Safety and Efficacy of Nabilone in Alzheimer's Disease
Safety and Efficacy of Nabilone in Alzheimer's Disease
Alzheimer's disease (AD) is commonly associated with behavioural changes such as agitation.
 Severe agitation is important to treat because it not only increases progression of AD and
 physical health problems (increased falls and weight loss), but it also decreases quality of
 life and increases caregiver stress. Currently prescribed treatments (i.e., antipsychotics)
 for agitation in AD do not work in everybody and when they do work the effect is small and
 they increase the risk of harmful side effects, including death. As a result, there is an
 urgent need for safer medication options. The cannabinoid nabilone can now be prescribed in
 capsule form for appetite and pain killing effects. Nabilone's calming effects may benefit
 those with agitation, and help the weight loss and untreated pain frequently associated with
 agitation. Through a clinical trial, the investigators hope identify the benefits of nabilone
 in the treatment of agitation in AD.

 The investigators objective is to determine whether nabilone is an efficacious and safe
 treatment for agitation, as well as having benefits for pain, weight and behavioural
 symptoms. This will be a 14 week clinical trial (participants take nabilone for 6 weeks,
 placebo for 6 weeks (order randomized) with 1 week between treatments). The investigators
 will assess and compare agitation, weight, pain, memory, behaviour and safety.

 Nabilone is a new class of medication that may be a safe and effective treatment for
 agitation in AD, with added benefits on appetite and pain. Reducing these symptoms would
 increase quality-of-life and reduce caregiver stress.
Objectives: The investigators objective is to provide pilot data addressing whether the
 ∆9-tetrahydrocannabinol (THC) analogue nabilone is a pharmacological option for managing
 agitation, a particularly difficult to treat neuropsychiatric symptom (NPS), as well as
 having benefits for pain, weight and overall NPS, and gather double-blind information on
 tolerability and safety. This group of symptoms is particularly prevalent in patients with
 moderate to severe AD.

 Rationale: The high prevalence and impact of agitation in patients with moderate to severe
 Alzheimer's disease (AD) makes this neuropsychiatric symptom (NPS) a key determinant of
 decreased quality of life. Associated with agitation are weight loss, and pain, both of which
 lead to additional loss of quality of life. Agitation frequently necessitates use of
 antipsychotics, which, while well-studied, have modest efficacy and severe side effects
 including increased mortality. With the development of synthetic THC analogues, the
 therapeutic potential of cannabinoids can now be evaluated. Cannabinoids can be prescribed as
 capsules to treat anorexia and pain in certain patient groups. In addition to these
 potentially beneficial effects on appetite and pain, a recent study suggested positive
 effects of nabilone on agitation in dementia. Importantly, in addition to psychotropic
 effects, emerging evidence suggests neuroprotective (inhibit Aβ-induced microglial activation
 and excitotoxicity) and anti-inflammatory abilities, which can decrease oxidative stress, in
 stark contrast to the negative effects of antipsychotics. As such, this system is of high
 potential relevance in agitated patients with AD.

 Research Plan: This will be a randomized cross-over study comparing 6 weeks of nabilone and
 placebo, with a 1 week placebo washout preceding each treatment phase in Long-term care (LTC)
 patients, and outpatients with moderate to severe AD and agitation. Study outcomes will be
 measured at baseline and end of treatment for each treatment phase. The primary outcome
 measure will be the Cohen-Mansfield Agitation Inventory (CMAI). The secondary outcomes will
 be the weight (kg), overall NPS (Neuropsychiatric Inventory (NPI)), NPI agitation/aggression
 subscale, nutrition (Mini Nutritional Assessment - Short Form (MNA-SF), body mass index
 (BMI), skin fold thickness), pain (The Pain Assessment In Advanced Dementia (PAINAD)),
 cognition (Mini-Mental State Examination (MMSE); Severe Impairment Battery (SIB)) and
 clinical significance (Alzheimer's Cooperative Study-Clinician Global Impression of change
 (ADCS-CGIC). Safety (heart rate, blood pressure, and adverse events) will also be assessed at
 every visit.
Inclusion Criteria:

 -  Males or females ≥55 years of age

 -  Diagnostic and Statistical Manual (DSM) -V criteria for Major Neurocognitive Disorder
 due to AD. Patients with both Major Neurocognitive Disorder due to AD and Major
 Vascular Neurocognitive Disorder (i.e., mixed AD and cerebrovascular disease) will
 also be included.

 -  Currently in moderate-to-severe stage of dementia (Mini-Mental Status Examination
 (MMSE) ≤24)

 -  Presence of clinically significant agitation (Neuropsychiatric Inventory (NPI)
 agitation subscale ≥3)

 -  If treated with cognitive-enhancing medications (cholinesterase inhibitors and/or
 memantine), dosage must be stable for at least 3 months. If the ChEI and/or memantine
 has been discontinued, they may enroll after 1 month.

 Exclusion Criteria:

 -  Change in psychotropic medications less than 1 month prior to study randomization
 (e.g., concomitant antidepressants)

 -  Contraindications to nabilone (history of hypersensitivity to any cannabinoid)

 -  Current or past significant cardiovascular disease (e.g. uncontrolled hypertension,
 ischemic heart disease, arrhythmia and severe heart failure)

 -  Presence or history of other psychiatric disorders or neurological conditions (e.g.
 psychotic disorders, schizophrenia, stroke, epilepsy), previous or current abuse
 of/dependence on marijuana