Trial of Dronabinol Adjunctive Treatment of Agitation in Alzheimer's Disease (AD) (THC-AD)

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging, affecting
an estimated 5.2 million Americans and predicted to increase to 13.8 million by 2050. AD
affects both cognition and emotion. Neuropsychiatric symptoms (NPS) in AD are a major cause
of burden to patients, caregivers, and society and are near-universal at some point in the AD
course with > 97% of AD patients having at least one symptom reported on the Neuropsychiatric
Inventory (NPI).

One of the most troubling of these symptoms is agitation (Agit-AD), typified by a variety of
problem behaviors including combativeness, yelling, pacing, lack of cooperation with care,
insomnia, and restlessness. In community-based samples, Agit-AD is common. Agit-AD is
associated with greater caregiver burden and shorter time to institutionalization, and there
is a particularly acute need for interventions for severe Agit-AD in advanced dementia.

While there are currently no FDA approved medications for Agit-AD, psychotropic medications
are widely prescribed "off-label" to treat Agit-AD. The most commonly used classes of
medications prescribed for "off-label" treatment are antipsychotics and antidepressants. The
evidence to date for efficacy remains mixed. Antipsychotics appear to have some degree of
efficacy, but the effects are not highly replicable and their use is associated with
increased mortality in elderly patients with dementia. Antidepressants (particularly
selective serotonin reuptake inhibitors,( SSRI)s) appear to have fewer and less severe
adverse effects compared to antipsychotics, as well as no known mortality risks, but are not
without limitation. Therefore, exploration of alternative treatments for Agit-AD,
particularly severe cases, is timely and warranted.

Dronabinol (Marinol®) is FDA-approved for the treatment of anorexia/weight loss in AIDS and
for nausea/emesis associated with chemotherapy, which is now being used off-label for
Agit-AD. Dronabinol is a synthetic oral formulation of delta-9-tetrahydrocannabinol (THC), a
psychoactive constituent of the cannabis plant that acts as a partial agonist at the Type 1
(CB1) and Type 2 (CB2) endocannabinoid receptors. This pharmacology is appropriate for
targeting Agit-AD because CB1 receptor agonism can produce anxiolytic and antidepressant
effects and CB2 receptor agonism can be anti-inflammatory.

The mechanism by which dronabinol exerts its effects on agitation and aggression in patients
with dementia may occur through its action at the CB1 and/or the CB2 receptor. Agonists at
the CB1 receptor in the brain improve anxiety and depression in humans as well as animal
models. Dronabinol is an effective agonist at the CB1 receptor, which is generally specific
to neurons and localized predominantly on the presynaptic terminal where it inhibits
glutamatergic, dopaminergic and other neurotransmitter release. The CB1 receptor effects has
been observed to mediate the observed anxiolytic and antidepressant effects of THC.
Dronabinol is also an agonist at CB2, a potent anti-inflammatory receptor localized on
activated microglia. Patients with AD have increased central and peripheral inflammation,
likely as a result of the accumulation of beta-amyloid. Increased inflammation may have a
number of behavioral effects that could drive the agitation and aggression in dementia
patients. Dronabinol's effects at the CB2 receptor therefore could also produce changes in
behavior in AD patients by reducing inflammation.

Inclusion Criteria:

1. Diagnosis of Dementia due to AD

2. Presence of Agit-AD as defined by the provisional criteria from the International
Psychogeriatric Association (IPA). The definition requires the presence of cognitive
impairment, evidence of emotional distress, one of three observable types of behavior
(excessive motor activity, verbal aggression, physical aggression), requires that the
behavior cause excess disability, and notes that the behaviors cannot be solely
attributable to another disorder such as psychiatric illness, medical illness, or
effects of substance use.

3. Clinically significant severity of agitation defined by NPI-C Agitation or NPI-C
Aggression > 4.

4. Able to give informed consent, or deemed to lack such capacity by clinical team and
legally authorized representative consents.

5. Must be fluent in English and/or Spanish (includes reading, writing, and speech)

6. Must be able to stay at McLean Hospital, Miami Jewish Health, or Johns Hopkins
Hospital for the study duration (3 weeks)

7. Must be 60-90 years old

8. Must begin enrollment in study within one week of being determined eligible

Exclusion Criteria:

1. Serious or unstable medical illness, including cardiovascular, hepatic, renal,
respiratory, endocrine, neurologic or hematologic disease, which might confound
assessment of safety outcomes.

2. Seizure disorder

3. Baseline delirium as determined by Confusion Assessment Method (CAM) and Diagnostic
and Statistical Manual of Mental Disorders (DSM) -5 criteria

4. Current use of lithium

5. Inability to swallow a pill