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Agitation is a prevalent and difficult-to-treat symptom in patients with moderate-to-severe Alzheimer's disease (AD). Though there are nonpharmacological and pharmacological interventions recommended for the treatment of agitation, the efficacy of these are modest and not always consistent. Furthermore, the safety profiles of currently prescribed medications are questionable. Nabilone, a synthetic cannabinoid, has a distinct pharmacological profile that may provide a safer and more effective treatment for agitation, while potentially having benefits for weight and pain. Additionally, emerging evidence suggests nabilone may have neuroprotective effects. We describe a clinical trial investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe AD. This will be a double-blind, randomized cross-over study comparing 6 weeks of nabilone (0.5–2 mg) and placebo, with a 1-week washout preceding each phase. Study outcomes will be measured at baseline and end of treatment for each treatment phase. The primary outcome measure will be agitation as assessed by the Cohen-Mansfield Agitation Inventory. The secondary outcomes include safety, behaviour (Neuropsychiatric Inventory), cognition (standardized Mini Mental Status Exam and either Severe Impairment Battery or Alzheimer's disease Assessment Scale-Cognitive subscale) and global impression (Clinician's Global Impression of Change). Exploratory outcomes include pain (Pain Assessment in Advanced AD), nutritional status (Mini-Nutritional Assessment-Short Form), caregiver distress (NPI caregiver distress), and blood-based biomarkers. A safe and efficacious pharmacological intervention for agitation, with effects on pain and weight loss in patients with moderate-to-severe AD could increase quality-of-life, reduce caregiver stress and avoid unnecessary institutionalization and related increases in health care costs. Clinical trials number: NCT02351882 Keywords: Agitation, Cannabinoid, Alzheimer's disease, Neuropsychiatric symptoms, Clinical trial

Objectives Cholinesterase inhibitors (ChEIs) offer modest benefits in Alzheimer disease (AD), which must be balanced against risks. Relatively few data delineate the benefits and risks of long-term ChEI administration in institutionalized patients with advanced AD. This study investigated the effects of ChEI discontinuation in institutionalized patients with AD. Design Institutionalized patients with moderate to severe AD (standardized Mini- Mental Status Examination ≤15) and treated with a ChEI for ≥2 years were randomized, double-blind, to ChEI continuation or placebo, with a 2-week tapering phase, for 8-weeks. Measurements The primary outcome of this pilot study was change on the Clinician's Global Impression of Change (CGI-C) scale. Secondary outcomes included safety, efficacy, and tolerability. Baseline (BL) predictors of clinical deterioration were also determined. Results Forty patients (mean ± standard deviation age = 89.3 ± 3.5 years, standardized Mini-Mental Status Examination = 8.1 ± 5.2, Neuropsychiatric Inventory–Nursing Home version total score = 21.1 ± 15.9, 80% male) were randomized to ChEI continuation (n = 21) or placebo (n = 19). There was no significant difference in clinical worsening in the ChEI continuation (28.6%) and placebo groups (36.8%) on CGI-C (odds ratio for worsening 1.58, 95% confidence interval .38–6.55, P = .53). The occurrence of adverse events was similar in both groups. There were no significant differences in any of the secondary outcome measures. In the placebo group, BL hallucinations predicted CGI-C worsening [F(1,17) = 6.4, P = .02], and there was a trend for BL delusions to predict CGI-C worsening [F(1,15) = 3.5, P = .08]. Conclusions These results suggest that ChEI discontinuation is safe and well tolerated in the majority of institutionalized patients with moderate to severe AD. When discontinuing ChEI, the presence of hallucinations and delusions may predict clinical deterioration, suggesting the need for increased caution.