Alzheimer's Disease and Medical Cannabis

Alzheimer’s Disease – causes, symptoms, and treatments

Alzheimer’s disease (AD) is the most common type of dementia accounting for 50-70% of cases of dementia.

Not all people with dementia have AD. The term “Alzheimer’s disease” is reserved for patients with characteristic changes in the brain including the formation of clumps called amyloid plaques, and of tangled bundles of fibres called tau tangles. In addition, with advancing age, AD can occur alongside other neurodegenerative and vascular diseases[1].

Other forms of dementia include vascular dementia (25%), dementia with Lewy bodies (15%), and frontotemporal dementia[2]. Vascular dementia is caused by a series of strokes or changes to the brain’s blood supply. A person may have both AD and vascular dementia[3].

Dementia is the second leading burden of disability among Australians aged 65 years and older, and it is expected to affect up to 550,000 people by 2030[4]. Core features of AD dementia include cognitive impairment, and behavioural and psychological symptoms[5].

As with all types of dementia, AD is an irreversible, progressive brain disorder that slowly destroys brain cells and neural connections, resulting in loss of memory and thinking skills and, eventually, the ability to carry out the simplest daily tasks.

Who can develop AD?

The exact cause of Alzheimer’s disease is not known but it may be the result of several genetic, hereditary, and environmental factors, as well as biochemical imbalances, immune processes and neuroinflammation[6]. The greatest single risk factor for AD is advanced age, with symptoms usually beginning after the age of 60. After age 65, the number of people affected doubles every five years, affecting nearly half of all people over 85[3].  

Specific genes, such as APOE-e4, may also place a person at higher risk of AD[7]. Other risk factors for AD are less well established, and may include severe or repeated head trauma, female gender (partly because women live longer), depression, higher parental age, smoking, family history of dementia, and cardiovascular disease[8]. Good health habits and remaining physically and mentally active may delay or slow the course of the disease[3].

What are the symptoms?

Symptoms of AD depend on the stage of the disease. The initial and most common symptom is periodic short-term memory loss. This is followed by impairment in problem solving, judgment, executive functioning, and lack of motivation and disorganisation that lead to problems with multitasking and abstract thinking. 

As the disease advances, language disorder and impairment of visual and spatial skills occur. Neuropsychiatric symptoms such as apathy, social withdrawal, disinhibition, agitation, psychosis, and wandering are also common in the mid to late stages. Difficulty performing learned motor tasks, loss of smell, sleep disturbances, and movement disorders occur late in the disease. Finally, these are followed by primitive reflexes, incontinence, and total dependence on caregivers[8].

What treatments are available?

AD is a complex disease and therefore there is yet no cure, only medications that treat symptoms. Approved pharmaceuticals include cholinesterase inhibitors and partial N-methyl D-aspartate (NMDA) antagonists.

Cholinesterase inhibitors increase the level of acetylcholine – a chemical used by nerve cells to communicate with each other, and which plays a role in learning, memory, and cognitive functions. Drugs under this category include donepezil, rivastigmine, and galantamine. NMDA antagonists, such as memantine, block NMDA receptors in the brain and protect them against high levels of the chemical glutamate, which may cause brain degeneration. NMDA receptors are involved in the transmission of nerve signals within the brain needed for learning and memory. Other symptoms such as anxiety, depression, insomnia, and psychosis can be treated with specific medications for these conditions. However, treatment with antidepressants and antipsychotics can be ineffective, can be associated with substantial side effects, including increased rate of stroke and mortality, and do not stop or reverse disease progression[9]

At the moment there are more than 600 clinical trials listed around the world testing new interventions. These include but are not limited to CT1812 (Elayta) which may prevent the development of amyloid plaques, new drugs such as MK-1942, repurposed drugs such as dopagliflozin, immunotherapy (e.g. pepinemab, GV1001) to reduce inflammation and oxidative stress, caffeine, and VGH-AD1 a traditional herbal medicine. Other studies are focusing on identifying new biomarkers in order to enable early detection, genetic testing, targeting gut microorganisms (known as the microbiome), using therapeutic diets, and supplementation with glutathione. Further interventions include cognitive training, blood-brain barrier disruption, deep brain stimulation, transcranial ultrasound stimulation, and stem cell infusion.

Community support is available for the person with Alzheimer’s disease, their families, and carers. For more information, contact Dementia Australia.

Can cannabinoids help?

Cannabinoids work through the endocannabinoid system (ECS) which plays a critical role in the regulation of nerve signal transmission in the central nervous system (CNS), which includes the brain10.  As a consequence, the ECS can control processes such as nerve and muscle function, cognition, memory, and learning[11]

There has been increasing interest in cannabinoids as promising agents in AD due to preclinical and early clinical research that suggest cannabinoids can reduce anxiety, depression, and inflammation[12]. In addition, cannabidiol (CBD) was recently shown to reverse social deficit and impaired spatial learning in an animal model of Alzheimer’s disease[13].  

Other animal studies have shown that the effect of cannabinoids is likely based on a combination of several protective activities, including reduction of neuroinflammation and NMDA receptor damage by glutamate[11, 14]. Cannabinoid 1 (CB1) receptors have been shown to regulate excessive glutamate production and subsequent oxidative stress, which can damage neurons and lead to neurodegeneration[15].  There is also evidence that cannabinoid 2 (CB2) receptors and CBD may be involved in neuroprotection by reducing neuroinflammation[16-20].  Neurodegeneration and neuroinflammation are features that are common to the various types of dementia, including AD, and the neuroprotective effects of cannabinoids may therefore be beneficial in slowing disease progression[21].

However, cannabinoids may have more specific effects in Alzheimer’s disease. Studies in animals have shown that tetrahydrocannabinol (THC) diminishes acetylcholinesterase-induced amyloid plaques and tau tangles, characteristic features of AD[22-24]. The same research group report that THC inhibits the enzyme acetylcholinesterase, a similar action to antidementia drugs like donepezil[21]

In humans, clinical studies have shown that cannabinoid-based medicines can inhibit some symptoms associated with dementia, with minimal adverse effects[9, 25-28].  In a 2019 study at the University of Geneva in Switzerland, 10 female patients with dementia were treated over a period of 2 months with low dose CBD:THC (2:1). The oral medication was acceptable, well tolerated, and improved rigidity and behaviour overall. It allowed the decrease or stop of other antidepressants, antipsychotics, mood stabilisers or antianxiety agents, in half of the patients[29]

In another 2019 study, 39 randomised patients with AD and agitation were treated with low dose THC or a placebo for one month, at the Sunnybrook Health Sciences Centre in Toronto, Canada. The findings suggested that low dose THC may be an effective treatment for agitation, with potential benefits on overall neuropsychiatric symptoms, caregiver burden, and nutritional status. However, the study recommended that side effects such as sedation, and possibly cognitive decline, should be closely monitored to ensure patient safety, and that larger clinical trials would be needed to confirm safety and efficacy[30].

Earlier studies in patients with dementia have had mixed results, with some showing that low-dose THC has no benefit for neuropsychiatric symptoms[31-33], and others showing a reduction in agitation, aggressiveness and nocturnal behavioural disturbances[26, 34-37].  Adverse events were reported as either absent or mild, and when present included  euphoria, somnolence, and tiredness, but did not result in medication discontinuation in any of the studies.

Preclinical and clinical evidence is beginning to show promise for the safety and efficacy of cannabinoids in the treatment of AD dementia, but it is clear that further and larger, well designed, randomised, double-blind, placebo-controlled trials will be needed to confirm the efficacy of various formulations and establish safe dosing in AD dementia[9, 21].

To see a list of current clinical trials of cannabinoids for dementia, including AD dementia, in Australia and overseas, visit the WHO International Clinical Trials Registry Platform.

[1] Villain N, Dubois B. Alzheimer’s Disease Including Focal Presentations. Semin Neurol. 2019;39(2):213-26.

[2] Burns A, Iliffe S. Dementia. BMJ. 2009;338:b75.

[3] Watwood C. Alzheimer’s Disease. In: University WK, editor. DLPS Faculty Publications Paper 39. http://digitalcommonswkuedu/dlps_fac_pub/392011.

[4] Australian Institute of Health and Welfare. Dementia. 2016. Accessed 9 April 2020.

[5] Charernboon T, Lerthattasilp T, Supasitthumrong T. Effectiveness of Cannabinoids for Treatment of Dementia: A Systematic Review of Randomized Controlled Trials. Clin Gerontol. 2020:1-9.

[6] Price BR, Johnson LA, Norris CM. Reactive Astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease. Ageing Res Rev. 2021:101335.

[7] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet. 2011;377(9770):1019-31.

[8] Kumar A, Sidhu J, Goyal A, Tsao JW. Alzheimer Disease.  StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2021, StatPearls Publishing LLC.; 2021.

[9] Timler A, Bulsara C, Bulsara M, Vickery A, Smith J, Codde J. Use of cannabinoid-based medicine among older residential care recipients diagnosed with dementia: study protocol for a double-blind randomised crossover trial. Trials. 2020;21(1):188.

[10] Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016;79(7):516-25.

[11] Fernandez-Ruiz J, Galve-Roperh I, Sagredo O, Guzman M. Possible therapeutic applications of cannabis in the neuropsychopharmacology field. Eur Neuropsychopharmacol. 2020;36:217-34.

[12] Outen JD, Burhanullah MH, Vandrey R, Amjad H, Harper DG, Patrick RE, et al. Cannabinoids for Agitation in Alzheimer’s Disease. Am J Geriatr Psychiatry. 2021.

[13] Watt G, Shang K, Zieba J, Olaya J, Li H, Garner B, et al. Chronic Treatment with 50 mg/kg Cannabidiol Improves Cognition and Moderately Reduces Abeta40 Levels in 12-Month-Old Male AbetaPPswe/PS1DeltaE9 Transgenic Mice. J Alzheimers Dis. 2020;74(3):937-50.

[14] Friedman D, French JA, Maccarrone M. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol. 2019;18(5):504-12.

[15] Grundy RI. The therapeutic potential of the cannabinoids in neuroprotection. Expert Opin Investig Drugs. 2002;11(10):1365-74.

[16] Mori MA, Meyer E, Soares LM, Milani H, Guimarães FS, de Oliveira RMW. Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia. Prog Neuropsychopharmacol Biol Psychiatry. 2017;75:94-105.

[17] Rom S, Persidsky Y. Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol. 2013;8(3):608-20.

[18] Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim Biophys Sin (Shanghai). 2017;49(10):853-66.

[19] Al-Ghezi ZZ, Miranda K, Nagarkatti M, Nagarkatti PS. Combination of Cannabinoids, Delta9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways. Front Immunol. 2019;10:1921.

[20] Garcia C, Gomez-Canas M, Burgaz S, Palomares B, Gomez-Galvez Y, Palomo-Garo C, et al. Benefits of VCE-003.2, a cannabigerol quinone derivative, against inflammation-driven neuronal deterioration in experimental Parkinson’s disease: possible involvement of different binding sites at the PPARgamma receptor. J Neuroinflammation. 2018;15(1):19.

[21] Krishnan S, Cairns R, Howard R. Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev. 2009(2):Cd007204.

[22] Eubanks LM, Rogers CJ, Beuscher AEt, Koob GF, Olson AJ, Dickerson TJ, et al. A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol Pharm. 2006;3(6):773-7.

[23] Aso E, Ferrer I. Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front Pharmacol. 2014;5:37.

[24] Aso E, Juvés S, Maldonado R, Ferrer I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J Alzheimers Dis. 2013;35(4):847-58.

[25] Fakhoury M. Could cannabidiol be used as an alternative to antipsychotics? J Psychiatr Res. 2016;80:14-21.

[26] Woodward MR, Harper DG, Stolyar A, Forester BP, Ellison JM. Dronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms. Am J Geriatr Psychiatry. 2014;22(4):415-9.

[27] Kales HC, Gitlin LN, Lyketsos CG. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62(4):762-9.

[28] Sun M, Mainland BJ, Ornstein TJ, Mallya S, Fiocco AJ, Sin GL, et al. The association between cognitive fluctuations and activities of daily living and quality of life among institutionalized patients with dementia. Int J Geriatr Psychiatry. 2018;33(2):e280-e5.

[29] Broers B, Patà Z, Mina A, Wampfler J, de Saussure C, Pautex S. Prescription of a THC/CBD-Based Medication to Patients with Dementia: A Pilot Study in Geneva. Medical Cannabis and Cannabinoids. 2019;2(1):56-9.

[30] Herrmann N, Ruthirakuhan M, Gallagher D, Verhoeff NPLG, Kiss A, Black SE, et al. Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer’s Disease. The American Journal of Geriatric Psychiatry. 2019;27(11):1161-73.

[31] van den Elsen GA, Tobben L, Ahmed AI, Verkes RJ, Kramers C, Marijnissen RM, et al. Effects of tetrahydrocannabinol on balance and gait in patients with dementia: A randomised controlled crossover trial. J Psychopharmacol. 2016;31(2):184-91.

[32] van den Elsen GAH, Ahmed AIA, Verkes RJ, Feuth T, van der Marck MA, Olde Rikkert MGM. Tetrahydrocannabinol in Behavioral Disturbances in Dementia: A Crossover Randomized Controlled Trial. Am J Geriatr Psychiatry. 2015;23(12):1214-24.

[33] van den Elsen GA, Ahmed AI, Verkes RJ, Kramers C, Feuth T, Rosenberg PB, et al. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial. Neurology. 2015;84(23):2338-46.

[34] Walther S, Schüpbach B, Seifritz E, Homan P, Strik W. Randomized, controlled crossover trial of dronabinol, 2.5 mg, for agitation in 2 patients with dementia. J Clin Psychopharmacol. 2011;31(2):256-8.

[35] Walther S, Mahlberg R, Eichmann U, Kunz D. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology (Berl). 2006;185(4):524-8.

[36] Mahlberg R, Walther S. Actigraphy in agitated patients with dementia. Monitoring treatment outcomes. Z Gerontol Geriatr. 2007;40(3):178-84.

[37] Passmore MJ. The cannabinoid receptor agonist nabilone for the treatment of dementia-related agitation. Int J Geriatr Psychiatry. 2008;23(1):116-7.

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