Background

Nabilone is a synthetic compound sold by Bausch Health, formerly Valeant Pharmaceuticals. Nabilone is related to delta-9-tetrahydrocannabinol, aka THC, the major psychoactive compound of cannabis. It is a partial agonist of CB1 and CB2 cannabinoid receptors found in the brain and in peripheral tissues. It is currently being tested to treat agitation in people with advanced AD dementia.

Nabilone crosses the blood-brain barrier, and has central actions similar to THC's. In trials, the most frequent side effects were drowsiness, dizziness, dry mouth, and euphoria. This drug has a high abuse potential. It causes mood and memory changes, and even psychosis, in some people (e.g. Udow et al., 2018). In a meta-analysis of clinical trials, nabilone was generally safe and well-tolerated in people over 50, but raised concerns because of increased alterations in thinking, as well as dizziness and lightheadedness (Velayudhan et al., 2021; Velayudhan et al., 2021; commentary by Fick, 2021).

For nausea associated with chemotherapy, the dose is 1 to 2 mg, taken in capsule form multiple times a day, up to a total of 6 mg. Because of its psychoactive effects and other adverse effects, it is a second-line treatment, used only when people do not respond to other anti-emetics. 

The primary interest in nabilone and other cannabinoids (see dronabinol, cannabidiol) for Alzheimer's disease currently focuses on symptomatic treatment of agitation and aggression. Cannabinoids are mildly sedative and anxiolytic, and may act by reducing neuroinflammation, regulating neurotransmission, and improving sleep and circadian rhythms (reviewed in Outen et al., 2021). These compounds also increase appetite and decrease pain, which may benefit people with dementia.

There is a large body of preclinical research on cannabinoids’ disease-modifying actions, in particular the role of CB2 receptors on microglia. In short, multiple receptor agonists have been shown to protect against Aβ-induced neural toxicity in AD animal models, by inhibiting inflammation, excitotoxity, mitochondrial dysfunction, oxidative stress, and tau hyperphosphorylation, and facilitating Aβ removal (reviewed by Cristino et al., 2020).

Findings

In a published case study, an advanced AD patient with agitation and aggressiveness who had not responded to anti-psychotic or anti-anxiety medications showed rapid and dramatic improvement on nabilone (Passmore, 2008).

In 2015-2019, a pilot Phase 2/3 safety and efficacy study ran at Sunnybrook Health Sciences Center in Toronto. The crossover design trial enrolled 38 patients with moderate to severe AD and agitation, who were in a nursing home or outpatients at a geriatric psychiatric facility. Participants received 1 to 2 mg daily nabilone or placebo sequentially for six weeks, and were assessed for agitation and other behaviors, adverse events, cogntition, overall clinical status, pain, nutritional status, caregiver distress, and blood-based biomarkers. The protocol and results are published (Ruthirakuhan et al., 2019; Herrmann et al., 2019; and commentary by Rosenberg et al., 2019). Nabilone moderately improved the primary outcome of the Cohen-Mansfield Agitation Inventory by four points, compared to placebo. Scores on the Neuropsychiatric Inventory, caregiver distress, and MMSE improved, but the Severe Impairment Battery worsened on drug. Treatment improved nutrition, with no change in weight or pain. Nearly half of people experienced sedation on nabilone, compared to a quarter of those on placebo, but in most sedation lessened when the dose was lowered, while agitation still improved. Falls and serious adverse events were similar in nabilone and placebo phases. Data on biomarkers related to oxidative stress and inflammation in this trial were separately published, and showed that proinflammatory cytokine TNFα levels correlated with agitation severity at baseline, and with treatment (Ruthirakuhan et al., 2020). A blood biomarker reflecting elevated brain cholesterol, serum 24-S-hydroxycholesterol, was associated with agitation severity, but did not change with nabilone treatment (Ruthirakuhan et al., 2019).

A meta-analysis including this trial and five others using dronabinol or natural THC found no overall benefit on agitation or aggression, but suggested a greater signal for a potential benefit in synthetic cannabinoids than natural THC (Ruthirakuhan et al., 2019). All forms caused sedation. A Cochrane review of four trials of nabilone, dronabinol, or THC in people with AD found insufficient evidence for benefits on cognition or behavior (Bosnjak Kuharic et al., 2021).

In February 2021, the Ontario investigators began a Phase 3 trial. Called NAB-IT, the study plans to enroll 112 people with a clinical diagnosis of AD and agitation. They will take 1-2 mg nabilone or placebo daily for nine weeks, followed by eight weeks of observation. The primary outcome is the Cohen-Mansfield Agitation Inventory, with secondaries including other neuropsychiatric measures, cognition, global clinical change, caregiver distress, and safety. Exploratory measures include pain, nutritional status and blood biomarkers of inflammation and oxidative stress, and 24-S-hydroxycholesterol. The study will run through October 2025 at five locations in Ontario and Alberta, Canada.

Nabilone has been studied in Parkinson’s disease. An early study in seven patients found it could lessen levodopa-induced dyskinesia (Sieradzan et al., 2001). More recently, in a single-center Phase 2 study of 47 people with Parkinson's, doses from 0.25 to 2 mg daily reduced the disease's non-motor symptoms, mainly by reducing anxiety and sleep disturbances (Peball et al., 2020). Most participants tolerated the treatment well, with typical side effects of mild fatigue, dizziness, dry mouth, and sleepiness. No severe adverse events were reported. A six-month open-label extension was completed in January 2020, and results are posted on clinicaltrials.gov.

Nabilone has also been tested for cannabis dependence, fibromyalgia, spasticity due to nerve damage, motor symptoms of Huntington disease, and neuropathic pain conditions. Trials are ongoing for obsessive compulsive disorder, obesity, inflammatory bowel disease, and neuropathic itching due to kidney disease.

For details on nabilone trials, see clinicaltrials.gov.