Commentary on “Cannabinoids for Agitation in Alzheimer’s Disease”

Agitation is a highly prevalent and debilitating neuropsychiatric symptom (NPS) in Alzheimer’s disease (AD). It is emotionally distressing to patients and caregivers alike. Agitation in AD (Agit-AD) is also associated with disability, poor quality of life, rapid institutionalization, accelerated cognitive and functional decline, and premature mortality. Unfortunately, nonpharmacological interventions in severe Agit-AD have limited value. Therefore, pharmacological therapies, including atypical antipsychotics and newer generation antidepressants, are commonly used to treat Agit-AD despite their questionable efficacy and/or life-threatening adverse consequences. With the anticipated worldwide explosion in AD cases, the need to identify safe and efficacious novel therapeutics to treat Agit-AD is becoming increasingly urgent. Equally important is the need to thoroughly understand the mechanisms whereby potential treatments exert their therapeutic efficacy.

Outen and coworkers¹ provide a state-of-the-art review on the scientific advances in understanding the complex mechanisms underlying Agit-AD. The improved ability to precisely measure amyloid and neurofibrillary tangles and structural brain volumes in vivo has led to a better understanding of the temporal relationship of core AD neuropathology and neurodegeneration with Agit-AD. The authors posit that structural and functional disconnections of specific brain networks (e.g., default mode and salience networks) due to AD pathology contribute to the evolution and severity of Agit-AD.² They also eloquently articulate the potential roles of neurochemical (e.g., acetylcholinergic, serotoninergic neurotransmission, etc.), circadian rhythm, and clinical and psychosocial influences in explaining distinct Agit-AD phenotypes. The temporal sequence of these mechanisms as contributors to Agit-AD remains to be clarified; a better understanding of this timing will accelerate the development of novel effective and safer treatments. It is also plausible that newer therapeutics targeting other biological systems may be attractive alternatives in managing Agit-AD. One such treatment class that is gaining traction is cannabinoids that modulate the endocannabinoid signaling (ECS) system.

The ECS system is a neuromodulatory system comprised of the G protein-coupled cannabinoid receptors 1 and 2 (CB1 and CB2), their lipid ligands (the endocannabinoids [eCBs] N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]), and the synthetic and degradative enzymes for the eCBs. Although less studied in humans, there is considerable preclinical evidence demonstrating that the ECS system modulates the multiple pathological processes that occur in AD.^{3, 4} CB1 receptors, the most abundant cannabinoid receptor in the brain, are widely expressed in AD-vulnerable regions and regulate multidomain cognitive and behavioral functions. CB2 receptors located mainly in the cells of the immune system, including the brain’s microglia, regulate cytokine release and modulate neuroinflammation. A varying pattern of CB1 and CB2 receptor expression is reported in different AD stages: the CB1 receptors that are more densely expressed in the medial temporal and frontal lobe regions during earlier disease stages appear reduced in the later stages, whereas CB2 receptor expression is greater in the advanced (neuroinflammatory) stage. Animal studies demonstrate that activation of the brain CB1 and CB2 receptors inhibits glutamate release, facilitates beta-amyloid clearance, mediates tau hyperphosphorylation, reduces oxidative stress-related damage and neuroinflammation, and enhances neurogenesis.³ Thus, cannabinoids, via CB1 and/or CB2 receptor agonism, may confer neuroprotection by reducing AD pathology-related neuronal excitotoxicity and neuroinflammation. Yet other cannabinoids may exert their action through cannabinoid receptor-independent mechanisms such as modulating the endocannabinoid AEA and/or serotonin and other neurotransmitter systems. Regardless, while the therapeutic potential of cannabinoids in preventing and treating cognitive decline in AD remains to be seen, this drug class has shown excellent promise as a treatment for NPS, specifically Agit-AD.

It is against this backdrop that Outen et al.’s timely review on the safety and efficacy of different cannabinoids in Agit-AD is relevant. Three cannabinoids have emerged as potential candidates to treat Agit-AD: two synthetic cannabinoids, dronabinol and nabilone, and a phytocannabinoid combination consisting of low Δ⁹-tetrahydrocannabinol (THC) and high cannabidiol (CBD). In a retrospective chart review of 40 severely demented inpatients with agitation, aggression, or appetite disturbances, the authors of the Outen et al. paper previously reported that dronabinol (a synthetic THC) at ~7 mg daily dose reduced agitation, and improved sleep and appetite.⁵ Similarly, in a 14-week double-blind, placebo-controlled crossover pilot trial, the synthetic THC analog nabilone (a partial CB1 and CB2 receptor agonist) was found to improve agitation in patients with moderate-to-severe AD.⁶ Nabilone may have anti-inflammatory properties as demonstrated by the association between lower pro-inflammatory cytokine levels and decreased agitation.⁷ Both synthetic cannabinoids were well tolerated, but side effects, particularly sedation and possibly cognitive worsening, may occur. Another cannabinoid agent that has shown promise is the oral low THC and high CBD combination, a preparation using varying proportions of the two major constituents of the Cannabis sativa plant. The rationale for the low THC/high CBD combination has scientific merit. While THC, the main psychoactive ingredient of cannabis, is anxiogenic and induces psychosis and worsens cognition at higher doses, it is found to be anxiolytic at lower doses. CBD, on the other hand, blocks the toxic effects of THC while restoring brain AEA levels via inhibition of the fatty acid amide hydrolase enzyme, thus theoretically resulting in clinical benefits. Preliminary evidence for these cannabinoids as Agit-AD therapies is encouraging, but safety and efficacy data from large confirmatory cannabinoid trials are lacking.

The National Institute on Aging (NIA) is paying attention; accordingly, two NIA-funded, clinical trials to evaluate the efficacy and tolerability of cannabinoids in Agit-AD are underway. One is a three-week, double-blind, randomized controlled trial in inpatients with Agit-AD funded in 2016 to evaluate the efficacy and safety of dronabinol (10 mg/day) versus placebo as an adjunct to currently used psychotropic medications. The other is the Life’s end Benefits of CannaBidiol and TetrahYdrocannabinol (LiBBY) trial, a 12-week, randomized, double-blind, placebo-controlled study funded in 2020 to examine the efficacy and tolerability of oral THC/CBD combination (i.e., 8 mg/day THC - 400 mg/day CBD) for the treatment of agitation in hospice care-eligible patients with AD or other dementias. The LiBBY trial is being conducted under the framework of the Alzheimer’s Clinical Trials Consortium, NIA’s next-generation clinical trials infrastructure that utilizes centralized resources and shared expertise, to accelerate the discovery of effective treatments for AD and related disorders.⁸ Results from these landmark trials will soon be available and could aid in establishing practice guidelines for the utility of cannabinoids in managing Agit-AD.

Can cannabinoids improve agitation in preclinical or prodromal dementia syndromes like mild behavioral impairment (MBI)? MBI, a relatively novel concept with operationalized research criteria developed by the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment, is a neurobehavioral syndrome characterized by changes in personality and behavior that can occur in advance of, in concert with, or following the onset of mild cognitive impairment.⁹ Agitation in mid- and late- life, which can be a clinical manifestation of MBI, may be a harbinger of later conversion to dementia. Early evidence suggests that the mechanisms underlying MBI and Agit-AD are similar;¹⁰ interestingly, cannabinoids are theorized to target some of these common biological mechanisms. Informed by data from the ongoing Agit-AD trials, future studies should clarify the biological targets of cannabinoids that improve agitation in pre-dementia syndromes as well.

Although our understanding of the role of cannabinoids in managing agitation in dementia is in its infancy, the current evidence summarized in Outen et al. sheds light on the significant potential of this medication class as a safe and efficacious Agit-AD treatment. This comprehensive review also underscores the importance of further studying not only the neurobiology of Agit-AD but also the biological targets whereby cannabinoids exert their therapeutic efficacy.