A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer’s Disease.

IMPORTANCE: Agitation in Alzheimer's disease (AD) is a great source of distress for patients and caregivers and a major public health burden. Current treatments are only modestly effective and many have safety issues including mortality risk. Novel therapeutic options are needed. There is preliminary evidence for the safety and efficacy of dronabinol (tetrahydrocannabinol, THC) for agitation in AD.

OBJECTIVE: Assess the safety and efficacy of dronabinol (THC) to decrease agitation in AD.

DESIGN: THC-AD was a 3-week randomized parallel double-blind placebo-controlled clinical trial, conducted between 2017 and 2024.

SETTING: 5 inpatient and outpatient academic clinical research centers in the Eastern U.S.

PARTICIPANTS: Volunteer sample of 75 participants meeting inclusion criteria for agitation of AD (International Psychogeriatric Association Provision Criteria) with Neuropsychiatric Inventory Clinician Version Agitation or Aggression (NPI-C A/A) domains total score of 4 or greater. Major exclusion criteria included seizure disorder, delirium, and non-AD dementia.

INTERVENTIONS: 3 weeks dronabinol vs. placebo titrated up to target dose of 10 mg daily in divided twice-daily.

MAIN OUTCOMES AND MEASURES: Prespecified co-primary agitation outcomes were the Pittsburgh Agitation Scale (PAS) and NPI-C A/A total score.

RESULTS: The majority of participants were female and were taking concomitant psychotropic medications (antidepressants and antipsychotics) at baseline. Study participants were moderately agitated at baseline, were diverse in ethnic background (9% Black, 11% Hispanic/Latina/Latino), and had severe cognitive impairment evidenced by MMSE or SIB-8. 84% completed the 3-week trial. Dronabinol decreased agitation on both primary outcomes greater than placebo to a clinically relevant extent. The fitted between-arm difference in PAS decline/week was -0.74 (SE 0.3, p = 0.015, effect size = 0.53) and for NPI-C A/A the decline was not significant at -1.26 (SE 0.67, p = 0.094, effect size = 0.36). No secondary outcomes differed between treatment arms including sleep, activities of daily living, Cohen-Mansfield Agitation Inventory (CMAI), cognition, intoxication, or use of 'as-needed' lorazepam or trazodone. Dronabinol treatment was not associated with greater intoxication nor with other adverse events (AEs) except for somnolence.

CONCLUSIONS AND RELEVANCE: Adjunctive dronabinol treatment was safe and effective for treating agitation in AD.

CLINICAL TRIALS REGISTRATION: NCT02792257.