Alzheimer’s disease (AD) is frequently associated with neuropsychiatric symptoms (NPS) such as agitation and aggression, especially in the moderate to severe stages of the illness. The limited efficacy and high-risk profiles of current pharmacotherapies for the management of agitation and aggression in AD have driven the search for safer pharmacological alternatives. Over the past few years, there has been a growing interest in the therapeutic potential of medications that target the endocannabinoid system (ECS). The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD. This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD. Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids—dronabinol or nabilone—on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.
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Wortmann M. Dementia: a global health priority—highlights from an ADI and World Health Organization report. Alzheimers Res Ther. 2012;4(5):40.
Garcia-Alberca JM, et al. Prevalence and comorbidity of neuropsychiatric symptoms in Alzheimer’s disease. Actas Esp Psiquiatr. 2008;36(5):265–70.
Lyketsos CG. Neuropsychiatric symptoms (behavioral and psychological symptoms of dementia) and the development of dementia treatments. Int Psychogeriatr. 2007;19(3):409–20.
Banerjee S, et al. Quality of life in dementia: more than just cognition. An analysis of associations with quality of life in dementia. J Neurol Neurosurg Psychiatry. 2006;77(2):146–8.
Cohen-Mansfield J, Libin A, Marx MS. Nonpharmacological treatment of agitation: a controlled trial of systematic individualized intervention. J Gerontol A Biol Sci Med Sci. 2007;62(8):908–16.
Cohen-Mansfield J, Werner P. Management of verbally disruptive behaviors in nursing home residents. J Gerontol A Biol Sci Med Sci. 1997;52(6):M369–77.
Ballard CG, et al. Management of agitation and aggression associated with Alzheimer disease. Nat Rev Neurol. 2009;5(5):245–55.
Ballard C, et al. Management of agitation and aggression associated with Alzheimer’s disease: controversies and possible solutions. Curr Opin Psychiatry. 2009;22(6):532–40.
Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev. 2006;1:Cd003476.
Schneider LS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525–38.
Herrmann N, Lanctot KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimers Res Ther. 2013;5((Suppl 1)):S5.
Bedse G, et al. The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer’s disease. J Alzheimers Dis. 2015;43(4):1115–36.
Rossi S, Motta C, Musella A, Centonze D. The interplay between inflammatory cytokines and the endocannabinoid system in the regulation of synaptic transmission. Neuropharmacology. 2015;96((Pt A)):105–12.
Sanchez AJ, Garcia-Merino A. Neuroprotective agents: cannabinoids. Clin Immunol. 2012;142(1):57–67.
Scotter EL, Abood ME, Glass M. The endocannabinoid system as a target for the treatment of neurodegenerative disease. Br J Pharmacol. 2010;160(3):480–98.
Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77(2):299–318.
Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005;168:299–325.
Kathmann M, Bauer U, Schlicker E. CB1 receptor density and CB1 receptor-mediated functional effects in rat hippocampus are decreased by an intracerebroventricularly administered antisense oligodeoxynucleotide. Naunyn Schmiedebergs Arch Pharmacol. 1999;360(4):421–7.
Karkkaine E, Tanila H, Laitinen JT. Functional autoradiography shows unaltered cannabinoid CB1 receptor signalling in hippocampus and cortex of APP/PS1 transgenic mice. CNS Neurol Disord Drug Targets. 2012;11(8):1038–44.
Rapp PR, Heindel WC. Memory systems in normal and pathological aging. Curr Opin Neurol. 1994;7(4):294–8.
Mann DM. The pathogenesis and progression of the pathological changes of Alzheimer’s disease. Ann Med. 1989;21(2):133–6.
Moise AM, et al. An endocannabinoid signaling system modulates anxiety-like behavior in male Syrian hamsters. Psychopharmacology. 2008;200(3):333–46.
Martin M, et al. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology. 2002;159(4):379–87.
Klegeris A, Bissonnette CJ, McGeer PL. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol. 2003;139(4):775–86.
Sheng WS, et al. Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes. Glia. 2005;49(2):211–9.
Tolon RM, et al. The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res. 2009;1283:148–54.
Vilela FC, Giusti-Paiva A. Cannabinoid receptor agonist disrupts behavioral and neuroendocrine responses during lactation. Behav Brain Res. 2014;263:190–7.
Rodriguez-Arias M, et al. CB1 cannabinoid receptor-mediated aggressive behavior. Neuropharmacology. 2013;75:172–80.
Lanctot KL, Herrmann N, Mazzotta P. Role of serotonin in the behavioral and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2001;13(1):5–21.
Lanctot KL, et al. GABAergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry. 2004;49(7):439–53.
Tanaka Y, et al. Decreased striatal D2 receptor density associated with severe behavioral abnormality in Alzheimer’s disease. Ann Nucl Med. 2003;17(7):567–73.
Pinto T, Lanctot KL, Herrmann N. Revisiting the cholinergic hypothesis of behavioral and psychological symptoms in dementia of the Alzheimer’s type. Ageing Res Rev. 2011;10(4):404–12.
Chami L, Checler F. BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer’s disease. Mol Neurodegener. 2012;7:52.
Aso E, et al. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AbetaPP/PS1 mice. J Alzheimers Dis. 2013;35(4):847–58.
Esposito G, et al. The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med (Berl). 2006;84(3):253–8.
Volicer L, et al. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int J Geriatr Psychiatry. 1997;12(9):913–9.
Walther S, et al. Randomized, controlled crossover trial of dronabinol, 2.5 mg, for agitation in 2 patients with dementia. J Clin Psychopharmacol. 2011;31(2):256–8.
Mahlberg R, Walther S. Actigraphy in agitated patients with dementia. Monitoring treatment outcomes. Z Gerontol Geriatr. 2007;40(3):178–84.
Walther S, et al. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology. 2006;185(4):524–8.
Woodward MR, et al. 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.
Passmore MJ. The cannabinoid receptor agonist nabilone for the treatment of dementia-related agitation. Int J Geriatr Psychiatry. 2008;23(1):116–7.
Cheer JF, et al. Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci. 2004;24(18):4393–400.
Pistis M, et al. Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biol Psychiatry. 2004;56(2):86–94.
Kirilly E, Hunyady L, Bagdy G. Opposing local effects of endocannabinoids on the activity of noradrenergic neurons and release of noradrenaline: relevance for their role in depression and in the actions of CB(1) receptor antagonists. J Neural Transm. 2013;120(1):177–86.
Haj-Dahmane S, Shen RY. Modulation of the serotonin system by endocannabinoid signaling. Neuropharmacology. 2011;61(3):414–20.
Best AR, Regehr WG. Serotonin evokes endocannabinoid release and retrogradely suppresses excitatory synapses. J Neurosci. 2008;28(25):6508–15.
Sigel E, et al. The major central endocannabinoid directly acts at GABA(A) receptors. Proc Natl Acad Sci USA. 2011;108(44):18150–5.
Spivak CE, Lupica CR, Oz M. The endocannabinoid anandamide inhibits the function of alpha4beta2 nicotinic acetylcholine receptors. Mol Pharmacol. 2007;72(4):1024–32.
Uriguen L, et al. Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors. Neuropharmacology. 2004;46(7):966–73.
Steiner MA, et al. Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice. Pharmacogenomics J. 2008;8(3):196–208.
Aso E, et al. BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice. J Neurochem. 2008;105(2):565–72.
Parker KJ, Schatzberg AF, Lyons DM. Neuroendocrine aspects of hypercortisolism in major depression. Horm Behav. 2003;43(1):60–6.
Arborelius L, et al. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1999;160(1):1–12.
Gregus A, et al. Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav Brain Res. 2005;156(1):105–14.
Vermeiren Y, et al. Brain region-specific monoaminergic correlates of neuropsychiatric symptoms in Alzheimer’s disease. J Alzheimers Dis. 2014;41(3):819–33.
Casarejos MJ, et al. Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J Alzheimers Dis. 2013;35(3):525–39.
Palmer AM, et al. Presynaptic serotonergic dysfunction in patients with Alzheimer’s disease. J Neurochem. 1987;48(1):8–15.
Procter AW, et al. Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms. Neurochem Res. 1992;17(9):917–22.
Lai MK, et al. Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Res. 2003;974(1–2):82–7.
Lanctot KL, et al. Central serotonergic activity is related to the aggressive behaviors of Alzheimer’s disease. Neuropsychopharmacology. 2002;27(4):646–54.
Mintzer J, et al. Fenfluramine challenge test as a marker of serotonin activity in patients with Alzheimer’s dementia and agitation. Biol Psychiatry. 1998;44(9):918–21.
Haring M, et al. Identification of the cannabinoid receptor type 1 in serotonergic cells of raphe nuclei in mice. Neuroscience. 2007;146(3):1212–9.
Egertova M, Cravatt BF, Elphick MR. Comparative analysis of fatty acid amide hydrolase and cb(1) cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience. 2003;119(2):481–96.
Alexander G, et al. Increased aggression in males in transgenic Tg2576 mouse model of Alzheimer’s disease. Behav Brain Res. 2011;216(1):77–83.
Pugh PL, et al. Non-cognitive behaviours in an APP/PS1 transgenic model of Alzheimer’s disease. Behav Brain Res. 2007;178(1):18–28.
Ramakers IH, et al. Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment. Psychol Med. 2013;43(5):911–20.
Wu J, et al. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging. 2013;34(3):791–804.
Martin-Moreno AM, et al. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflamm. 2012;9:8.
Guadagna S, et al. Tau phosphorylation in human brain: relationship to behavioral disturbance in dementia. Neurobiol Aging. 2012;33(12):2798–806.
Holmes C, Butchart J. Systemic inflammation and Alzheimer’s disease. Biochem Soc Trans. 2011;39(4):898–901.
Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int J Dev Neurosci. 2006;24(2–3):167–76.
Puffenbarger RA, Boothe AC, Cabral GA. Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia. 2000;29(1):58–69.
Facchinetti F, et al. Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia. 2003;41(2):161–8.
van der Stelt M, et al. Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels. Cell Mol Life Sci. 2006;63(12):1410–24.
Farkas S, et al. [(1)(2)(5)I]SD-7015 reveals fine modalities of CB(1) cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer’s disease. Neurochem Int. 2012;60(3):286–91.
Robson PJ. Therapeutic potential of cannabinoid medicines. Drug Test Anal. 2014;6(1–2):24–30.
Zogopoulos P, et al. The role of endocannabinoids in pain modulation. Fundam Clin Pharmacol. 2013;27(1):64–80.
Wiley JL, et al. CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br J Pharmacol. 2005;145(3):293–300.
Whyte LS, et al. Cannabinoids and bone: endocannabinoids modulate human osteoclast function in vitro. Br J Pharmacol. 2012;165(8):2584–97.
Burston JJ, Woodhams SG. Endocannabinoid system and pain: an introduction. Proc Nutr Soc. 2014;73(1):106–17.
Ballard C, Corbett A. Agitation and aggression in people with Alzheimer’s disease. Curr Opin Psychiatry. 2013;26(3):252–9.
Husebo BS, et al. Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ. 2011;343:d4065.
Bestard JA, Toth CC. An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Pract. 2011;11(4):353–68.
Skrabek RQ, et al. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9(2):164–73.
Wissel J, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol. 2006;253(10):1337–41.
Fattore L, Fratta W. Beyond THC: the new generation of cannabinoid designer drugs. Front Behav Neurosci. 2011;5:60.
Hudson S, Ramsey J. The emergence and analysis of synthetic cannabinoids. Drug Test Anal. 2011;3(7–8):466–78.
Vardakou I, Pistos C, Spiliopoulou C. Spice drugs as a new trend: mode of action, identification and legislation. Toxicol Lett. 2010;197(3):157–62.
Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011;72(5):735–44.
CADTH Rapid Response Reports, in Nabilone for non-chemotherapy associated nausea and weight loss due to medical conditions: a review of the clinical effectiveness and guidelines. 2014, Canadian Agency for Drugs and Technologies in Health Copyright (c). Ottawa: 2014 Canadian Agency for Drugs and Technologies in Health.
Lemberger L, Rowe H. Clinical pharmacology of nabilone, a cannabinol derivative. Clin Pharmacol Ther. 1975;18(06):720–6.
Whiting PF, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456–73.
Smith PH, et al. Marijuana withdrawal and aggression among a representative sample of US marijuana users. Drug Alcohol Depend. 2013;132(1–2):63–8.
Budney AJ, et al. Marijuana abstinence effects in marijuana smokers maintained in their home environment. Arch Gen Psychiatry. 2001;58(10):917–24.
Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008;153(2):319–34.
Han S, et al. Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists. J Med Chem. 2013;56(21):8224–56.
Lee JH, et al. Intact cannabinoid CB1 receptors in the Alzheimer’s disease cortex. Neurochem Int. 2010;57(8):985–9.
Conflict of interest
Krista L. Lanctôt has received research grants from the Alzheimer Drug Discovery Fund, the Alzheimer Society of Canada, the National Institute of Health, AbbVie, Lundbeck, Pfizer, Sanofi-Aventis, Janssen-Ortho Inc., and Roche and Wyeth, and honoraria from AbbVie, Pfizer, Janssen-Ortho Inc., and MedImmune. Nathan Herrmann has received research grants from the Alzheimer Drug Discovery Fund, the Alzheimer Society of Canada, the National Institute of Health, Canadian Institute of Health Research, Lundbeck, and Roche, and consultant fees from Lundbeck, AbbVie, and Eli Lilly. Celina S. Liu, Sarah A. Chau, and Myuri Ruthirakuhan report no conflicts of interest.
This research was supported by the Alzheimer’s Drug Discovery Foundation (Grant 20140503) and the Alzheimer Society of Canada (Grant 15–17).
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Liu, C.S., Chau, S.A., Ruthirakuhan, M. et al. Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease. CNS Drugs 29, 615–623 (2015). https://doi.org/10.1007/s40263-015-0270-y
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