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RationaleData on safety, pharmacodynamics, and pharmacokinetics of tetrahydrocannabinol (THC) are lacking in dementia patients.MethodsIn this randomized, double-blind, placebo-controlled, crossover trial, we evaluated the safety, pharmacodynamics, and pharmacokinetics of THC in ten patients with dementia (mean age 77.3 ± 5.6). For 12 weeks, participants randomly received oral THC (weeks 1–6, 0.75 mg; weeks 7–12, 1.5 mg) or placebo twice daily for 3 days, separated by a 4-day washout period.ResultsOnly 6 of the 98 reported adverse events were related to THC. Visual analog scale (VAS) feeling high, VAS external perception, body sway-eyes-open, and diastolic blood pressure were not significantly different with THC. After the 0.75-mg dose, VAS internal perception (0.025 units; 95 % CI 0.010–0.040) and heart rate (2 beats/min; 95 % CI 0.4–3.8) increased significantly. Body sway-eyes-closed increased only after 1.5 mg (0.59°/s; 95 % CI 0.13–1.06). Systolic blood pressure changed significantly after both doses of THC (0.75 mg, −7 mmHg, 95 % CI −11.4, −3.0; 1.5 mg, 5 mmHg, 95 % CI 1.0–9.2). The median Tmax was 1–2 h, with THC pharmacokinetics increasing linearly with increasing dose, with wide interindividual variability (CV% up to 140 %). The mean Cmax (ng/mL) after the first dose (0–6 h) was 0.41 (0.18–0.90) for the 0.75-mg dose and 1.01 (0.53–1.92) for the 1.5-mg dose. After the second dose (6–24 h), the Cmax was 0.50 (0.27–0.92) and 0.98 (0.46–2.06), respectively.ConclusionsTHC was rapidly absorbed and had dose-linear pharmacokinetics with considerable interindividual variation. Pharmacodynamic effects, including adverse events, were minor. Further studies are warranted to evaluate the pharmacodynamics and efficacy of higher THC doses in older persons with dementia.

Objective: To study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the treatment of dementia-related neuropsychiatric symptoms (NPS).Methods: This is a randomized, double-blind, placebo-controlled study. Patients with dementia and clinically relevant NPS were randomly assigned to receive THC 1.5 mg or matched placebo (1:1) 3 times daily for 3 weeks. Primary outcome was change in Neuropsychiatric Inventory (NPI), assessed at baseline and after 14 and 21 days. Analyses were based on intention-to-treat.Results: Twenty-four patients received THC and 26 received placebo. NPS were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant (mean difference NPI total : 3.2, 95% confidence interval [CI] 23.6 to 10.0), nor were changes in scores for agitation (Cohen-Mansfield Agitation Inventory 4.6, 95% CI 23.0 to 12.2), quality of life (Quality of Life-Alzheimer's Disease 20.5, 95% CI 22.6 to 1.6), or activities of daily living (Barthel Index 0.6, 95% CI 20.8 to 1.9). The number of patients experiencing mild or moderate adverse events was similar (THC, n 5 16; placebo, n 5 14, p 5 0.36). No effects on vital signs, weight, or episodic memory were observed.Conclusions: Oral THC of 4.5 mg daily showed no benefit in NPS, but was well-tolerated, which adds valuable knowledge to the scarce evidence on THC in dementia. The benign adverse event profile of this dosage allows study of whether higher doses are efficacious and equally welltolerated. Classification of evidence:This study provides Class I evidence that for patients with dementiarelated NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is welltolerated. Neurology ® 2015;84:2338-2346 GLOSSARY AD 5 Alzheimer disease; AE 5 adverse event; CCGIC 5 Caregiver Clinical Global Impression of Change; CI 5 confidence interval; CMAI 5 Cohen-Mansfield Agitation Inventory; NPI 5 Neuropsychiatric Inventory; NPS 5 neuropsychiatric symptoms; PAL WMS-R 5 Paired Associate Learning Wechsler Memory Scale-Revised; QoL-AD 5 Quality of Life-Alzheimer's Disease Scale; RCT 5 randomized controlled trial; THC 5 D-9-tetrahydrocannabinol.