Mark Montebello

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

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.

A placebo‐controlled trial of mirtazapine for the management of methamphetamine withdrawal

INTRODUCTION AND AIMS As an antidepressant with sedative and anxiolytic properties, mirtazapine may be an appropriate pharmacotherapy for methamphetamine withdrawal. This study sought to examine whether mirtazapine improves retention and alleviates methamphetamine withdrawal symptoms in an out-patient setting. DESIGN AND METHODS An out-patient double-blind, randomised placebo-controlled trial of mirtazapine for the treatment of methamphetamine withdrawal was conducted (15 mg nocte for 2 days, 30 mg nocte for 12 days). Both groups were offered narrative therapy counselling. Measures recorded on days 0, 3, 7, 14 and 35 included: treatment retention, Amphetamine Cessation Symptoms Assessment, the Athens Insomnia Scale, the Brief Symptom Inventory, the Depression-Anxiety-Stress Scale (DASS), Severity of Dependence scale and the Opiate Treatment Index Drug Use subscale. RESULTS Thirty-one participants were recruited (18 placebo, 13 mirtazapine) and 52% completed the 2-week medication phase. No significant differences between the mirtazapine and placebo groups in retention, or any symptom measure were observed, except greater DASS-anxiety and longer sleep duration were measured at baseline among the mirtazapine group. DISCUSSION AND CONCLUSIONS Results suggest that mirtazapine does not facilitate retention or recruitment in out-patient methamphetamine withdrawal treatment, although recruitment may have been insufficient to identify a significant treatment effect. The potential role of narrative therapy for methamphetamine dependent patients deserves further exploration.

Exercise increases plasma THC concentrations in regular cannabis users

BACKGROUND The major psychoactive ingredient of cannabis, Δ(9)-tetrahydrocannabinol (THC) accumulates in fat tissue from where it slowly diffuses back into blood. THC pre-treated rats can show elevated plasma cannabinoid levels when subjected to conditions that promote fat utilization, such as fasting. Here we examine whether fasting and exercise increase plasma THC concentrations in regular cannabis users. METHODS Fourteen regular cannabis users completed 35 min of exercise on a stationary bicycle in either a fed or overnight fasted state. Plasma cannabinoid levels were assessed prior to exercise, immediately post-exercise and 2h post-exercise. Plasma samples were also analyzed for indices of lipolysis (free fatty acids (FFA) and glycerol). RESULTS Exercise induced a small, statistically significant increase in plasma THC levels accompanied by increased plasma FFA and glycerol levels. Exercise-induced increases in plasma THC concentrations were positively correlated with body mass index. Fasting induced a significant increase in plasma FFA levels, and a lowering of blood glucose, but did not significantly alter plasma cannabinoid levels. CONCLUSIONS Here we demonstrate that exercise enhances plasma THC levels in regular cannabis users. The lack of a fasting effect may reflect the modest duration of fasting used which was associated with only a modest increase in fat utilization relative to exercise. Overall, these results suggest that exercise may elevate blood THC levels by releasing dormant THC from fat stores. These data suggest the interpretation of blood THC levels in roadside and workplace tests might be complicated by recent exercise.

Misuse and Associated Harms of Quetiapine and Other Atypical Antipsychotics

Recent years have seen a significant increase in the reports of atypical antipsychotic diversion, misuse and even dependency syndrome. These reports have arisen amidst a marked increase in prescribing of these agents. Much of this increase in prescribing is because of a preferential use of these medications over typical antipsychotic agents to treat schizophrenia and bipolar disorder due to perceptions of fewer extrapyramidal side effects. However, there has also been a significant increase in the off-label prescribing of these medicines to treat less well evidence-based conditions. Misuse and abuse are perhaps surprising given the putative central role of dopamine in addiction and that these agents are dopamine antagonists. However, there may be other factors such as other pharmacological effects and increasing availability driving this misuse. It is also apparent that certain patient groups appear to be more at risk. Here, we explore the evidence behind the misuse of atypical antipsychotics with a focus of quetiapine. We consider the factors that may be driving this misuse, and then, we also detail some of the adverse effects that may ensue. We end by suggesting interventions at a prescriber and systems level that may be implemented to reduce the risk of atypical antipsychotic misuse.

Are cannabis users who participate in a randomized clinical trial different from other treatment seekers

Randomized controlled trials (RCTs) provide the most convincing evidence for clinical questions concerning the efficacy of interventions. When participants in RCTs are characteristically different to those in usual clinical practice, it may be difficult to generalize findings. This study compares profiles taken from a centralized intake process for those presenting with cannabis as their main drug, which were then separated into three categories, (a) those who were offered a specialist assessment for cannabis dependence over the phone but did not attend their appointment, (b) those who presented for their initial appointment, and c) those attending and subsequently recruited into an RCT. To explore whether issues such as severity of cannabis use and co-occurring disorders acted as a barrier to attending treatment or to inclusion in an RCT, we examined basic triage information. Results indicated that there were no statistically significant differences on selected characteristics between groups, suggesting that RCT participants were representative of treatment seekers, and that the filtering that occurs between those who make phone contact with professional services and those who present to treatment are not necessarily due to presence of patient characteristics such as coexisting medical, psychological issues, or severity of their cannabis use.

Survey of Australian psychiatrists’ and psychiatry trainees’ knowledge about and attitudes towards medicinal cannabinoids

Objective: To assess Australian psychiatrists’ and psychiatry trainees’ knowledge about and attitudes towards medicinal cannabinoids, given the recent relaxation of cannabinoid-prescribing laws in Australia. Method: All Australian members of the Royal Australian and New Zealand College of Psychiatrists were invited to participate in an anonymous, 64-item online questionnaire, through Royal Australian and New Zealand College of Psychiatrists’ newsletters. The questionnaire ran for a 10-week period from March to May 2017. Participants were asked about their knowledge of the evidence for and against prescribing pharmaceutical-grade cannabidiol and tetrahydrocannabinol, and their concerns about prescribing medicinal cannabinoids. Results: In total, 88 doctors responded to the survey, with 55 completing all items (23 psychiatrists, 32 trainees). Overall, 54% of respondents would prescribe medicinal cannabinoids if it was legal to do so. Participants believed there was evidence for the use of cannabidiol and tetrahydrocannabinol in treating childhood epilepsy, chronic pain, and nausea and vomiting. They were most concerned about medicinal cannabinoids leading to psychotic symptoms, addiction and dependence, apathy and recreational use. Conclusions: Our sample of Australian psychiatrists and trainees were aware of the main clinical indications for medicinal cannabinoids, but were poor at differentiating between the indications for cannabidiol versus tetrahydrocannabinol. Further education about medicinal cannabinoids appears necessary.