Understanding Clinical Predictors of Response to Nabilone in Alzheimer Agitation

Krista L. Lanctôt, PhD

(Credit: American Association for Geriatric Psychiatry)

Research has long shown that agitation is a common and challenging neuropsychiatric symptom in Alzheimer disease (AD), often managed with atypical antipsychotics, which carry significant risks, particularly for older patients. Recently, cannabis-based medications have emerged as a potential alternative for managing agitation and associated comorbidities, with mechanisms believed to include neurotransmitter modulation and reduction of neuroinflammation.¹ For instance, a recent randomized, placebo-controlled crossover trial demonstrated that nabilone, a synthetic cannabinoid, significantly reduced agitation in patients with AD.²

More recently, data presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain, provided new insights on the use of nabilone for agitation in AD. The findings indicated that patients who had symptoms such as pain, irritability, depression, and appetite changes, along with less cognitive impairment and no use of cholinesterase inhibitors, were more likely to respond positively to nabilone compared to placebo. These results aligned with previous studies on cannabinoids and, if further validated, could offer clinicians clinical predictors to guide the use of nabilone as a treatment option for agitation in AD.³

At CTAD 2024, Krista L. Lanctôt, PhD, professor of psychiatry and pharmacology at the University of Toronto and senior author of the study, discussed the clinical predictors identified for nabilone response in AD. In her interview with NeurologyLive^®, she explored the role of cognitive status and symptoms such as pain and irritability in modulating treatment response to cannabinoid therapies. Additionally, Lanctôt highlighted the observed interaction between cholinesterase inhibitor use and nabilone’s effectiveness, suggesting potential implications for clinical guidelines on cannabinoid use in patients with AD.

NeurologyLive: What were key findings of the post hoc analysis on nabilone for treating agitation in AD dementia?

The presentation I gave was a post hoc analysis of a study we recently published. That study examined cannabinoids for treating agitation in patients with AD dementia. Specifically, we used the cannabinoid nabilone, a synthetic derivative of THC. It was a proof-of-concept trial designed as a crossover study. Each patient received nabilone or a placebo in a randomized order, with a one-week placebo run-in or washout period in between.

In that study, we observed a significant decrease in agitation, measured using the Cohen-Mansfield Agitation Inventory at six weeks, which marked the end of treatment. There was a 10-point difference favoring nabilone for each phase. However, when we looked at a secondary outcome—clinical global impression of change—we found that 47% of participants on nabilone showed a clinically significant improvement, compared to 23% on placebo. This raised the question: who were the people that responded? This post hoc analysis aimed to explore that.

What clinical predictors influenced participants' response to nabilone in this study?

We specifically wanted to examine clinical predictors because these are tools clinicians can use to make predictions. We analyzed demographics, behavioral changes, and several potential clinical predictors that were selected a priori. From this, we identified six significant clinical predictors.

The first was the MMSE score, which reflects cognitive impairment. All participants had moderate to severe cognitive impairment, but those with less impairment were more likely to respond to nabilone compared to placebo.

The next four predictors were associated with concomitant symptoms. These included pain, irritability, appetite changes, and depressive changes. These symptoms were observed in varying degrees among participants, but if someone exhibited any of them, they were more likely to respond to nabilone than placebo. This aligns with what we know about these medications in non-Alzheimer populations, as these symptoms are commonly associated with cannabinoid use.

The sixth predictor surprised us. Participants who were not on cholinesterase inhibitors were more likely to respond to nabilone. This could be related to overlapping mechanisms of action, but it’s something we’ll need to explore further.

Overall, 47% of participants responded to nabilone across the study population. The more predictors a participant had, the higher their likelihood of responding. For example, among those with multiple predictors, 88% responded, compared to less than a third of participants with fewer predictors.

What are the next steps in research on the safety and efficacy of nabilone in this patient population?

This study was made possible through the generous funding of the Alzheimer’s Drug Discovery Foundation (ADDF) and the Alzheimer Society of Canada. I’d like to thank them, our participants, and the collaborators mentioned in the paper, as well as my graduate student, Ori Feldman, who conducted the analysis.

I also want to emphasize that, particularly across Canada and the U.S., the elderly population is one of the fastest-growing groups using medical marijuana and related medications. It’s critical to have robust information on their safety and efficacy from randomized, placebo-controlled trials. These findings help determine whether such medications should be used, who they should be used for, and who they shouldn’t.

We’re currently running another larger randomized, placebo-controlled trial with cannabidiol, funded by the Western Brain Institute, as well as a larger trial with nabilone, funded by the ADDF. Hopefully, these studies will shed more light on these important questions.

Transcript edited for clarity. Click here for more coverage of CTAD 2024.

REFERENCES
1. Outen JD, Burhanullah MH, Vandrey R, et al. Cannabinoids for Agitation in Alzheimer's Disease. Am J Geriatr Psychiatry. 2021;29(12):1253-1263. doi:10.1016/j.jagp.2021.01.015
2. Herrmann N, Ruthirakuhan M, Gallagher D, et al. Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease. Am J Geriatr Psychiatry. 2019;27(11):1161-1173. doi:10.1016/j.jagp.2019.05.002
3. Feldman OJ, Ruthirakuhan M, Herrmann N, et al. Heterogeneity of treatment response: A post hoc analysis of clinical factors from a randomized placebo-controlled trial of nabilone for agitation in Alzheimer’s disease. Presented at: 2024 CTAD; October 29-November 1; Madrid, Spain. LBS4. Presentation 1.