Scientific Online Resource System

Izvestia Journal of the Union of Scientists - Varna. Medicine and Ecology Series

Influence of the endocannabinoid system on memory processes

Dobrinka Doncheva, Miroslav Marinov, Margarita Velikova


The endocannabinoid system (ECS) is a lipid signaling system, which consists of the endocannabinoids (EC) anandamide (AEA) and 2-arachidonylglycerol (2-AG), the cannabinoid receptors (CB1 and CB2), and the enzymes that regulate their production and degradation. AEA and 2-AG are lipid compounds derived presynaptically from the degradation of membrane phospholipids and act as key modulators on synaptic transmission. This article presents accumulated data on the mechanisms by which ECS affects learning and memory. Substances that modulate the activity of ECS have impact on different phases of memory formation through direct and indirect influences. Studies show contradictory results on the role of the ECS in learning and memory processes.


endocannabinoid system, tetrahydrocannabinol, synaptic plasticity, training, memory

Full Text


Auer R, Vittinghoff E, Yaffe K, et al. Association between lifetime marijuana use and cognitive function in middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. JAMA Intern Med. 2016; 176: 352-361.

Batalla A, Bhattacharyya S, Yücel M, et al. Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings. PloS One. 2013; 8: e55821.

Blest-Hopley G, Colizzi M, Giampietro V, Bhattacharyya S. Is the adolescent brain at greater vulnerability to the effects of cannabis? A narrative review of the evidence. Front Psychiatry. 2020; 11: 859.

Broyd SJ, van Hell HH, Beale C, Yücel M, Solowij N. Acute and Chronic effects of cannabinoids on human cognition-a systematic review. Biol Psychiatry. 2016; 79: 557-567.

Campolongo P, Morena M, Scaccianoce S et al. Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity. Neuropsychopharmacology. 2013; 38: 1276-1286.

Campolongo P, Trezza V, Cassano T, et al. Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict Biol. 2007; 12: 485-495.

Chianese R, Meccariello R. The endocannabinoid system in human physiology. In: Chianese R, Meccariello R. eds. Cannabinoids in health and disease. Intech, Rijeka, Croatia, 2016: 1-10.

Djeungoue-Petga MA, Hebert-Chatelain E. Linking mitochondria and synaptic transmission: the CB1 receptor. Bioessays. 2017; 39: 1700126.

Gleason KA, Birnbaum SG, Shukla A, Ghose S. Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia. Transl Psychiatry. 2012; 2: e199.

Gómez-Gonzalo M, Navarrete M, Perea G et al. Endocannabinoids Induce Lateral Long-Term Potentiation of Transmitter Release by Stimulation of Gliotransmission.Cereb Cortex. 2015; 25: 3699-3712.

Han J, Kesner P, Metna-Laurent M et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. 2012;148: 1039-1050.

Hebert-Chatelain E, Desprez T, Serrat R et al. A cannabinoid link between mitochondria and memory. Nature. 2016; 539 (7630): 555-559.

Heifets BD, Castillo PE. Endocannabinoid signaling and long-term synaptic plasticity. Annu. Rev. Physiol. 2009; 71: 283-306.

Hoffman AF, Hwang EK, Lupica CR. Impairment of synaptic plasticity by cannabis, Δ9-THC, and synthetic cannabinoids. Cold Spring Harb Perspect Med. 2020: a039743.

Horton KA, Goonawardena AV, Sesay J, Howlett AC, Hampson RE. Systemic blockade of the CB1 receptor augments hippocampal gene expression involved in synaptic plasticity but perturbs hippocampus-dependent learning task. Cannabis Cannabinoid Res. 2019; 4: 33-41.

Jacob W, Marsch R, Marsicano G, Lutz B, Wotjak CT. Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo. Neurobiol Learn Mem. 2012; 98: 47-55.

Kano M. Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2014; 90: 235-250.

Koenders L, et al. Longitudinal study of hippocampal volumes in heavy cannabis users. J Psychopharmacol. 2017; 31: 1027-1034.

Kruk-Slomka M, Dzik A, Budzynska B, Biala G. Endocannabinoid system: the direct and indirect involvement in the memory and learning Processes - a short review. Mol Neurobiol. 2017; 54: 8332-8347.

Li Y, J Kim. Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long-term potentiation in the mouse hippocampus. Hippocampus. 2016; 26: 275-281.

Litvin Y, Phan A, Hill MN, Pfaff DW, McEwen BS. CB1 receptor signaling regulates social anxiety and memory. Genes Brain Behav. 2013; 12: 479-489.

Lovell ME, Akhurst J, Padgett C, Garry MI, Matthews A. Cognitive outcomes associated with long-term, regular, recreational cannabis use in adults: A meta-analysis. Exp Clin Psychopharmacol. 2020; 28: 471-494.

Lovinger DM. Presynaptic modulation by endocannabinoids. Handb Exp Pharmacol. 2008; (184): 435-477.

Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016; 79: 516-525.

Lupica CR, Hoffman AF. Cannabinoid disruption of learning mechanisms involved in reward processing. Learn Mem. 2018; 25: 435-445.

Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008; 60: 748-766.

Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013; 64: 21-47.

Monory K, Polack M, Remus A, Lutz B, Korte M. Cannabinoid CB1 receptor calibrates excitatory synaptic balance in the mouse hippocampus. J Neurosci. 2015; 35 (9): 3842-3850.

Mouro FM, Ribeiro JA, Sebastião AM, Dawson N. Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity. J Neurochem. 2018; 147: 71-83.

Navarrete M, Díez A, Araque A. Astrocytes in endocannabinoid signalling. Philos Trans R Soc Lond B Biol Sci. 2014; 369 (1654): 20130599.

Ohno-Shosaku T, Kano M. Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr Opin Neurobiol. 2014; 29: 1-8.

Pagliaccio D, Barch DM, Bogdan R, et al. Shared predisposition in the association between cannabis use and subcortical brain structure. JAMA Psychiatry. 2015; 72: 994-1001.

Paul S, Bhattacharyya S. Cannabis use-related working memory deficit mediated by lower left hippocampal volume. Addict Biol. 2020: e12984.

Puighermanal E, Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R, Ozaita A. Dissociation of the pharmacological effects of THC by mTOR blockade. Neuropsychopharmacology. 2013; 38: 1334–1343.

Puighermanal E, Busquets-Garcia A, Maldonado R, Ozaita A. Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids. Philos Trans R Soc Lond B Biol Sci. 2012; 367: 3254-3263.

Riedel G, Davies SN. Cannabinoid function in learning, memory and plasticity. Handb Exp Pharmacol. 2005; (168): 445-477.

Rubino T, Parolaro D. The Impact of exposure to cannabinoids in adolescence: iInsights from animal models. Biol Psychiatry. 2016; 79: 578-585.

Rubino T, Realini N, Braida D, et al. Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood. Hippocampus. 2009; 19: 763-772.

Smith NA, Bekar LK, Nedergaard M. Astrocytic endocannabinoids mediate hippocampal transient heterosynaptic depression. Neurochem Res. 2020; 45: 100-108.

Astrocytic endocannabinoids mediate hippocampal transient heterosynaptic depression. Neurochem Res. 2020; 45: 100-108.

Volkow ND, Swanson JM, Evins AE, et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry. 2016; 73: 292-297.



Font Size