.09) was computed with all remaining patients censored at day 6 to assess the effect of treatment allocation on retention during the medication administration phase. The day 9 HR (1.5) was computed with all remaining patients censored at day 9 to assess the overall effect of treatment allocation on retention, including the 3-day postmedication washout period.

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