Cannabinoids for Agitation in Alzheimer’s Disease

Abstract

Agitation is a common neuropsychiatric symptom of Alzheimer’s disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacological options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to pre-clinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

Article Summary

This review examines the neurobiological mechanisms that contribute to agitation in Alzheimer’s disease, including brain atrophy, degradation of neurotransmission, disrupted circadian rhythms, and frailty. A synthesis of preclinical and early clinical research suggests that cannabinoids could provide therapeutic benefit by reducing neuroinflammation, regulating neurotransmitters, and improving comorbidities and circadian rhythms. However, cannabinoids pose an increased risk of seizures, sedation, and possible drug interactions, thus confirming the need for further investigation in this population.

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease of aging, accounting for an estimated 70% of all cases [1]. In the United States, nearly 6 million individuals have AD, resulting in an annual direct cost of $290 billion and 18.5 billion informal care hours [2]. The two canonical molecular hallmarks of AD are beta-amyloid (Aβ) and hyperphosphorylated tau protein, which begin to accumulate while brain structure, brain volume, and cognitive performance decline as early as 20 to 30 years prior to the onset of symptoms [3]. Extracellular accumulations of insoluble, aggregated Aβ create senile plaques, initiating a neurodegenerative cascade that increases oxidative stress and inflammation, resulting in neural cell death [4]. Tau, an intracellular microtubule-associated protein, becomes misfolded and hyperphosphorylated, thereby clumping together and forming neurofibrillary tangles (NFTs). NFTs prevent the formation of functional microtubules, which disrupts axonal nutrient transport and causes neural senescence [5]. Current FDA-approved treatments for AD include: three cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), which can delay cognitive decline in the early to moderate stages by increasing available acetylcholine; and two glutamate receptor antagonists (memantine and memantine + donepezil), which can assist cognition and behavioral symptoms in the moderate to late stages by regulating glutamate hyperactivity that is associated with AD [6]. These treatments have only modest symptomatic efficacy, no effect on disease progression, and are frequently associated with adverse effects, such as headache, nausea, loss of appetite, and, more seriously, bradycardia, falls and fractures [7, 8].

Agitation in Alzheimer’s Disease: Current Evidence

In addition to cognitive decline, neuropsychiatric symptoms (NPS) are considered a hallmark of the disease and impact over 97% of individuals with AD [9]. Common NPS include anxiety, apathy, depression, and psychosis. Agitation is observed in more than 40% of AD patients and greatly contributes to patient distress, caregiver burden, and patient institutionalization [10]. While the overall number of NPS has been reported to increase with AD progression, agitation is of specific concern as it becomes more prevalent over time, especially in males, whereas females show higher rates of depression [11]. Furthermore, a study from the United Kingdom found that AD patients with agitation required on average an additional $6,000 of care annually compared to their non-agitated AD peers, representing 12% of total health care costs for AD [12].

Clinical Characteristics

Agitation is easily recognizable when aggression is simultaneously present (screaming, hitting, kicking), but can also be expressed without aggression in subtle behaviors such as pacing or hand-wringing [13]. While it is a common clinical presentation in similar diseases such as dementia with Lewy bodies, frontotemporal dementia, bipolar illness, and schizophrenia, agitation in cognitive disorders did not receive a consensus definition until 2015. The International Psychogeriatric Association characterized it as excessive motor activity (pacing, restlessness), verbal aggression (screaming, shouting), or physical aggression (hitting, kicking, biting) that is recurrent, causes excess disability over and above the patient’s cognitive impairment, is atypical for the patient’s personality and behavior, and is not attributable to other comorbidities [13].

Potential Mechanisms: Neuronal Dysfunction

Part of the difficulty in developing treatments for agitation in AD (Agit-AD) is due to a limited understanding of underlying brain mechanisms. Neuronal dysfunction and damage due to AD may lead to disruptions in specific brain structures and networks. Neuroimaging studies suggest that Agit-AD is associated with atrophy in the frontal cortex, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), insula, amygdala, and hippocampus [14]. Bilateral ACC and left insula volume loss are associated with agitation [15], while disinhibition is associated with volume loss in bilateral ACC and right middle frontal gyri [16]. Right hemisphere posterior atrophy and temporal white matter hyperintensities are also associated with Agit-AD [17]. Another study reported an inverse relation between increased irritability and decreased white matter integrity through diffusion tensor imaging [18]. One brain network that may be impacted is the salience network (SN), which plays a role in emotional thoughts, social behavior, and self-awareness. Functional magnetic resonance imaging (fMRI) revealed increased connectivity in areas of the SN (ACC and right insula) with hyperactivity in AD patients [19], an association that may be compensatory in nature. Likewise, atrophy of frontolimbic regions, thought to be key players in the SN, were associated with increased agitation, as were the right PCC and left hippocampus [20]. In addition, NFT burden in the left orbitofrontal cortex and the left ACC was significantly related to agitation [21]. Single photon-emission computed tomography studies revealed that aggression and agitation were associated with decreased perfusion in the right medial temporal lobe (hippocampus, parahippocampus, and posterior amygdala [22]) and in the left anterior temporal, bilateral dorsolateral prefrontal, and right superior parietal cortices [23].

Potential Mechanisms: Neurotransmission and Genetics

Another hypothesis of the neurobiological mechanisms of Agit-AD includes disruptions to cholinergic and serotonergic pathways, which play a role not only in cognitive deterioration and AD progression [24], but also specifically in increased expression of agitation, such as the 102T polymorphism of the 5-HT2A receptor involved with serotonin neurotransmission [25]. A homozygous polymorphism (*L/*L genotype) of the serotonin transporter promoter region (5-HTTPR) was also found to be associated with increased aggression in AD (Aggre-AD) [26], as was a B2/B2 polymorphism of DRD1, a dopamine receptor gene [27]. Genetic variability certainly warrants further investigation, as six hippocampal genes have recently been associated with Aggre-AD, including the androgen receptor (AR), brain-derived neurotrophic factor (BDNF), catechol-O-methyl transferase (COMT), neuronal specific nitric oxide synthase (NOS1), dopamine beta-hydroxylase (DBH), and tryptophan hydroxylase (TPH1/TPH2) [28].

Potential Mechanisms: Circadian Rhythm Disturbance

Agit-AD may also be caused by disturbances in circadian rhythms. Biological clocks receive input from the environment, mainly sunlight, or innate timing mechanisms to regulate cycles of physiological changes and behavior. Circadian rhythms control patterns such as mood, wakefulness, and alertness, but may become disrupted with age [29]. Many AD patients become more agitated and confused in the evening (“sundowning”), and it is plausible that poor sleep and network dysfunction in AD are likely contributors [30, 31]. In relation to timing, severe cases may be expressed constantly (calling out, wandering behaviors) with little relief for caregivers, but agitation is more often observed in short bursts of activity. Therefore, it is important to remove triggers that can instigate heated episodes, and identify AD patients who are at an increased risk of combative and disruptive behaviors. Circadian phase misalignment in combination with Agit-AD greatly affects caregiver burden, often leading to exhaustion from inability to maintain adequate rest.

Potential Mechanisms: Clinical and Psychosocial Influences

Another potential source of agitation is frailty and burdensome comorbidities. Biological factors such as pain, infection, and medication effects, as well as psychological factors, including caregiver characteristics, communication issues, socio-economic status, patient environment, and family conflict, can all contribute toward agitation, complicating the clinician’s ability to discern origins of behavioral issues and to effectively relieve agitation [32]. Delirium is a common presentation among dementia patients and is greatly associated with agitation and aggression [33, 34]. Increased interleukin-1β and decreased natural killer cell activity suggest that inflammation may be a driving mechanism for Agit-AD [35]. In addition, it is possible that NPS may develop simultaneously with AD due to other health problems, such as vascular disease, or as a psychological response to realization about cognitive decline [36].

Potential Mechanisms: Summary

Altogether, NPS manifestation is presumably multifactorial and interrelated. Agitation and aggression are likely most evident in AD individuals with the ‘perfect storm’ of brain burden, neurotransmitter dysfunction, and troublesome comorbidities (Fig 1.). It is plausible that different expressions (phenotypes) of agitation and aggression have different underlying responsible mechanisms. For example, multiple origins of aggression have been identified, including defensive (fear-induced), predatory, dominance, inter-male, resident-intruder, maternal, sex-related, territorial, isolation-induced and irritability-associated aggression [28]. It is important to determine if Agit-AD shares common themes with agitation in other cognitive disorders, or if it represents a unique syndrome among the wide spectrum of AD clinical presentations. Further elucidation of possible combinations of underlying neurobiological mechanisms will greatly benefit the progress of treatment development.

Figure 1. Therapeutic Impact of Cannabinoids on Factors of Agitation in AD.

A schematic representing the factors (left) which contribute to agitation in Alzheimer’s disease [Agit-AD], and the indirect positive outcomes of cannabinoids on Agit-AD (right).

Treatment

Non-pharmacologic strategies for mild Agit-AD, such as environmental changes, group activities, recreational enjoyment (music, art therapy), exercise and physical therapy, and caregiver education are safe, first-line strategies to reduce acute distress, especially for AD of milder severity [37]. Common pharmacologic treatments for more severe agitation not responsive to non-pharmacologic strategies include antidepressants, antipsychotics, anxiolytics, and mood stabilizers. However, none of these medications are approved by the FDA for treating Agit-AD and their off-label use is controversial due to poor efficacy and high risk for adverse events, particularly mortality with antipsychotics, which has led to a “black-box” warning for these products in the U.S. [38]. Thus, more effective and safer treatments for Agit-AD are needed.

Introduction to the Endocannabinoid System

Given the lack of appropriate and effective treatments for NPS in AD, there has been increasing interest in utilizing cannabinoids as an alternative treatment option. Cannabinoids are a class of chemical entities that modulate endogenous cannabinoid receptors. G-protein coupled cannabinoid receptors 1 and 2 (CB₁ and CB₂) are the primary structural components of the endocannabinoid system (ECS). CB₁ receptors are abundant in the spinal cord, peripheral nervous system, and brain tissue (hippocampus, basal ganglia, cerebellum, amygdala, frontal cortex, hypothalamus, and nucleus accumbens), while CB₂ receptors are also found in the CNS, but predominately reside in peripheral immune cells, and are highly concentrated in the GI tract [39]. Cannabinoid receptor ligands (Table 1) can be classified as 1) endocannabinoids (eCBs) that are endogenous and naturally produced in the body, such as N-arachidonoylethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG), 2) phytocannabinoids that are found in Cannabis sativa [Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD)], and 3) synthetic cannabinoids, including pharmaceutical drug products nabilone and dronabinol (note, dronabinol is a synthetic formulation of THC, which is also a phytocannabinoid) [39].

Table 1.

Cannabinoids Mentioned in this Review

Classification	Name	Receptor Specificity
Endogenous Cannabinoids	N-arachidonoylethanolamine (anandamide or AEA)	CB1 >> CB2 agonist
	2-Arachidonoyl glycerol (2-AG)	CB1 and CB2 agonist
Phytocannabinoids	Δ9-Tetrahydrocannabinol (THC)	CB1 and CB2 agonist
	Medical Canabis Oil (contains THC) (MCO)	CB1 and CB2 agonist
	Cannabidiol (CBD)	No CB1 & CB2 activity Inhibition of AEA
	High CBD/Low THC Solution	Limited CB1 & CB2 agonist
Synthetic Cannabinoids	Dronabinol	CB1 and CB2 agonist
	Nabilone	CB1 and CB2 agonist
	JWH-015	CB2 selective agonist

A list of discussed cannabinoids, their classification, and their cannabinoid receptor specificity. Modified from the table reported by [61]. (CB₁ = cannabinoid receptor 1. CB₂ = cannbinoid receptor 2).

A brief discussion of the cannabinoids relevant for Agit-AD is outlined here (preliminary clinical results are shown in Table 2). THC is the primary psychoactive constituent in cannabis; it is most often inhaled (smoked or vaporized cannabis) or orally consumed through edible products. THC is lipophilic and is stored in adipose tissue well after initial metabolism. CBD is another main constituent of over 100 compounds and terpenes in cannabis; likewise, it is most often inhaled, consumed in edibles, or immersed in oil. CBD has low abuse liability, usually does not cause impairment or intoxication, and acute drug effects that are experienced after CBD use are distinct and different from those common to THC. CBD likely alters the effects of THC when they are metabolized simultaneously, such as in cannabis or medical cannabis oil. CBD is FDA-approved for treating seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Nabiximols is an oromucosal spray containing THC and CBD; it is approved in Canada for spasticity in multiple sclerosis. There are also several other combination products containing THC and CBD that are under investigation. Dronabinol is a synthetic formulation of THC that is consumed in capsule or liquid form. Dronabinol is FDA-approved for 1) anorexia and weight loss in AIDS and 2) nausea and vomiting due to chemotherapy. Nabilone (a similar synthetic THC analog) is also an FDA-approved drug for nausea and vomiting due to chemotherapy and is consumed in capsules. JWH-15 is a synthetic cannabinoid analog with limited clinical data that has also been used in illicit synthetic preparations, such as K2/Spice.

Table 2.

Recent Clinical Evaluations of Cannabinoids in AD

Authors	Cannabinoids	Indications	Primary Findings
Walther et al. (2006) [62] open-label	Dronabinol	Nocturnal Agitation	Reduced nocturnal motor activity. Improved agitation. No side effects.
Passmore et al. (2008) [63] case report	Nabilone	Agit-AD	Improved agitation. Less resistance to care. No side effects.
Krishnan et al. (2009) [64] systematic review	Dronabinol	NPS-AD Dementia Anorexia-AD	Lack of quantitative data. Small sample size. Insufficient conclusion.
Amanullah et al. (2013) [65] case reports (2)	Nabilone	Agit-AD	Improved psychomotor agitation. Improved aggression. Improved communication.
van den Elsen et al. (2014) [52] systematic review	THC THC + CBD	Dyskinesia Breathlessness Chemotherapy-Nausea NPS-Dementia	Possible improvement in NPS-dementia and anorexia. Sedation most common AE.
Shelef et al. (2016) [66] open-label	MCO	NPS-AD	Improved agitation, aggression, irritability, apathy, delusions, sleep & nocturnal activities, and caregiver distress.
Weier et al. (2017) [53] systematic review	Dronabinol	NPS-AD	Well tolerated. No improvements in NPS.
Lim et al. (2017) [67] systematic review	Dronabinol	Psychiatric, Movement, Neurodegenerative Disorders	Reduced agitation in AD. Strengthened circadian rhythms.
Tampi et al. (2018) [68] systematic review	Dronabinol Nabilone THC	NPS-Dementia	Improved symptoms in 7/8 studies (agitation, aggression, impulsivity, nocturnal restlessness, wandering, poor sleep). Tolerable AEs.
Ruthirakuhan et al. (2019) [69] systematic review	Synthetics THC	Agit-AD	No change in NPS or BMI. Trend for agitation improvement with synthetics over THC.
Bahji et al. (2019) [54] systematic review	Dronabinol Nabilone THC	NPS-Dementia	Improved NPS, including agitation and nocturnal movement. Well tolerated.
Hillen et al. (2019) [55] systematic review	Dronabinol Nabilone THC	NPS-Dementia	Improved NPS. Mild AEs. Sedation most common.
Hoch et al. (2019) [70] systematic review	CBD Dronabinol THC	Mental Disorders	Reduction in weight and negative affect in 1 out of 3 trials. Mild AEs.
Peprah et al. (2019) [71] systematic review	Dronabinol MCO Nabilone THC	NPS-Dementia	Limited evidence of efficacy for agitation, disinhibition, irritability, aberrant motor behavior, nocturnal behaviors, aberrant vocalization, and resisting care.
Broers et al. (2019) [72] open-label	THC + CBD	NPS-Dementia	NPS decreased. Psychotropic medications reduced. Easier patient care. Well tolerated.
Charernboon et al. (2020) [73] systematic review	Dronabinol THC Nabilone	NPS-Dementia	Nabilone may improve agitation. Insufficient evidence for THC.
Paunescu et al. (2020) [74] systematic review	Dronabinol Nabilone	NPS-AD	No clear conclusions for agitation and aggression in AD.
Defrancesco et al. (2020) [75] case report	Dronabinol	NPS-AD	Reduction in psychotropics. Improvement in emotional state, disruptive behavior, aggression, and agitation. No AEs.

Recent clinical reviews of various cannabinoids, their indications, and primary findings (AD = Alzheimer’s disease. Agit-AD = agitation in Alzheimer’s disease. NPS = neuropsychiatric symptoms. AEs = adverse events. THC = Δ⁹-tetrahydrocannabinol. CBD = cannabidiol. MCO = medical cannabis oil).

Role of the Endocannabinoid System in Alzheimer’s Disease: Current Evidence

Substantial preclinical data suggest that the ECS plays an important neuromodulatory role in AD pathology. CB₁ activation hyperpolarizes neural membranes, thereby regulating signal transduction pathways and modulating neurotransmitter and cytokine release [40]. One study [41] reported CB₁ upregulation in early AD, which may be a compensatory neuroprotective and anti-inflammatory response to excitotoxicity. CB₁ density inversely correlated with Braak tau pathology, indicating that neurons expressing CB₁ degenerated with increasing brain burden in advanced dementia. This finding was observed in the prefrontal cortex, an area where CB₁ receptors are highly localized and with well-studied relevance to AD progression [41]. CB₁ neurons are also greatly reduced in inflammatory areas of Aβ-induced microglial activation [42]. Additionally, CB₁ protein nitration is enhanced in AD, possibly contributing to receptor impairment and decreased downstream signaling [42]. Together, these findings suggest that CB₁ agonism may promote neural survival during dementia excitotoxicity and could be a therapeutic target for Agit-AD.

Another potential target is fatty acid amide hydrolase (FAAH, an enzyme that breaks down AEA and is a key regulator of the ECS). FAAH was overexpressed in astrocytes near Aβ plaques in entorhinal and parahippocampal regions of AD brain samples, and may contribute to neuroinflammation by increased degradation of AEA into arachidonic acid [43]. Furthermore, microglial cells found in the same plaques showed upregulation of the CB₂ receptor [43]. Similar reports found that CB₂ levels were 40% higher in the frontal cortex of AD samples as compared to controls and were positively correlated with a 40% increase in Aβ₄₂ levels, a 3 fold increase in senile plaque scores, and a 2.5 fold increase in glial cells as measured by glial fibrillar acidic protein [44]. A CB₂ agonist (JWH-015) removed Aβ deposits in vitro by as much as 64%, proposing the idea that CB₂ levels may increase in response to increased Aβ burden, and agonism at the CB₂ receptor may trigger increased Aβ removal by macrophages [45].

Therapeutic Impact of Cannabinoids on Agitation in AD

While it is unlikely that cannabinoids influence genetic risk factors for Agit-AD, cannabinoids may improve NPS by directly regulating neurotransmitters. One study [46] reports that CBD and THC may increase serotonergic signaling by increasing available tryptophan, an essential amino acid that serves as a precursor for serotonin and other metabolites. As decreased serotonin production is implicated in the emergence of mood and behavioral disorders, reducing tryptophan degradation that is associated with several inflammatory diseases, such as AD, could be an effective therapy [46]. Cannabinoids likely confer neuroprotection by limiting oxidative stress, reducing tumor necrosis factor-α, and inhibiting glutamate release [42]. Interestingly, cannabinoids may provide a synergistic or enhanced effect with typical AD acetylcholinesterase inhibitors by also competitively binding to acetylcholinesterase, thereby blocking Aβ generation and increasing available acetylcholine [47]. Cannabinoids may also improve circadian rhythm disturbances that are highly prevalent in AD, as the ECS has been linked to regulating core body temperature, nociception, activity, sleep/wake cycles, and food consumption [48]. Additionally, cannabinoids may have a positive impact on agitation by improving common comorbidities, such as insomnia, anxiety and pain, and by limiting microglial and cytokine production, effectively reducing neuroinflammation [49]. Furthermore, AD often presents simultaneously with underlying vascular disease, and cannabinoids may provide benefit by increasing vasodilation and cerebral blood flow [50].

Clinical Reviews

Legalization and increased acceptance of cannabis use by society has resulted in a widespread emergence of medicinal cannabis use for many medical conditions, despite often lacking sufficient clinical evidence [51]. In recent years, several systematic reviews and case studies have reported on the use of cannabinoids in a broad range of AD patients with variable clinical environments, disease progression, and demographics (Table 2). These studies varied widely in cannabinoid selection, treatment design, outcome measures, and heavily favored study bias, thus making it difficult to provide a unified consensus of the data. However, several RCTs and case studies yielded promising results through improved NPS scores (agitation, aggression, and circadian disturbances). The safety profile was relatively benign: cannabinoids were generally well tolerated and there were minimal adverse events, with most concerns focusing on sedation and seizure risk [52–55].

Caution and Safety Concerns

However, each cannabinoid has unique pharmacology, and clinicians should consider that a patient’s response is determined by factors such as genetic differences, previous cannabinoid use, concomitant medications, and comorbidities. Importantly, several studies have indicated that many cannabinoids express biphasic dose-dependent effects, such as anxiolytic effects from low doses of THC, but anxiogenic effects from high doses of THC [56]. Thus, cannabinoid receptors are powerful therapeutic targets that can be viewed as double-edged swords. Applied carefully, cannabinoids can be effective therapeutic options, but in higher doses, inherently pose significant risks of negative health outcomes and the potential for addiction or abuse.

For example, CBD can increase the risk of developing toxic side effects from other medications, as CBD is an inhibitor of multiple cytochrome P450 enzymes (3A4, 2C9, 2C19, and possibly others), which are activated in the metabolism of common antibiotics, antipsychotics, antidepressants, and blood thinners [57]. Additionally, many products incorrectly labeled as “CBD only” likely contain THC as well, which in high doses has been associated with cognitive impairment, aggression, paranoia, anxiety, and depression [57]. Another well-known example is rimonabant, a CB₁ antagonist/inverse agonist that is indicated as an anti-obesity medication. Rimonabant is effective in improving glycemic control and reducing lipid levels and fat storage, but was ultimately not approved in the United States and was banned in Europe for being associated with mood disturbances, including depression, anxiety, and suicidal ideation [58]. Caution should be used when considering appropriate doses for investigatory cannabinoids in Agit-AD, as older patients may metabolize cannabinoids more slowly. This emphasizes the importance of determining the therapeutic window, which may be narrower than expected in this population, to maximize pharmacologic benefits while minimizing adverse events. In addition, the FDA has issued guidance that acknowledges a recent surge in the cannabinoid market with products that are often unlawful, lacking quality control, and providing various unsubstantiated claims to improve health [59].

Cannabinoids for AD: Summary

With safety in mind, the current literature suggests that cannabinoids may be beneficial in treating symptoms of AD, especially agitation, as well as aggression, impulsivity, circadian rhythms, nocturnal activity, and sleep (Table 2). However, it will be important to determine if there are AD subgroups who do not respond to cannabinoid treatment, if the therapeutic window evolves based on disease progression, and if typical concomitant medications for AD impact cannabinoid efficacy. Further work from controlled studies with larger participant cohorts, variable dosing, longitudinal analysis, and additional pharmacological combinations is warranted to investigate the safety and efficacy of cannabinoids in a frail and vulnerable AD population.

Current Research and Future Directions

Two of the authors of this article (Forester, Harper) published a case series of 40 dementia inpatients who were treated with dronabinol (mean dose of 7 mg daily) for agitation, aggression, or poor appetite for a mean of 17 days [60]. Minimal adverse events suggested that dronabinol can be tolerated in this population, and improvements in agitation scales, food consumption, and sleep duration provided preliminary encouragement for a larger, controlled study. Two of the authors of this article (Rosenberg, Forester) are now leading a 3-week, double-blind, RCT of dronabinol in 80 AD patients with severe agitation. A dose of 10 mg (5 mg BID) was chosen to maximize efficacy and limit possible adverse reactions (sedation, seizures) in a vulnerable population who may be more sensitive to higher dosages. The half-life of dronabinol is approximately four hours, so study medication is administered BID at 08:00 and 14:00 to maximize daytime coverage for agitation and to minimize sundowning. This pilot trial could open the door to “re-purposing” dronabinol as a novel and safe treatment for agitation in AD.

One of the authors of this article (Forester) is also performing an 8-week, open-label clinical trial of a proprietary high percentage CBD/low percentage THC sublingual solution for anxiety and agitation in mild to moderate AD. Administered BID, the coconut oil-based solution is titrated up to a dose of approximately 45 mg CBD/day, with the option to increase to a maximum dose of approximately 60 mg CBD/day. This trial will help to determine the safety and efficacy of a predominantly CBD-based solution for anxious and agitated AD outpatients.

Conclusion

AD is a common neurodegenerative disease that increases in prevalence with advancing age and has a significant impact on global healthcare. NPS in AD are nearly universal, with agitation and aggression frequently resulting in diminished quality of life, increased caregiver burnout, and shorter time to institutionalization. There are likely multiple neurobiological mechanisms that play a role in the expression of agitation and aggression, including dysfunction in specific brain regions and networks, dysregulation of neurotransmitters, disruptive comorbidities, and disturbances in circadian rhythms. The classic adage of “start low, go slow” is especially important when considering the clinical use of cannabinoids in this elderly population often accompanied by multiple concomitant medications and complicated health factors. Nausea, sedation, seizures, and other AEs associated with cannabinoid use could pose serious concerns. We strongly recommend guidance by a clinical professional to determine the appropriate cannabinoid and dose for off-label use in Agit-AD, and caution against self-medication using dispensary or illicit products for this indication. Cannabinoids require further investigation, but show promising preliminary results for mitigating the damaging consequences of agitation and aggression in AD.

Highlights:

1). What is the primary question addressed by this study? (1 sentence)

This manuscript examines the mechanisms that lead to agitation in Alzheimer’s disease and aims to determine if cannabinoids are a safe and effective treatment.

2). What is the main finding of this study? (2 sentences)

There are multiple neurobiological mechanisms that contribute toward expression of agitation and aggression in Alzheimer’s disease, including dysfunction in specific brain networks, dysregulation of neurotransmitters, disruptive comorbidities, and disturbances in circadian rhythms. Pre-clinical and early clinical research suggests that cannabinoids may provide some benefit in agitation in Alzheimer’s disease by reducing neuroinflammation, regulating neurotransmitters, and improving comorbidities and circadian rhythms.

3). What is the meaning of the finding? (1 sentence)

Cannabinoids have a relatively mild safety profile, but adverse events concerning sedation, elevated risk of seizures, and potential drug interactions suggest that further investigation is required to validate promising early results for an indication that currently has no FDA-approved treatments.