Background

Dronabinol is synthetic delta-9-tetrahydrocannabinol, aka THC, the major psychoactive compound of cannabis. It is an agonist of CB1 and CB2 cannabinoid receptors found in the brain and in peripheral tissues. Taken in capsule or liquid form, dronabinol has the same central actions as THC. It was approved by the FDA in 1985 for the treatment of nausea and vomiting associated with cancer chemotherapy, and in 1992 for the treatment of anorexia and weight loss in people with AIDS. The term dronabinol refers to generic versions of Abbvie's brand Marinol.

In trials, the most frequent side effects were euphoria, dizziness, sleepiness, nausea and vomiting, abnormal thinking, paranoia, and abdominal pain. Risks of dronabinol in older people include delirium, sedation, seizures, blood pressure changes, and increased heart rate. It has a low potential for abuse or dependence.

The dose for appetite stimulation is 5 to 10 mg per day, reached after gradual titration and taken as two divided doses. For nausea, the maximum dose is 15 mg, four to six times daily. Older people are started on lower doses to minimize CNS symptoms.

The primary interest in repurposing dronabinol and other cannabinoids (see nabilone, cannabidiol) for Alzheimer's disease currently focuses on the 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 their effects 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

An early dronabinol study evaluated effects of a six-week course on appetite and agitation in 15 patients with severe AD dementia who refused to eat (Volicier et al., 1997). In the crossover trial, 5 mg dronabinol daily was better than placebo at improving body weight and decreasing symptom severity on the Cohen Mansfield Agitation Inventory and other scales. Side effects were euphoria and sleepiness; one patient suffered a grand mal seizure after the first dose of dronabinol.

In a small, open-label pilot study, 2.5 mg dronabinol given in the evening reduced nighttime agitation in six severely demented patients with day/night rhythm disturbances and evening agitation, aka sundowning (Walther et al., 2006).

A review of off-label use of dronabinol in 40 severely demented patients with agitation in a geriatric neuropsychiatric inpatient unit reported that adding it to regular psychiatric medications was associated with improvement on the Pittsburg Agitation Scale, the Clinical Global Impression of Change, sleep duration, and eating after one week (Woodward et al., 2014). The average dose taken was 7 mg/day, for an average of 17 days. The most frequent side effects were sedation and delirium, although neither was clearly related to the drug. No severe adverse events were reported. Thirteen of the 40 participants were diagnosed with AD; the others had vascular or mixed dementia, or FTD, or were unspecified. 

Between 2011 and 2014, an alternative formulation of delta-9-THC was tested. Namisol (Echo Pharmaceuticals) is a proprietary tablet designed to give quicker onset of action. Initial work in the Netherlands found its pharmacokinetics varied between people, but side effects were negligible after doses of 1.5 or 3 mg per day in older people with dementia (Ahmed et al., 2015). A subsequent Phase 2, placebo-controlled pilot trial  found no effect of three days of these doses on daily on neuropsychiatric symptoms in 22 people with severe dementia, mainly due to Alzheimer’s. No adverse events were reported. Five patients completed an optional six-month open-label extension; the low doses of THC appeared safe but did not improve behavioral symptoms (van den Elsen et al., 2015; van den Elsen et al., 2017). In 2012-2014, the same group conducted a second study with a higher dose. Fifty participants with AD or vascular dementia and moderate agitation/aggression or motor disturbances took 4.5 mg Namisol daily, divided in three doses, or placebo, for three weeks. The primary outcome of Neuropsychiatric Inventory scores after two or three weeks showed reduced symptoms in both groups, with no difference between placebo and Namisol. Side effects were similar between drug and placebo (Van den Elsen et al., 2015). A systematic review of these trials of THC, plus studies of dronabinol, and nabilone, found insufficient evidence for benefits on cognition or behavior (Bosnjak Kuharic et al., 2021).

In March 2017, a Phase 2 pilot trial began testing three weeks of 10 mg daily dronabinol added to usual medications in 160 AD patients with severe agitation. Treatment starts at 5 mg daily for one week, then increases to 10 mg for two weeks. Participants take half at 8 am and 2 pm, to maximize daytime coverage and minimize sundowning. The coprimary outcomes are scores on the Pittsburgh agitation scale and NPI-Clinician agitation and aggression subscales, with a secondary of the Cohen-Mansfield Agitation Inventory. The study will also assess function, cognition, sleep and safety. Of the first 44 participants, three quarters are women, most are white and in good health (Cohen et al., 2021). The trial is running at three U.S. hospitals until May 2023. The trial uses Abbvie's brand Marinol but is sponsored by Johns Hopkins University; Abbvie does not list Marinol in its development pipeline for this indication.

In December 2021, a Phase 2 study started in Israel to test a combination of dronabinol plus the endogenous cannabinoid palmitoylethanolamide (PEA) in 20 people with AD and agitation severe enough to require medication. The single center, open label study begins with a two to three-week titration of dronabinol from 2.5 mg to 12.5 mg daily, or the highest tolerated dose, plus 800 mg PEA, then 10 days at that dose. Dosing is twice daily, added on to existing medications. The primary outcomes are dropouts and adverse events. The study will finish in June 2023.

Dronabinol has also been tested in Huntington's disease.

For details on these trials, see clinicaltrials.gov.