Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence : A pilot randomized clinical trial

Jose M. Trigo, Alexandra Soliman, Lena C. Quilty, Benedikt Fischer, JuÈrgen Rehm, Peter Selby, Allan J. Barnes11¤a, Marilyn A. Huestis, Tony P. George, David L. Streiner, Gregory Staios, Bernard Le Foll

PLoS ONE, 2018, 13, (1), e0190768.

https://doi.org/10.1371/journal.pone.0190768

 

Abstract

Background
The current lack of pharmacological treatments for cannabis use disorder (CUD) warrants novel approaches and further investigation of promising pharmacotherapy. We previously showed that nabiximols (27 mg/ml Δ9-tetrahydrocannabinol (THC)/ 25 mg/ml cannabidiol (CBD), Sativex®) can decrease cannabis withdrawal symptoms. Here, we assessed in a pilot study the tolerability and safety of self-titrated nabiximols vs. placebo among 40 treatment- seeking cannabis-dependent participants.

Methods
Subjects participated in a double blind randomized clinical trial, with as-needed nabiximols up to 113.4 mg THC/105 mg CBD or placebo daily for 12 weeks, concurrently with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT). Primary outcome measures were tolerability and abstinence, secondary outcome measures were days and amount of cannabis use, withdrawal, and craving scores. Participants received up to CDN$ 855 in compensation for their time.

Results
Medication was well tolerated and no serious adverse events (SAEs) were observed. Rates of adverse events did not differ between treatment arms (F1,39 = 0.205, NS). There was no significant change in abstinence rates at trial end. Participants were not able to differentiate between subjective effects associated with nabiximols or placebo treatments (F1,40 = 0.585, NS). Cannabis use was reduced in the nabiximols (70.5%) and placebo groups (42.6%). Nabiximols reduced cannabis craving but no significant differences between the nabiximols and placebo groups were observed on withdrawal scores.

Conclusions
Nabiximols in combination with MET/CBT was well tolerated and allowed for reduction of cannabis use. Future clinical trials should explore the potential of high doses of nabiximols for cannabis dependence.

Introduction

Cannabis is the most widely used illicit substance worldwide [1]. Those who have used cannabis at least once (aged 15 to 64) are estimated to be 128±232 million, or 2.7 to 4.9% of the world’s population [2]. There is a high prevalence of use in North America and a gradual increase since 2007 [2]. Cannabis use prevalence has important implications for public health [3±5] and its use has been associated with a variety of health problems including cognitive [6] and respiratory impairment [7], psychotic episodes [8], injury risk [9] and dependence [10,11]. Research indicates that about 8% of those who ever use cannabis may develop cannabis dependence [12,13]. However, there is currently no approved pharmacotherapy for cannabis dependence [14,15]. Due to the significant impact of problematic cannabis use on individuals and society, and thereby, the increasing demand for treatment, several research teams have focused on developing medications for cannabis dependence treatment [14,16]. These studies have mainly tested the potential utility of pharmacotherapies available for other indications (e.g. cannabinoid drugs, antidepressants, anxiolytics, and antipsychotics). Reviews indicated that Δ9-tetrahydrocannabinol (THC), the anticonvulsant gabapentin and the glutamatergic modulator N-acetylcysteine (clinical trials # NCT00974376 and NCT01675661, respectively), are the most promising approaches [14,17,18]. Although recent studies have also shown that N-acetylcysteine might have limited effects in adults [19]. The potential benefits of cannabinoid agonist preparations like THC or the synthetic analogs Nabilone and Dronabinol for cannabis dependence treatment have been evaluated in several studies [20±26]. Though these THC and THC-analogs showed promising effects on cannabis withdrawal symptoms, they did not reduce cannabis use in some of these laboratory studies [21,23]. On the other hand, more recent studies have shown that participants used less cannabis while maintained on Nabilone [26] or a combination of Nabilone and Zolpidem [27] under laboratory conditions.

Preclinical studies suggest that cannabidiol (CBD) might modulate neuronal circuits involved in drug addiction, featuring the potential to reduce addiction (see [28] review). Recently, there is growing interest in the ~1:1 THC/CBD combination (also called nabiximols or Sativex1 [brand name]) for cannabis dependence treatment [29]. This ~1:1 THC/CBD combination (developed by GW Pharma) was approved for multiple sclerosis treatment in humans in several European countries and Canada. Recently, we showed that nabiximols is effective to alleviate cannabis withdrawal [30]. In addition, Allsop et al. tested nabiximols in Australian treatment-seeking participants with cannabis dependence showing reduction in cannabis withdrawal scores and improved treatment retention but no reduction in cannabis use compared to placebo [31]. However, pharmacological treatment was limited to six days of exposure and participants were treated initially in an inpatient unit, so the trial was limited in its ability to test efficacy for long-term cannabis use or abstinence. Therefore, there is a great need to explore the impact of prolonged administration of THC/CBD combinations in treatment- seeking participants with cannabis dependence.

In the present study, we explored the effects of a three month course of self-titrated nabiximols treatment combined with Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT) on cannabis dependence. The main objective of this pilot study was to determine if the self-titrated dosage was well tolerated and sufficient to observe any effects on cannabis use, craving and withdrawal in comparison with placebo.

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journal.pone.0190768