Nabiximols for the Treatment of Cannabis Dependence: A Randomized Clinical Trial.

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.

Randomised Controlled Trial (RCT) of cannabinoid replacement therapy (Nabiximols) for the management of treatment-resistant cannabis dependent patients: a study protocol.

BACKGROUND: The cannabis extract nabiximols (Sativex®) effectively supresses withdrawal symptoms and cravings in treatment resistant cannabis dependent individuals, who have high relapse rates following conventional withdrawal treatments. This study examines the efficacy, safety and cost-effectiveness of longer-term nabiximols treatment for outpatient cannabis dependent patients who have not responded to previous conventional treatment approaches. METHODS/DESIGN: A phase III multi-site outpatient, randomised, double-blinded, placebo controlled parallel design, comparing a 12-week course of nabiximols to placebo, with follow up at 24 weeks after enrolment. Four specialist drug and alcohol outpatient clinics in New South Wales, Australia. One hundred forty-two treatment seeking cannabis dependent adults, with no significant medical, psychiatric or other substance use disorders. Nabiximols is an oromucosal spray prescribed on a flexible dose regimen to a maximum daily dose of 32 sprays; 8 sprays (total 21.6 mg tetrahydrocannabinol (THC) and 20 mg cannabidiol (CBD)) four times a day, or matching placebo, dispensed weekly. All participants will receive six-sessions of individual cognitive behavioural therapy (CBT) and weekly clinical reviews. Primary endpoints are use of non-prescribed cannabis (self-reported cannabis use days, urine toxicology), safety measures (adverse events and abuse liability), and cost effectiveness (incremental cost effectiveness in achieving additional Quality Adjusted Life Years). Secondary outcomes include, improvement in physical and mental health parameters, substance use other than cannabis, cognitive functioning and patient satisfaction measures. DISCUSSION: This is the first outpatient community-based randomised controlled study of nabiximols as an agonist replacement medication for treating cannabis dependence, targeting individuals who have not previously responded to conventional treatment approaches. The study and treatment design is modelled upon an earlier study with this population and more generally on other agonist replacement treatments (e.g. nicotine, opioids). TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12616000103460 (Registered 1st February 2016).

Nutritional approaches to breaking the intergenerational cycle of obesity.

The link between poor maternal nutrition and an increased burden of disease in subsequent generations has been widely demonstrated in both human and animal studies. Historically, the nutritional challenges experienced by pregnant and lactating women were largely those of insufficient calories and severe micronutrient deficiencies. More recently, however, Western societies have been confronted with a new nutritional challenge; that of maternal obesity and excessive maternal intake of calories, fat, and sugar. Exposure of the developing fetus and infant to this obesogenic environment results in an increased risk of obesity and metabolic disease later in life. Furthermore, increased caloric, fat, and sugar intake can occur in conjunction with micronutrient deficiency, which may further exacerbate these programming effects. In light of the current epidemic of obesity and metabolic disease, attention has now turned to identifying nutritional interventions for breaking this intergenerational obesity cycle. In this review, we discuss the approaches that have been explored to date and highlight the need for further research.