Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's disease (AD) (THC-AD)

Background: Agitation in AD is a major cause of burden to patients, caregivers, and society, and current treatments are limited in efficacy and/or associated with toxicity. Tetrahydrocannabinol (THC) is known to have anxiolytic effects likely mediated through the CB1 cannabinoid receptor, and there is increasing clinical of flabel use of THC in the form of the generic drug dronabinol for agitation in AD. A case series reported improved agitation in AD with mean of 7 mg of dronabinol daily (Woodward MR et al., 2013). A recent randomized controlled trial (RCT) of a similar THC preparation at target dose of 4.5 mg daily was null; however, this study suggested that dosing greater than 4.5mg daily may be required for therapeutic efficacy (van den Elsen et al., 2015). We therefore propose to assess effects of THC on agitation in AD at a higher dose (10 mg daily). Methods: THC‐AD is a 3‐week, double blind, placebo‐controlled RCT, which will evaluate the effects of dronabinol (10 mg daily) vs. placebo on agitation and aggression in inpatients with AD. We will enroll 80 participants, between 60‐90 years old, who have been diagnosed with AD (by most recent criteria from McKhann et al., 2011), and are experiencing severe agitation in AD (Agit‐AD) as defined by the IPA, 2015. The participants will be inpatients at two sites (Johns Hopkins Bayview Medical Center or McLean Hospital) for the study's duration. Agitation will be assessed weekly using the PAS and NPI‐C as our primary outcome measures. Results: Both sites are planning to enroll participants in February 2017. Compared to placebo, we anticipate dronabinol treatment will be associated with a greater reduction in symptoms of agitation as measured on the PAS and the agitation and aggression domains of the Neuropsychiatric Inventory‐Clinician Version (NPI‐C). We also believe Dronabinol treatment will be well tolerated with no more than mild adverse events (AEs). Conclusions: THC in the form of the generic drug dronabinol has the potential to treat agitation and aggression in AD. THC‐AD is the first U.S. RCT to assess its efficacy for this treatment target.