Nabilone reduces agitation in Alzheimer’s disease
The synthetic cannabinoid nabilone significantly improves noncognitive symptoms, in particular agitation, in people with moderate-to-severe Alzheimer's disease (AD), suggests a small randomized controlled trial.
While AD is well known for its associated cognitive symptoms, it is the noncognitive symptoms such as agitation, anxiety, depression, and insomnia that often cause the greatest challenges to caregivers. If left untreated, these symptoms can lead to functional decline and negatively impact quality of life.
“These underrecognized and undertreated symptoms in people with Alzheimer’s and other dementias are often very difficult to live with and challenging to treat,” said Dr Maria Carrillo, Alzheimer’s Association Chief Science Officer.
“Currently prescribed treatments for agitation in Alzheimer’s do not work in everybody, and when they do work the effect is small and they increase risk of harmful side effects, including increased risk of death. As a result, there is an urgent need for safer medication options,” said lead author Professor Krista Lanctôt from Sunnybrook Research Institute in Toronto, Canada.
Currently, no drugs have been approved for treating noncognitive symptoms of AD. Antipsychotics that are being used “off-label” have been associated with increased risk of death.
Nabilone is approved by the US FDA for treating nausea and vomiting associated with chemotherapy.
Reduced agitation, behavioural change with nabilone
In the double-blind, cross-over trial, 39 patients (mean age 87 years, 77 percent male) with moderate-to-severe AD (sMMSE* ≤24) were randomized to nabilone 1–2 mg or placebo for 6 weeks, before crossing over to the other treatment group, with a washout period of 1 week between treatments. [AAIC 2018, abstract F4-02-04]
Nabilone significantly reduced the primary outcome of agitation by four points on the CMAI** compared with placebo (p=0.003). The agitation/aggression subscore on Neuropsychiatric Inventory (NPI) was also lower by 1.5 points while the patients were receiving nabilone than when they were on placebo (p=0.001).
Furthermore, the overall behavioural symptoms were significantly improved during treatment with nabilone vs placebo, as indicated by a 4.6-point difference in the NPI-nursing home version (NH) total score (p=0.004). Caregivers also reported less distress when the patients were taking nabilone, scoring 1.7 points lower on the NPI-NH total caregiver distress scores during the nabilone phase compared with the placebo phase (p=0.041).
On the Clinician's Global Impression of Change scale, 47 percent of patients experienced improvement while taking nabilone compared with 23 percent when taking placebo.
More patients experienced sedation during the nabilone phase than the placebo phase (45 percent vs 16 percent), although this was not treatment limiting, according to the researchers.
“These findings suggest that nabilone may be an effective treatment for agitation; however, the risk of sedation must be carefully monitored,” said Lanctôt. “We would ask [caregivers] to report any increase in sedation to their primary care physician. Our goal was improved agitation without sedation, which we were able to achieve in most patients with dose adjustment.”
In the population as a whole, there was a slight improvement in cognition in favour of nabilone, “which is great because other medications used for agitation decrease cognition,” according to Lanctôt. However, a small number of patients showed worsening cognition during nabilone, she pointed out, saying some questions remained unanswered regarding the cognitive effects of nabilone, which warrants further studies.
“A larger clinical trial would allow us to confirm our findings regarding how effective and safe nabilone is in the treatment of agitation for Alzheimer’s,” said Lanctôt, calling for studies involving a longer duration, more study sites, and other medications in the same drug class, as well as studies to explore biomarkers predictive of a positive response to help in patient selection.
“It is very important that as we continue to make advances in treating and preventing the memory and thinking symptoms of Alzheimer’s and other dementias, we also focus on therapeutic strategies for the behavioural and other noncognitive symptoms,” Carrillo urged.
The Alzheimer’s Association also encourages non-pharmacologic strategies, for eg, psychosocial interventions, as first-line alternatives to drug-based approach to manage noncognitive symptoms of dementia. Psychosocial strategies include reminiscence, validation therapy, and other personalized interventions.