Cannabinoids are natural compounds found in the hemp (Cannabis sativa). Scientific interest in cannabinoids arose after the discovery of the major psychoactive component in hemp, Δ9-tetrahydrocannabinol. Subsequent studies detected receptors in the brain subject to the actions of this compound, along with ligands for these receptors, i.e., endogenous cannabinoids (EC), which make up, along with the enzymes synthesizing, transporting, and degrading them, the endocannabinoid system (ECS). Interest in EC has consistently increased in recent years, especially after their important role in cognitive functions was discovered. They are regulators of synaptic transmission in the brain, mediate numerous forms of plasticity, and control neuron energy metabolism. EC exert influences using a series of mechanisms and interactions with neuromediators, neurotrophic factors, and neuropeptides. The main functions of EC in the brain are retrograde synaptic signaling and neuromodulation, which maintain cellular homeostasis. Information on the influences of cannabinoid drugs on cognitive functions is very contradictory. The cause of this may be that there are still inadequate strictly scientific data from clinical and sociological studies, while in animal experiments different authors use different methods and approaches for actions on the ECS. Thus, effects can differ depending on the substances used, their doses, and routes of administration, and the tasks and experimental conditions selected for testing. There is an extensive literature on the protective effect of ECS activation in neurodegenerative diseases in humans and models of cognitive deficit in animals. This review addresses data providing evidence of the influences of cannabinoid drugs and activation of the EC system on cognitive functions in the normal brain and in neurodegenerative diseases, Alzheimer’s disease, and temporal epilepsy. The possible causes of contradictions in existing data are also discussed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abel, E. L., “Marihuana and memory: acquisition or retrieval?” Science, 73, 1038–1040 (1971).
Abuhasira, R., Schleider, L. B., Mechoulam, R., and Novack, V., “Epidemiological characteristics, safety and effi cacy of medical cannabis in the elderly,” Eur. J. Intern. Med., 49, 44–50 (2018).
Abush, H. and Akirav, I., “Cannabinoids modulate hippocampal memory and plasticity,” Hippocampus, 20, 1126–1138 (2010).
Abush, H. and Akirav, I., “Short- and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats,” PLoS One, 7, e3173–3171 (2012).
Alexander, S. P., “Therapeutic potential of cannabis-related drugs,” Prog. Neuropsychopharmacol. Biol. Psychiatry, 2016 64, 157–166.
Altamura, C., Ventriglia, M., Martini, M. G., et al., “Elevation of plasma 2-arachidonoylglycerol levels in Alzheimer’s disease patients as a potential protective mechanism against neurodegenerative decline,” J. Alzheimers Dis., 46, 497–506 (2015).
Andrade-Talavera, Y., Duque-Feria, P., Paulsen, O., and RodriguezMoreno, A., “Presynaptic spike timing-dependent long-term depression in the mouse hippocampus,” Cereb. Cortex, 26, No. 8, 3637–3654 (2016).
Anokhin, K. V., Tiunova, A. A., and Rose, S. P., “Reminder effects – reconsolidation or retrieval deficit? Pharmacological dissection with protein synthesis inhibitors following reminder for a passive-avoidance task in young chicks,” Eur. J. Neurosci., 15, 1759–1765 (2002).
Aso, E. and Ferrer, I., “Cannabinoids for treatment of Alzheimer’s disease: Moving toward the clinic,” Front. Pharmacol., 5, 37 (2014).
Aso, E., Juvis, S., Maldonado, R., and Ferrer, I., “CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice,” J. Alzheimers Dis., 35, 847–858 (2013).
Aso, E., Palomer, E., Juves, S., et al., “CB1 agonist ACEA protects neurons and reduces the cognitive impairment of Abeta PP/PS1 mice,” J. Alzheimers Dis., 30, 439–459 (2012).
Aso, E., Sánchez-Pla, A., Vegas-Lozano, E., et al., “Cannabis-based medicine reduces multiple pathological processes in AsPP/PS1 mice,” J. Alzheimers Dis., 43, 977–991 (2015).
Atakan, Z., Bhattacharyya, S., Allen, P., et al., “Cannabis affects people differently: intersubject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers,” Psychol. Med., 43, 1255–1267 (2013).
Atwood, B. K., Huffman, J., Straiker, A., and Mackie, K., “JWH018, a common constituent of ‘Spice’ herbal blends, is a potent and efficacious cannabinoid CB receptor agonist,” Br. J. Pharmacol., 160, 585–593 (2010).
Axmacher, N., Henseler, M. M., Jensen, O., et al., “Cross-frequency coupling supports multi-item working memoryin the human hippocampus,” Proc. Natl. Acad. Sci. USA, 107, 3228–3233 (2010).
Aymerich, M. S., Aso, E., Abellanasa, M. A., et al., “Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system,” Biochem. Pharmacol., 157, 67–84 (2018).
Ballard, M. E., Gallo, D. A., and de Wit, H., “Psychoactive drugs and false memory: comparison of dextroamphetamine and delta-9-tetrahydrocannabinol on false recognition,” Psychopharmacology, 219, 15–24 (2012).
Basavarajappa, B. S., Shivakumar, M., Joshi, V., and Subbanna, S., “Endocannabinoid system in neurodegenerative disorders,” J. Neurochem., 142, 624–648 (2017).
Batalla, A., Crippa, J. A., Busatto, G. F., et al., “Neuroimaging studies of acute effects of THC and CBD in humans and animals: A systematic review,” Curr. Pharmaceut. Design., 20, 2168–2185 (2014).
Batista, L. A., Gobira, P. H., Viana, T. G., et al., “Inhibition of endocannabinoid neuronal uptake and hydrolysis as strategies for developing anxiolytic drugs,” Behav. Pharmacol., 25, 425–433 (2014).
Battisti, R. A., Roodenrys, S., Johnstone, S. J., et al., “Chronic use of cannabis and poor neural efficiency in verbal memory ability,” Psychopharmacology, 209, 319–330 (2010).
Bayrakçı, A., Sert, E., Zorlu, N., et al., “Facial emotion recognition deficits in abstinent cannabis dependent patients,” Compr. Psychiatry., 58, 160–164 (2015).
Bedse, G., Bluett, R. J., Patrick, T. A., et al., “Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors,” Transl. Psychiatry, 8, 92 (2018).
Bedse, G., Romano, A., Cianci, S., et al., “Altered expression of the CB1 cannabinoid receptor in the triple transgenic mouse model of Alzheimer’s disease,” J. Alzheimers Dis., 40, 701–712 (2014).
Bedse, G., Romano, A., Lavecchia, A. M., et al., “The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer’s Disease,” J. Alzheimers Dis., 43, 1115–1136 (2015).
Bénard, G., Massa, F., Puente, N., et al., “Mitochondrial CB1 receptors regulate neuronal energy metabolism,” Nat. Neurosci., 15, 558–564 (2012).
Bhattacharyya, S., Morrison, P. D., Fusar-Poli, P., et al., “Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology,” Neuropsychopharmacology, 35, 764–774 (2010).
Bilel, S., Tirri, M., Arfi , R., et al., “Pharmacological and behavioral effects of the synthetic cannabinoid AKB48 in rats,” Front. Neurosci., 13, 1163 (2019).
Bilkei-Gorzo, A., Albayram, O., Draffehn, A., et al., “A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice,” Nat. Med., 23, 782–787 (2017).
Bisogno, T., Howell, F., Williams, G., et al., “Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain,” J. Cell Biol., 163, 463–468 (2003).
Blankman, J. L., Simon, G. M., and Cravatt, B. F., “A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol,” Chem. Biol., 14, 1347–1356 (2007).
Bloomfield, M. A. P., Hindocha, C., Green, S. F., et al., “The neuropsycho-pharmacology of cannabis: A review of human imaging studies,” Pharmacol. Ther., 195, 132–161 (2019).
Böcker, K. B., Hunault, C. C., Gerritsen, J., et al., “Cannabinoid modulations of resting state EEG θ power and working memory are correlated in humans,” J. Cogn. Neurosci., 22, 1906–1916 (2010).
Boggio, P. S., Zaghi, S., Villani, A. B., et al., “Modulation of risk-taking in marijuana users by transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC),” Drug Alcohol Depend., 112, 220–225 (2010).
Bolla, K. I., Brown, K., Eldreth, D., et al., “Dose-related neurocognitive effects of marijuana use,” Neurology, 59, 1337–1343 (2002).
Borgan, F., Beck, K., Butler, E., et al., “The effects of cannabinoid 1 receptor compounds on memory,” Psychopharmacology (Berlin), 236, 3257–3270 (2019).
Bornstein, A. M., Khaw, M. W., Shohamy, D., and Daw, N. D., “Reminders of past choices bias decisions for reward in humans,” Nat. Commun., 8, 15958 (2017).
Bossong, M. G., Jager, G., van Hell, H. H., et al., “Effects of Delta9-tetrahydrocannabinol administration on human encoding and recall memory function: a pharmacological FMRI study,” J. Cogn. Neurosci., 24, 588–599 (2012).
Bossong, M. G., van Hell, H. H., Jager, G., et al., “The endocannabinoid system and emotional processing: a pharmacological fMRI study with Δ9-tetrahydrocannabinol,” Eur. Neuropsychopharmacol., 23, 1687–1697 (2013).
Bragin, A., Jandy, G., Nadasdy, Z., et al., “Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat,” J. Neurosci., 15, 47–60 (1995).
Brodkin, J. and Moerschbaecher, J. M., “SR141716A antagonizes the disruptive effects of cannabinoid ligands on learning in rats,” J. Pharmacol. Exp. Ther., 282, 1526–1532 (1997).
Broyd, S. J., van Hell, H. H., Beale, C., et al., “Acute and chronic effects of cannabinoids on human cognition – a systematic review,” Biol. Psychiatry, 79, 557–567 (2016).
Burgess, N., Maguire, E., and O’Keefe, J., “The human hippocampus and spatial and episodic memory,” Neuron, 35, 625–641 (2002).
Burggren, A. C., Shirazi, A., Ginder, N., and London, E. D., “Cannabis effects on brain structure, function, and cognition: considerations for medical uses of cannabis and its derivatives,” Am. J. Drug Alcohol Abuse, 45, 563–579 (2019).
Busquets-Garcia, A., Desprez, T., Metna-Laurent, M., et al., “Dissecting the cannabinergic control of behavior: The where matters,” Bioessays, 37, 1215–1225 (2015).
Busquets-Garcia, A., Oliveira Da Cruz, J. F., Terral, G., et al., “Hippocampal CB1 receptors control incidental associations,” Neuron, 99, 1247–1259.e7 (2018).
Busquets-Garcia, A., Puighermanal, E., Pastor, A., et al., “Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses,” Biol. Psychiatry, 70, 479–486 (2011).
Buzsàki, G. and Moser, E. I., “Memory, navigation and theta rhythm in the hippocampal-entorhinal system,” Nat. Neurosci., 16, 130–138 (2013).
Buzsàki, G. and Watson, B. O., “Brain rhythms and neural syntax: implications for efficient coding of cognitive content and neuropsychiatric disease,” Dialogues Clin. Neurosci., 14, 345–367 (2012).
Buzsàki, G., “Large-scale recording of neuronal ensembles,” Nat. Neurosci., 7, 446–451 (2004).
Buzsàki, G., “Theta oscillations in the hippocampus,” Neuron, 33, 325–340 (2002).
Buzsàki, G., Rhythms of the Brain, Oxford University Press, New York (2006).
Campolongo, P., Roozendaal, B., Trezza, V., et al., “Fat-induced satiety factor oleoylethanolamide enhances memory consolidation,” Proc. Natl. Acad. Sci. USA, 106, 8027–8031 (2009).
Cariccio Lanza, V., Scionti, D., Raffa, A., et al., “Treatment of periodontal ligament stem cells with MOR and CBD promotes cell survival and neuronal differentiation via the PI3K/Akt/mTOR pathway,” Int. J. Mol. Sci., 19, pii: E2341 (2018).
Castellano, C., Rossi-Arnaud, C., Cestari, V., and Costanz, M., “Cannabinoids and memory: Animal studies,” Curr. Drug Targets CNS Neurol. Disord., 2, 3 89–402 (2003).
Cavanagh, J. F., Cohen, M. X., and Allen, J. J., “Prelude to and resolution of an error: EEG phase synchrony reveals cognitive control dynamics during action monitoring,” J. Neurosci., 29, 98–105 (2009).
Centonze, D., Battista, N., Rossi, S., et al., “A critical interaction between dopamine D2 receptors and endocannabinoids mediates the effects of cocaine on striatal GABAergic transmission,” Neuropsychopharmacology, 29, 1488–1497 (2004).
Chang, J. W., Niphakis, M. J., Lum, K. M., et al., “Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates,” Chem. Biol., 19, 579–588 (2012).
Chang, L., Yakupov, R., Cloak, C., and Ernst, T., “Marijuana use is associated with a reorganized visual-attention network and cerebellar hypoactivation,” Brain, 129, Pt. 5, 1096–1112 (2006).
Cheng, D., Spiro, A. S., Jenner, A. M., et al., “Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice,” J. Alzheimers Dis., 42, 1383–1396 (2014).
Choi, K., Le, T., McGuire, J., et al., “Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear,” J. Psychiatr. Res., 46, 882–889 (2012).
Clendinning, J., “Observation on the medicinal properties of . Cannabis sativa of India,” Med. Chir. Trans., 26, 188–210 (1843).
Colangeli, R., Pierucci, M., Benigno, A., et al., “The FAAH inhibitor URB597 suppresses hippocampal maximal dentate after discharges and restores seizure-induced impairment of short and long-term synaptic plasticity,” Sci. Rep., 7, 11152 (2017).
Constoe, P. F., Jones, B. C., and Chin, L., “Delta-9-tetrahydrocannabinol, EEG and behavior: the importance of adaptation to the testing milieu,” Pharmacol. Biochem. Behav., 3, 173–177 (1975).
Contarini, G., Ferretti, V., and Papaleo, F., “Acute administration of URB597 fatty acid amide hydrolase inhibitor prevents attentional impairments by distractors in adolescent mice,” Front. Pharmacol., 10, 787 (2019).
Cooper, R. E., Williams, E., Seegobin, S., et al., “Cannabinoids in attention-deficit/hyperactivity disorder: a randomised-controlled trial,” Eur. Neuropsychopharmacol., 27, 795–808 (2017).
Crane, N. A., Schuster, R. M., and Gonzalez, R., “Preliminary evidence for a sex-specific relationship between amount of cannabis use and neurocognitive performance in young adult cannabis users,” J. Int. Neuropsychol. Soc., 19, 1009–1015 (2013a).
Crane, N. A., Schuster, R. M., Fusar-Poli, P., and Gonzalez, R., “Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences,” Neuropsychol. Rev., 23, 117–137 (2013b).
Cravatt, B. F., Giang, D. K., Mayfield, S. P., et al., “Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides,” Nature, 384, 83–87 (1996).
Crean, R. D., Crane, N. A., and Mason, B. J., “An evidence-based review of acute and long-term effects of cannabis use on executive cognitive functions,” J. Addict. Med., 5, 1–8 (2011).
Cristino, L., Bisogno, T., and Di Marzo, V., “Cannabinoids and the expanded endocannabinoid system in neurological disorders,” Nat. Dev. Neurol., 16, 9–28 (2020a).
Cristino, L., Bisogno, T., and Di Marzo, V., “Cannabinoids and the expanded endocannabinoid system in neurological disorders,” Nat. Rev., 16, 9–28 (2020b).
Crunfli, F., Vrechi, T. A., Costa, A. P., and Torrão, A. S., “Cannabinoid receptor type 1 agonist ACEA improves cognitive deficit on STZInduced neurotoxicity through apoptosis pathway and NO modulation,” Neurotox. Res., 35, 516–529 (2019).
Curran, H. V., Brignell, C., Fletcher, S., et al., “Cognitive and subjective dose-response effects of acute oral D9-tetrahydrocannabinol (THC) in infrequent cannabis users,” Psychopharmacology, 164, 61–70 (2002).
Cuttler, C. and Spradlin, A., “Measuring cannabis consumption: psychometric properties of the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ-CU),” PLoS One, 12, 1–14 (2017).
Danandeh, A., Vozella, V., Lim, J., et al., “Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced longterm anxiety,” Psychopharmacology, 235, 3211–3221 (2018).
Davies, S. N., Pertwee, R. G., and Riedel, G., “Functions of cannabinoid receptors in the hippocampus,” Neuropharmacology, 42, 993–1007 (2002).
de Curtis, M., Jefferys, J. G. R., and Avoli, M., “Interictal epileptiform discharges in partial epilepsy: Complex neurobiological mechanisms based on experimental and clinical evidence,” in: Jasper’s Basic Mechanisms of the Epilepsies, Noebels, J. L. et al. (eds.), Oxford University Press, Oxford (2012), pp. 1–20.
De Petrocellis, L., Nabissi, M., Santoni, G., and Ligresti, A., “Actions and regulation of ionotropic cannabinoid receptors,” Adv. Pharmacol., 80, 249–289 (2017).
Degenhardt, L., Chiu, W. T., Sampson, N., et al., “Toward a global view of alcohol, tobacco, cannabis, and cocaine use: findings from the WHO World Mental Health Surveys,” PLos Medicine, 5, e141 (2008).
Delatte, M. S., Winsauer, P. J., and Moerschbaecher, J. M., “Tolerance to the disruptive effects of Delta (9)-THC on learning in rats,” Pharmacol. Biochem. Behav., 74, 129–140 (2002).
Devane, W. A., Hanus, L., Breuer, A., et al., “Isolation and structure of a brain constituent that binds to the cannabinoid receptor,” Science, 258, 1946–1949 (1992).
Devinsky, O., Cross, J. H., Laux, L., et al., “Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome,” New Engl. J. Med., 376, 2011–2020 (2017).
Devinsky, O., Marsh, E., Friedman, D., et al., “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurol., 15, 270–278 (2016).
Devinsky, O., Patel, A. D., Thiele, E. A., et al., “Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome,” Neurology, 90, e1204–e1211 (2018).
Di Iorio, G., Lupi, M., Sarchione, F., et al., “The endocannabinoid system: a putative role in neurodegenerative diseases,” Int. J. High Risk Behav. Addict., 2, 100–106 (2013).
Di Marzo, V. and Petrosino, S., “Endocannabinoids and the regulation of their levels in health and disease,” Curr. Opin. Lipidol., 18, 129–140 (2007).
Di Marzo, V. and Wang, J. (eds.), The Endocannabinoidome: The World of Endocannabinoids and Related Mediators, Elsevier Academic Press, London (2015).
Di Marzo, V., “New approaches and challenges to targeting the endocannabinoid system,” Nat. Rev. Drug Discov., 17, 623–639 (2018).
Di Marzo, V., “Targeting the endocannabinoid system: to enhance or reduce?” Nat. Rev. Drug Discov., 7, 438–455 (2008).
Di Marzo, V., Bifulco, M., and De, P. L., “The endocannabinoid system and its therapeutic exploitation,” Nat. Rev. Drug Discov., 3, 771–784 (2004).
Di Petrosino, M. V. S., “Endocannabinoids and the regulation of their levels in health and disease,” Curr. Opin. Lipidol., 18, 129–140 (2007).
Dinh, T. P., Carpenter, D., Leslie, F. M., et al., “Brain monoglyceride lipase participating in endocannabinoid inactivation,” Proc. Natl. Acad. Sci. USA, 99, 10819–10824 (2002).
dos Santos, R. G., Hallak, J. E., Leite, J. P., et al., “Phytocannabinoids and epilepsy,” J. Clin. Pharm. Ther, 40, 135–143 (2015).
Dragoi, G. and Buzsaki, G., “Temporal encoding of place sequences by hippocampal cell assemblies,” Neuron, 50, 145–157 (2006).
Dregan, A. and Gulliford, M. C., “Is illicit drug use harmful to cognitive functioning in the mid-adult years? A cohort-based investigation,” Am. J. Epidemiol., 175, 218–227 (2012).
D’Souza, D. C., Cortes-Briones, J. A., Ranganathan, M., et al., “Rapid changes in CB1 receptor availability in cannabis dependent males after abstinence from cannabis,” Biol. Psychiatry Cogn. Neurosci. Neuroimaging, 1, 60–67 (2016).
D’Souza, D. C., Ranganathan, M., Braley, G., et al., “Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis,” Neuropsychopharmacology, 33, 2505–2516 (2008).
Elsohly, M. A. and Slade, D., “Chemical constituents of marijuana: the complex mixture of natural cannabinoids,” Life Sci., 78, 539–548 (2005).
Esposito, G., De Filippis, D., Carnuccio, R., 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, 253–258.
Eubanks, L. M., Rogers, C. J., Beuscher, A. E., IV., et al., “A molecular link between the active component of marijuana and Alzheimer’s disease pathology,” Mol. Pharm., 3, 773–777 (2006).
Fagundo, A. B., de la Torre, R., Jiménez-Murcia, S., et al., “Modulation of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) on executive functions in humans,” PLoS One, 8, e66387 (2013).
Fakhfouri, G., Ahmadiani, A., Rahimian, R., et al., “WIN55212-2 attenuates amyloidbeta-induced neuroinfl ammation in rats through activation of cannabinoid receptors and PPAR-gamma pathway,” Neuropharmacology, 63, 653–666 (2012).
Fell, J., Ludowig, E., Rosburg, T., et al., “Phase-locking within human mediotemporal lobe predicts memory formation,” Neuroimage, 43, 410–419 (2008).
Fernandez-Serrano, M. J., Perez-Garcia, M., Schmidt RioValle, J., and Verdejo-Garcia, A., “Neuropsychological consequences of alcohol and drug abuse on different components of executive functions,” J. Psychopharmacol., 24, 1317–1332 (2010).
Ferrer, I., “Defi ning Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia,” Prog. Neurobiol., 97, 38–51 (2012).
Fisk, J. E. and Montgomery, C., “Real-world memory and executive processes in cannabis users and non-users,” J. Psychopharmacol., 22, 727–736 (2008).
Fonken, Y. M., Kam, J. W. Y., and Knight, R. T., “A differential role for human hippocampus in novelty and contextual processing: Implications for P300,” Psychophysiology, e13400 (2019).
Fontes, M. A., Bolla, K. I., Cunha, P. J., et al., “Cannabis use before age 15 and subsequent executive functioning,” Brit. J. Psychiatry, 198, 442–447 (2011).
Ford, T. C., Hayley, A. C., Downey, L. A., and Parrott, A. C., “Cannabis: an overview of its adverse acute and chronic effects and its implications,” Curr. Drug Abuse Rev, 10, 6–18 (2018).
Freund, T. F., Katona, I., and Piomelli, D., “Role of endogenous cannabinoids in synaptic signaling,” Physiol. Rev., 83, 1017–1066 (2003).
Fridberg, D. J., Queller, S., Ahn, W. Y., et al., “Cognitive mechanisms underlying risky decision-making in chronic cannabis users,” J. Math. Psych., 54, 28–38 (2010).
Fried, P., Watkinson, B., James, D., and Gray, R., “Current and former marijuana use: preliminary findings of a longitudinal study of effects on IQ in young adults,” CMAJ, 166, 887–891 (2002).
Fusar-Poli, P., Crippa, J. A., Bhattacharyya, S., et al., “Distinct effects of Δ9- tetrahydrocannabinol and cannabidiol on neural activation during emotional processing,” Arch. Gen. Psychiatry, 66, 95–105 (2009).
Galiegue, S., Mary, S., Marchand, J., et al., “Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations,” Eur. J. Biochem., 232, 54–61 (1995).
Gaoni, Y. and Mechoulam, R., “Isolation, structure and partial synthesis of an active constituent of hashish,” J. Am. Chem. Soc., 86, 1646–1647 (1964).
Garcia-Arencibia, M., Gonzalez, S., De Lago, E., et al., “Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptorindependent properties,” Brain Res., 1134, 162–170 (2007).
García-Gutiérrez, M. S., Ortega-Álvaro, A., Busquets-García, A., et al., “Synaptic plasticity alterations associated with memory impairment induced by deletion of CB2 cannabinoid receptors,” Neuropharmacology, 73, 388–396 (2013).
Giacoppo, S., Pollastro, F., Grassi, G., et al., “Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis,” Fitoterapia, 116, 77–84 (2017).
Goffin, K., Van Paesschen, W., and Van Laere, K., “In vivo activation of endocannabinoid system in temporal lobe epilepsy with hippocampal sclerosis,” Brain, 134, 1033–1040 (2011).
Gonzalez, R., Schuster, R. M., Crane, N. A., et al., “Decision-making performance influences the relationship between amount of cannabis use and its negative consequences,” J. Int. Neuropsychol. Sol., 35, 573–583 (2013).
Goonawardena, A. V., Sesay, J., Sexton, C. A., et al., “Pharmacological elevation of anandamide impairs short-term memory by altering the neurophysiology in the hippocampus,” Neuropharmacology, 61, 1016–1025 (2011).
Grant, J. E., Chamberlain, S. R., Schreiber, L., and Odlaug, B. L., “Neuropsychological deficits associated with cannabis use in young adults,” Drug and Alcohol Depend., 121, 159–162 (2011).
Grotenhermen, F., “Cannabinoids,” Curr. Drug Targets CNS Neurol. Disord., 4, 507–530 (2005).
Gruber, S. A. and Sagar, K. A., “Marijuana on the mind? The impact of marijuana on cognition, brain structure, and brain function, and related public policy implications,” Policy Insights Behav. Brain Sci., 4, 104–111 (2017).
Gruber, S. A., Dahlgren, M. K., Sagar, K. A., et al., “Decreased Cingulate Cortex activation during cognitive control processing in bipolar disorder,” J. Affect. Disord., 213, 86–95 (2017).
Gruber, S. A., Rogowska, J., and Yurgelun-Todd, D. A., “Altered affective response in marijuana smokers: an FMRI study,” Drug Alcohol Depend., 105, 139–153 (2009).
Gruber, S. A., Sagar, K. A., Dahlgren, M. K., et al., “The grass might be greener: medical marijuana patients exhibit altered brain activity and improved executive function after 3 months of treatment,” Front. Pharmacol., 8, 983 (2018).
Gruber, S. A., Sagar, K. A., Dahlgren, M. K., et al., “Splendor in the grass? A pilot study assessing the impact of medical marijuana on executive function,” Front. Pharmacol., 7, 355 (2016).
Haghani, M., Shabani, M., Javan, M., et al., “CB1 cannabinoid receptor activation rescues amyloid beta-induced alterations in behaviour and intrinsic electrophysiological properties of rat hippocampal CA1 pyramidal neurones,” Cell. Physiol. Biochem., 29, 391–406 (2012).
Hampson, R. E. and Deadwyler, S. A., “Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats,” J. Neurosci., 20, 8932–8942 (2000).
Hampson, R. E. and Deadwyler, S. A., “Cannabinoids, hippocampal function and memory,” Life Sci., 65, 715–723 (1999).
Hanson, K. L., Winward, J. L., Schweinsburg, A. D., et al., “Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence,” Addict. Behav., 35, 970–976 (2010).
Harding, I. H., Solowij, N., Harrison, B., et al., “Functional connectivity in brain networks underlying cognitive control in chronic cannabis users,” Neuropsychopharmacology, 37, 1923–1933 (2012).
Hardingham, G. E. and Bading, H., “Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders,” Nat. Rev. Neurosci., 11, 682–696 (2010).
Hardy, J. and Selkoe, D. J., “The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics,” Science, 297, 353–356 (2002).
Hardy, J., “The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal,” J. Neurochem., 110, 1129–1134 (2009).
Harris, K. D., Csicsvari, J., Hirase, H., et al., “Organization of cell assemblies in the hippocampus,” Nature, 424, 552–556 (2003).
Hart, C. L., Ilan, A. B., Gevins, A., et al., “Neurophysiological and cognitive effects of smoked marijuana in frequent users,” Pharmacol. Biochem. Behav., 96, 333–341 (2010).
Harvey, M. A., Sellman, J. D., Porter, R. J., and Frampton, C. M., “The relationship between non-acute adolescent cannabis use and cognition,” Drug Alcohol Rev., 26, 309–319 (2007).
Hasanein, P. and Far, M. T., “Pharmacology, biochemistry and behavior effects of URB597 as an inhibitor of fatty acid amide hydrolase on WIN55, 212-2-induced learning and memory defi cits in rats,” Pharmacol. Biochem. Behav., 131, 130–135 (2015).
Hasumi, T., Fukushima, T., Haisa, T., et al., “Focal dural arteriovenous fistula (DAVF) presenting with progressive cognitive impairment including amnesia and alexia,” Intern. Med., 46, 1317–1320 (2007).
Hebert-Chatelain, E., Desprez, T., Serrat, R., et al., “A cannabinoid link between mitochondria and memory,” Nature, 539, No. 7630, 555–559 (2016).
Hergenrather, J., Cannabis and Dementia, Cannabis Expertise, Columbus, OH (2017).
Hermann, D., Sartorius, A., Welzel, H., et al., “Dorsolateral prefrontal cortex N-acetylaspartate/total creatine (NAA/tCr) loss in male recreational cannabis users,” Biol. Psychiatry, 61, 1281–1289 (2007).
Hill, M. N., Patel, S., Carrier, E. J., et al., “Down-regulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress,” Neuropsychopharmacology, 30, 508–515 (2005).
Hillen, J. B., Soulsby, N., Alderman, C., and Caughey, G. E., “Safety and effectiveness of cannabinoids for the treatment of neuropsychiatric symptoms in dementia: a systematic review,” Ther. Adv. Drug Saf., 10, 1–23 (2019).
Hindocha, C., Freeman, T. P., Schafer, G., et al., “Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users,” Eur. Neuropsychopharmacol., 25, 325–334 (2015).
Hirvonen, J., Goodwin, R. S., Li, C. T., et al., “Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers,” Mol. Psychiatry, 17, 642–649 (2012).
Holter, S. M., Kallnik, M., Wurst, W., et al., “Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively motivated learning task,” Eur. J. Pharmacol., 510, 69–74 (2005).
Hooper, S. R., Woolley, D., and De Bellis, M. D., “Intellectual, neurocognitive, and academic achievement in abstinent adolescents with cannabis use disorder,” Psychopharmacology (Berlin), 231, 1467–1477 (2014).
Horton, K. A., Goonawardena, A. V., Sesay, J., et al., “Systemic blockade of the CB1 receptor augments hippocampal gene expression involved in synaptic plasticity but perturbs hippocampus-dependent learning task,” Cannabis Cannabinoid Res., 4, No. 1, 33–41 (2019).
Howlett, A. C., “The cannabinoid receptors,” Prostaglandins Other Lipid Mediat., 68–69, 619–631 (2002).
Howlett, A. C., Cannabinoids: Handbook of Experimental Pharmacology, Pertwee, R. G. (ed.), Springer, Berlin (2005), pp. 53–79
Ilan, A. B., Smith, M. E., and Gevins, A., “Effects of marijuana on neurophysiological signals of working and episodic memory,” Psychopharmacology (Berlin), 176, 214–222 (2004).
Iuvone, T., Esposito, G., Esposito, R., et al., “Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on b-amyloid-induced toxicity in PC12 cells,” J. Neurochem., 89, 134–141 (2004).
Izzo, A. A., Borrelli, F., Capasso, R., et al., “Nonpsychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb,” Trends Pharmacol. Sci., 30, 515–527 (2009).
Jacobsen, L. K., Mencl, W. E., Westerveld, M., and Pugh, K. R., “Impact of cannabis use on brain function in adolescents,” Ann. N.Y. Acad. Sci., 1021, 384–390 (2004).
Jacobsen, L. K., Pugh, K. R., Constable, R. T., et al., “Functional correlates of verbal memory deficits emerging during nicotine withdrawal in abstinent adolescent cannabis users,” Biol. Psychiatry, 61, 31–40 (2007).
Jager, G., Bloc, R. I., Luijten, M., and Ramsey, N. F., “Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter functional magnetic resonance imaging study,” J. Am. Acad. Child Adolesc. Psychiatry, 49, 561–572, e561–563 (2010).
Johnson, D. E., Heald, S. L., Dally, R. D., and Janis, R. A., “Isolation, identification and synthesis of an endogenous arachidonic amide that inhibits calcium channel antagonist 1,4-dihydropyridine binding,” Prostaglandins Leukot. Essent. Fatty Acids, 48, 429–437 (1993).
Jung, K. M., Clapper, J. R., Fu, J., et al., “2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism,” Cell Metab., 15, 299–310 (2012).
Kalant, H., “Adverse effects of cannabis on health: an update of the literature since 1996,” Prog. Neuropsychopharmacol. Biol. Psychiatry, 28, 849–863 (2004).
Kano, M., Ohno-Shosaku, T., Hashimotodani, Y., et al., “Endocannabinoidmediated control of synaptic transmission,” Physiol. Rev., 89, 309–380 (2009).
Katona, I. and Freund, T. F., “Endocannabinoid signaling as a synaptic circuit breaker in neurological disease,” Nat. Med., 14, 923–930 (2008).
Khan, M. I., Sobocicska, A. A., Czarnecka, A. M., et al., “The therapeutic aspects of the endocannabinoid system (ECS) for cancer and their development: From nature to laboratory,” Curr. Pharm. Des., 22, 1756–1766 (2016).
Khaspekov, L. G. and Bobrov, M. Yu., “The endogenous cannabinoid system and its protective role in ischemic and cytotoxic damage to cerebral neurons,” Neirokhimiya, 23, 85–105 (2006).
Khaspekov, L. G., Brenz-Verca, M. S., Frumkina, L. E., et al., “Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity,” Eur. J. Neurosci., 19, 1691–1698 (2004).
Kiroĭ, V. N. and Choraian, O. G., “The neuronal ensembles of the brain,” Usp. Fiziol. Nauk., 31, 23–38 (2000).
Klein, T. W., “Cannabinoid-based drugs as anti-infl ammatory therapeutics,” Nat. Rev. Immunol., 5, 400–411 (2005).
Krook-Magnuson, E., Armstrong, C., Oijala, M., and Soltesz, I., “Ondemand optogenetic control of spontaneous seizures in temporal lobe epilepsy,” Nat. Commun., 4, 1376 (2013).
Kroon, E., Kuhns, L., Hoch, E., and Cousijn, J., “Heavy cannabis use, dependence and the brain: a clinical perspective,” Addiction, 115, 559–572 (2020).
Kruk-Slomka, M. and Biala, G., “CB1 receptors in the formation of the different phases of memory-related processes in the inhibitory avoidance test in mice,” Behav. Brain Res., 301, 84–95 (2016).
Kuhnert, S., Meyer, C., and Koch, M., “Involvement of cannabinoid receptors in the amygdala and prefrontal cortex of rats in fear learning, consolidation, retrieval and extinction,” Behav. Brain Res., 250, 274–284 (2013).
Lane, S. D., Cherek, D. R., Tcheremissine, O. V., et al., “Acute marijuana effects on human risk taking,” Neuropsychopharmacology, 30, 800–809 (2005).
Lane, S. D., Cherek, D. R., Tcheremissine, O. V., et al., “Response perseveration and adaptation in heavy marijuana-smoking adolescents,” Addict. Behav., 32, 977–990 (2007).
Laspada, N., Delker, E., Blanco, E., et al., “Marijuana use associated with worse verbal learning and delayed recall in a sample of young adults,” Rev. Med. Chil., 147, 206–211 (2019).
Laviolette, S. R. and Grace, A. A., “Cannabinoids potentiate emotional learning plasticity in neurons of the medial prefrontal cortex through basolateral amygdala inputs,” J. Neurosci., 26, 6458–6468 (2006).
Laviolette, S. R., Lipski, W. J., and Grace, A. A., “A subpopulation of neurons in the medial prefrontal cortex encodes emotional learning with burst and frequency codes through a dopamine D4 receptor-dependent basolateral amygdala input,” J. Neurosci., 25, 6066–6075 (2005).
Lega, B., Dionisio, S., Bingaman, W., et al., “The gamma band effect for episodic memory encoding is absent in epileptogenic hippocampi,” Clin. Neurophysiol., 126, 866–872 (2015).
Lemak, M. S. and Balaban, P. M., “The endogenous cannabinoid system in the CNS of vertebrates and invertebrates,” in: Scientific Session Proceedings, National Research Nuclear University, Moscow Engineering Physics Institute (2010), Vol. 2, pp. 172–191.
Lichtman, A. H., Varvel, S. A., and Martin, B. R., “Endocannabinoids in cognition and dependence,” Prostaglandins Leukot. Essent. Fatty Acids, 66, 269–285 (2002).
Lisdahl, K. M., Wright, N. E., Kirchner-Medina, C., et al., “Considering cannabis: the effects of regular cannabis use on neurocognition in adolescents and young adults,” Curr. Addict. Rep., 1, 144–156 (2014).
Lisman, J. E. and Jensen, O., “The theta-gamma neural code,” Neuron, 77, 1002–1016 (2013).
Ludanyi, A., Eross, L., Czirjak, S., et al., “Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus,” J. Neurosci., 28, 2976–2990 (2008).
Lutz, B. and Marsicano, G., Encyclopedia of Neuroscience, Squire, L. R. (ed.), Elsevier (2009), pp. 963–975.
Lyketsos, C. G., Garrett, E., Liang, K. Y., and Anthony, J. C., “Cannabis use and cognitive decline in persons under 65 years of age,” Am. J. Epidemiol., 149, 794–800 (1999).
Magloczky, Z. and Freund, T. F., “Impaired and repaired inhibitory circuits in the epileptic human hippocampus,” Trends Neurosci., 28, 334–340 (2005).
Magloczky, Z., Toth, K., Karlocai, R., et al., “Dynamic changes of CB1-receptor expression in hippocampi of epileptic mice and humans,” Epilepsia, 51, No. S3, 115–120 (2010).
Malkov, A. E., Shubina, L. V., and Kitchigina, V. F., “Effects of endocannabinoid-related compounds on the activity of septal and hippocampal neurons in a model of kainic neurotoxicity: study ex vivo,” Opera Med. Physiol., 4, 23–34 (2018).
Mallet, P. E. and Beninger, R. J., “The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by delta-9-tetrahydrocannabinol or anandamide,” Psychopharmacology, 140, 11–19 (1998).
Mandelbaum, D. E. and de la Monte, S. M., “Adverse structural and functional effects of marijuana on the brain: evidence reviewed,” Pediatr. Neurol., 66, 12–20 (2017).
Manuel, I., Gonzalez de San Roman, E., Giralt, M. T., et al., “Type-1 cannabinoid receptor activity during Alzheimer’s disease progression,” J. Alzheimers Dis., 42, 761–766 (2014).
Marsicano, G., Goodenough, S., Monory, K., et al., “CB1 cannabinoid receptors and on-demand defense against excitotoxicity,” Science, 302, 84–88 (2003).
Marsicano, G., Wotjak, C. T., Azad, S. C., et al., “The endogenous cannabinoid system controls extinction of aversive memories,” Nature, 418, 530–534 (2002).
Martin-Moreno, A. M., Brera, B., Spuch, C., et al., “Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice,” J. Neuroinflammation, 9, 8 (2012).
Mason, B. J., Crean, R., Goodell, V., et al., “A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults,” Neuropsychopharmacology, 37, 1689–1698 (2012).
Mason, N. L., Theunissen, E. L., Hutten, N. R. P. W., et al., “Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users,” Addict. Biol., 22, e12870 (2019).
Mato, S. and Pazos, A., “Infl uence of age, postmortem delay and freezing storage period on cannabinoid receptor density and functionality in human brain,” Neuropharmacology, 46, 716–726 (2008).
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., et al., “Structure of a cannabinoid receptor and functional expression of a cloned cDNA,” Nature, 346, 561–564 (1990).
Mazzola, C., Medalie, J., Scherma, M., et al., “Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-alpha nuclear receptors,” Learn. Mem., 16, 332–337 (2009).
McHale, S. and Hunt, N., “Executive function deficits in short-term abstinent cannabis users,” Hum. Psychopharmacol., 23, 409–415 (2008).
Mechoulam, R., “Marihuana chemistry,” Science, 168, No. 3936, 1159–1166 (1970).
Mechoulam, R., Peters, M., Murillo-Rodriguez, E., and Hanus, L. O., “Cannabidiol – recent advances,” Chem. Biodivers., 4, 1678–1692 (2007).
Mechoulam, R., Shvo, Y., and Hashish, I., “The structure of cannabidiol,” Tetrahedron, 19, 2073–2078 (1963).
Medina, K. L., Hanson, K. L., Schweinsburg, A. D., et al., “Neuropsychological functioning in adolescent marijuana users: subtle defi cits detectable after a month of abstinence,” J. Int. Neuropsychol. Soc., 13, 807–820 (2007).
Meier, M. H., Caspi, A., Ambler, A., et al., “Persistent cannabis users show neuropsychological decline from childhood to midlife,” Proc. Natl. Acad. Sci. USA, 109, E2657–E2664 (2012).
Mikheeva, I. B., Shubina, L., Matveeva, N., et al., “Fatty acid amide hydrolase inhibitor URB597 may protect against kainic acid–induced damage to hippocampal neurons: Dependence on the degree of injury,” Epilepsy Res., 137, 84–94 (2017).
Milton, N. G., “Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide,” Neurosci. Lett., 332, 127–130 (2002).
Mokrysz, C., Landy, R., Gage, S., et al., “Are IQ and educational outcomes in teenagers related to their cannabis use? A prospective cohort study,” J. Psychopharmacol., 30, 159–168 (2016).
Monory, K., Polack, M., Remus, A., et al., “Cannabinoid CB1 receptor calibrates excitatory synaptic balance in the mouse hippocampus,” J. Neurosci., 35, 3842–3850 (2015).
Montgomery, C., Seddon, A. L., Fisk, J. E., et al., “Cannabis-related deficits in real-world memory,” Hum. Psychopharmacol., 27, 217–225 (2012).
Morales, M., Wang, S. D., Diaz-Ruiz, O., and Jho, D. H., “Cannabinoid CB1 receptor and serotonin 3 receptor subunit A (5-HT3A) are co-expressed in GABA neurons in the rat telencephalon,” J. Comp. Neurol., 468, 205–216 (2004).
Moreau, J. J., Du Hachish et de l’Aliénation Mentale: Études Psychologiques, Libraire de Roxten, Maison Paris, Paris (1845).
Moreira, F. A. and Lutz, B., “The endocannabinoid system: emotion, learning and addiction,” Addict. Biol., 13, 196–212 (2008).
Morena, M. and Campolongo, P., “The endocannabinoid system: An emotional buffer in the modulation of memory function,” Neurobiol. Learn. Mem., 112, 30–43 (2013).
Morena, M., Roozendaal, B., Trezza, V., et al., “Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training,” Proc. Natl. Acad. Sci. USA, 111, 18333–18338 (2014).
Morgan, C. J., Gardener, C., Schafer, G., et al., “Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being,” Psychol. Med., 42, 391–400 (2012).
Morgan, C. J., Schafer, G., Freeman, T. P., and Curran, H. V., “Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study,” Brit J. Psychiatry, 197, 285–290 (2010).
Morin, J. F. G., Afzali, M. H., Bourque, J., et al., “A population-based analysis of the relationship between substance use and adolescent cognitive development,” Am. J. Psychiatry, 176, 98–106 (2019).
Morrison, B. J. and Thatcher, K., “Overpopulation effects on social reduction of emotionality in the albino rat,” J. Comp. Physiol. Psychol., 69, 658–662 (1969).
Mouro, F. M., Batalha, V. L., Ferreira, D. G., et al., “Chronic and acute adenosine A 2A receptor blockade prevents long-term episodic memory disruption caused by acute cannabinoid CB1 receptor activation,” Neuropharmacology, 117, 316–327 (2017).
Mouro, F. M., Ribeiro, J. A., Sebastigo, A. M., and Dawson, N., “Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity,” J. Neurochem., 147, 71–83 (2018).
Murav’eva, E. V. and Anokhin, K. V., “The role of protein synthesis in memory reconsolidation at different time points after fear conditioning in mice,” Zh. Vyssh. Nerv. Deyat., 56, No. 2, 1–8 (2006).
Murphy, M., Mills, S., Winstone, J., et al., “Chronic adolescent Δ9-Tetrahydrocannabinol treatment of male mice leads to long-term cognitive and behavioral dysfunction, which are prevented by concurrent cannabidiol treatment,” Cannabis Cannabinoid Res., 2, 235–246 (2017).
Navarrete, M. and Araque, A., “Endocannabinoids mediate neuron-astrocyte communication,” Neuron, 58, 883–893 (2008).
Navarro, G., Morales, P., Rodriguez-Cueto, C., et al., “Targeting cannabinoid CB2 receptors in the central nervous system. Medicinal chemistry approaches with focus on neurodegenerative disorders,” Front. Neurosci., 10, 406 (2016).
Nestor, L., Roberts, G., Garavan, H., and Hester, R., “Deficits in learning and memory: parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users,” NeuroImage, 40, 1328–1339 (2008).
Niesink, R. J. M. and van Laar, M. W., “Does cannabidiol protect against adverse psychological effects of THC?” Front. Psychol., 4, 1–8 (2013).
Okamoto, Y., Morishita, J., Tsuboi, K., et al., “Molecular characterization of a phospholipase D generating anandamide and its congeners,” J. Biol. Chem., 279, 5298–5305 (2004).
Pacher, P., Batkai, S., and Kunos, G., “The endocannabinoid system as an emerging target of pharmacotherapy,” Pharmacol. Rev., 58, 389–462 (2006).
Padula, C. B., Schweinsburg, A. D., and Tapert, S. F., “Spatial working memory performance and fMRI activation interaction in abstinent adolescent marijuana users,” Psychol. Addict. Behav., 21, 478–487 (2007).
Pamplona, F. A. and Takahashi, R. N., “WIN 55212–2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors,” Neurosci. Lett., 397, 88–92 (2006).
Pamplona, F. A., Prediger, R. D., Pandolfo, P., and Takahashi, R. N., “The cannabinoid receptor agonist WIN 55,212–2 facilitates the extinction of contextual fear memory and spatial memory in rats,” Psychopharmacology, 188, 641–649 (2006).
Panlilio, L. V., Thorndike, E. B., Nikas, S. P., et al., “Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats,” Psychopharmacology, 233, 1879–1888 (2016).
Panza, F., Lozupone, M., Logroscino, G., and Imbimbo, B. P., “A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease,” Nat. Rev., 15, 73–88 (2019a).
Panza, F., Lozupone, M., Seripa, D., and Imbimbo, B. P., “Amyloid-β-immunotherapy for Alzheimer disease: Is it now a long shot?” Ann. Neurol., 85, 303–315 (2019b).
Panza, F., Lozupone, M., Watling, M., and Imbimbo, B. P., “Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease?” Expert Rev. Neurother., 19, 599–602 (2019c).
Parkes, S. L. and Westbrook, R. F., “Role of the basolateral amygdala and NMDA receptors in higher-order conditioned fear,” Rev. Neurosci., 22, 317–333 (2011).
Paronis, C. A., Nikas, S. P., Shukla, V. G., and Makriyannis, A., “Δ9-Tetrahydrocannabinol acts as a partial agonist/ antagonist in mice,” Behav. Pharmacol., 23, 802–805 (2012).
Pellati, F., Brighenti, V., Sperlea, J., et al., “New methods for the comprehensive analysis of bioactive compounds in Cannabis sativa L. (hemp),” Molecules, 23, No. 10, 2639 (2018).
Pertwee, R. G., “Endocannabinoids and their pharmacological actions,” Handb. Exp. Pharmacol., 231, 1–37 (2015).
Piomelli, D., “The molecular logic of endocannabinoid signaling,” Nat. Rev. Neurosci., 4, 873–884 (2003).
Pistis, M., Muntoni, A. L., Pillolla, G., and Gessa, G. L., “Cannabinoids inhibit excitatory inputs to neurons in the shell of the nucleus accumbens: an in vivo electrophysiological study,” Eur. J. Neurosci., 15, 1795–1802 (2002).
Post, J. M., Loch, S., Lerner, R., et al., “Antiepileptogenic effect of subchronic palmitoylethanolamide treatment in a mouse model of acute epilepsy,” Front. Mol. Neurosci., 11, 67 (2018).
Przybyslawski, J. and Sara, S. J., “Reconsolidation of memory after its reactivation,” Behav. Brain Res., 84, 241–246 (1997).
Puighermanal, E., Marsicano, G., Busquets-Garcia, A., et al., “Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling,” Nat. Neurosci., 12, 1152–1158 (2009).
Querfurth, H. W. and La Ferla, F. M., “Alzheimer’s disease,” New Engl. J. Med., 362, 329–344 (2010).
Ramaekers, J. G., Theunissen, E. L., de Brouwer, M., et al., “Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users,” Psychopharmacology, 214, 391–401 (2011).
Ramirez, B. G., Blázquez, C., Gómez del Pulgar, T., et al., “Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation,” J. Neurosci., 25, 1904–1913 (2005).
Ranganathan, M. and D’Souza, D. C., “The acute effects of cannabinoids on memory in humans: a review,” Psychopharmacology, 188, 425–444 (2006).
Ratano, P., Palmery, M., Trezza, V., and Campolongo, P., “Cannabinoid modulation of memory consolidation in rats: beyond the role of cannabinoid receptor subtype 1,” Front. Pharmacol., 8, 200 (2017).
Ratano, P., Petrella, C., Forti, F., et al., “Pharmacological inhibition of 2-arachidonoilglycerol hydrolysis enhances memory consolidation in rats through CB2 receptor activation and mTOR signaling modulation,” Neuropharmacology, 138, 210–218 (2018).
Reibaud, M., Obinu, M. C., Ledent, C., et al., “Enhancement of memory in cannabinoid CB1 receptor knock-out mice,” Eur. J. Pharmacol., 379, No. 1, R1–2 (1999).
Rivera, P., Bindila, L., Pastor, A., et al., “Pharmacological blockade of the fatty acid amide hydrolase (FAAH) alters neural proliferation, apoptosis and gliosis in the rat hippocampus, hypothalamus and striatum in a negative energy context,” Front. Cell. Neurosci., 9, 98 (2015).
Robbe, D. and Buzsàki, G., “Alteration of theta timescale dynamics of hippocampal place cells by a cannabinoid is associated with memory impairment,” J. Neurosci., 29, 12597–12605 (2009).
Robin, L. M., Oliveira da Cruz, J. F., Langlais, V. C., et al., “Astroglial CB1 receptors determine synaptic D-serine availability to enable recognition memory,” Neuron, 98, No. 5, 935–944.e5 (2018).
Rogeberg, O., “Correlations between cannabis use and IQ change in the Dunedin cohort are consistent with confounding from socioeconomic status,” Proc. Natl. Acad. Sci. USA, 110, 4251 (2013).
Romigi, A., Bari, M., Placidi, F., et al., “Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy,” Epilepsia, 51, 768–772 (2010).
Russo, E. B., “Cannabis and epilepsy: an ancient treatment returns to the fore,” Epilepsy Behav., 70, 292–297 (2017a).
Russo, E. B., “Cannabis therapeutics and the future of neurology,” Front. Integr. Neurosci., 12, 51 (2008).
Russo, E. B., “History of cannabis as medicine: nineteenth century Irish physicians and correlations of their observations to modern research, and in Cannabis Sativa, L.,” in: Botany and Biotechnology, Chanda, S. et al. (eds.), Springer International Publishing, Switzerland (2017b), pp. 63–78.
Russo, E. B., “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” Br. J. Pharmacol., 163, 1344–1364 (2011).
Sagar, K. A. and Gruber, S. A., “Interactions between recreational cannabis use and cognitive function: lessons from functional magnetic resonance imaging,” Ann. N. Y. Acad. Sci., 1451, 42–70 (2019).
Sara, S. J., “Retrieval and reconsolidation: toward a neurobiology of remembering,” Learn. Mem., 7, 73–84 (2000).
Scheggia, D., Zamberletti, E., Realini, N., et al., “Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex,” Mol. Psychiatry, 25, 2529–2541 (2018).
Schoeler, T. and Bhattacharyya, S., “The effect of cannabis use on memory function: an update,” Subst. Abuse Rehabil., 4, 11–27 (2013).
Scholes-Balog, K. E. and Martin-Iverson, M. T., “Cannabis use and sensorimotor gating in patients with schizophrenia and healthy controls,” Hum. Psychopharmacol., 26, 373–385 (2011).
Schuster, R. M., Gilman, J., Schoenfeld, D., et al., “One month of cannabis abstinence in adolescents and young adults is associated with improved memory,” J. Clin. Psychiatry, 79, No. 6, pii: 17m11977 (2018).
Schweinsburg, A. D., Brown, S. A., and Tapert, S. F., “The influence of marijuana use on neurocognitive functioning in adolescents,” Curr. Drug Abuse Rev., 1, 99–111 (2008).
Schweinsburg, A. D., Schweinsburg, B. C., Medina, K. L., et al., “The influence of recency of use on fMRI response during spatial working memory in adolescent marijuana users,” J. Psychoactive Drugs, 42, 401–412 (2010).
Scott, J. C., Rosen, A. F. G., Moore, T. M., et al., “Cannabis use in youth is associated with limited alterations in brain structure,” Neuropsychopharmacology, 44, 1362–1369 (2019).
Scott, J. C., Slomiak, S. T., Jones, J. D., et al., “Association of cannabis with cognitive functioning in adolescents and young adults: a systematic review and metaanalysis,” JAMA Psychiatry, 75, 585–595 (2018).
Scott, J. C., Wolf, D. H., Calkins, M. E., et al., “Cognitive functioning of adolescent and young adult cannabis users in the Philadelphia Neurodevelopmental Cohort,” Psychol. Addict. Behav., 31, 423–434 (2017).
Scuderi, C., Esposito, G., Blasio, A., et al., “Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide,” J. Cell. Mol. Med., 15, 2664–2674 (2011).
Shimasue, K., Urushidani, T., Hagiwara, M., and Nagao, T., “Effects of anandamide and arachidonic acid on specifi c binding of (+) -PN200-110, diltiazem and (–) -desmethoxyverapamil to L-type Ca2+ channel,” Eur. J. Pharmacol., 296, 347–350 (1996).
Shubina, L. V. and Kichigina, V. F., “The protective influence of the CB1 receptor agonist WIN55,212-2 on development of convulsive activity in the brain in models of temporal epilepsy,” Zh. Vyssh. Nerv. Deyat., 61, 1–8 (2011).
Shubina, L. V., Modulation of Convulsive Activity by Endogenous Cannabinoids in a Model of Temporal Epilepsy, Dissertation for Master of Biological Sciences degree, Pushchino (2015).
Shubina, L., Aliev, R., and Kitchigina, V., “Attenuation of kainic acid-induced status epilepticus by inhibition of endocannabinoid transport and degradation in guinea pigs,” Epilepsy Res., 111, 33–44 (2015).
Shubina, L., Aliev, R., and Kitchigina, V., “Endocannabinoid-dependent protection against kainic acid-induced long-term alteration of brain oscillations in guinea pigs,” Brain Res., 1661, 1–14 (2017).
Sokolic, L., Long, L. E., Hunt, G. E., et al., “Disruptive effects of the prototypical cannabinoid Δ9-tetrahydrocannabinol and the fatty acid amide inhibitor URB-597 on go/no-go auditory discrimination performance and olfactory reversal learning in rats,” Behav. Pharmacol., 22, 191–202 (2011).
Solowij, N. and Michie, P. T., “Cannabis and cognitive dysfunction: Parallels with endophenotypes of schizophrenia?” J. Psychiatry Neurosci., 32, 30–52 (2007).
Solowij, N. and Pesa, N., “Cannabis and cognition: Short and long-term effects,” in: Marijuana and Madness, Castle, D. et al. (eds.), Cambridge University Press, Cambridge (2012), 2nd ed., pp. 91–102.
Solowij, N. and Pesa, N., “Cognitive abnormalities and cannabis use,” Braz. J. Psychiatry, 32, S31–S40 (2010).
Solowij, N., Jones, K. A., Rozman, M. E., et al., “Verbal learning and memory in adolescent cannabis users, alcohol users and non-users,” Psychopharmacology (Berlin), 216, 131–144 (2011).
Stone, J. M., Morrison, P. D., Nottage, J., et al., “Delta-9-tetrahydrocannabinol disruption of time perception and of self-timed actions,” Pharmacopsychiatry, 43, 236–237 (2010).
Su, S. H., Wang, Y. Q., Wu, Y. F., et al., “Cannabinoid receptor agonist WIN55,2122 and fatty acid amide hydrolase inhibitor URB597 may protect against cognitive impairment in rats of chronic cerebral hypoperfusion via PI3K/AKT signaling,” Behav. Brain Res., 313, 334–344 (2016).
Sugarman, D. E., Poling, J., and Sofuoglu, M., “The safety of modafinil in combination with oral 9-tetrahydrocannabinol in humans,” Pharmacol. Biochem. Behav., 98, 94–100 (2011).
Suleymanova, E. M., Borisova, M. A., and Vinogradova, L. V., “Early endocannabinoid system activation attenuates behavioral impairments induced by initial impact but does not prevent epileptogenesis in lithium-pilocarpine status epilepticus model,” Epilepsy Behav., 92, 71–78 (2019).
Suleymanova, E. M., Shangaraeva, V. A., van Rijn, C. M., and Vinogradova, L. V., “The cannabinoid receptor agonist WIN55.212 reduces consequences of status epilepticus in rats,” Neuroscience, 334, 191–200 (2016).
Suliman, N. A., Taib, C. N. M., Moklas, M. A. M., and Basir, R., “Delta-9-Tetrahydrocannabinol (Δ9-THC) induce neurogenesis and improve cognitive performances of male Sprague Dawley rats,” Neurotox. Res., 33, 402–411 (2018).
Suzuki, A., Josselyn, S. A., Frankland, P. W., et al., “Memory reconsolidation and extinction have distinct temporal and biochemical signatures,” J. Neurosci., 24, 4787–4795 (2004).
Tagliaferro, P., Javier Ramos, A., Onaivi, E. S., et al., “Neuronal cytoskeleton and synaptic densities are altered after a chronic treatment with the cannabinoid receptor agonist WIN 55,212-2,” Brain Res., 1085, 163–176 (2006).
Tait, R. J., Mackinnon, A., and Christensen, H., “Cannabis use and cognitive function: 8-year trajectory in a young adult cohort,” Addiction, 106, 2195–2203 (2011).
Takahashi, R. N., Pamplona, F. A., and Fernandes, M. S., “The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T-maze,” Neurosci. Lett., 380, 270–275 (2005).
Tanveer, R., Gowran, A., Noonan, J., et al., “The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-beta and in the cortex of aged rats,” J. Biol. Chem., 287, 34709–34721 (2012).
Terranova, J. P., Storme, J. J., Lafon, N., et al., “Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716,” Psychopharmacology, 126, 165–172 (1996).
Theunissen, E. L., Hutten, N. R. P. W., Mason, N. L., et al., “Neurocognition and subjective experience following acute doses of the synthetic cannabinoid JWH-018: Responders versus nonresponders,” Cannabis Cannabinoid Res., 4, 51–61 (2019).
Tinklenberg, J. R., Melges, F. T., Hollister, L. E., and Gillespie, H. K., “Marijuana and immediate memory,” Nature, 226, 1171–1172 (1970).
Tsou, K., Brown, S., Sanudo-Pena, M. C., et al., “Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system,” Neuroscience, 83, 393–411 (1998).
Tzadok, M., Uliel-Siboni, S., Linder, I., et al., “CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience,” Seizure, 35, 41–44 (2016).
Van Cauwenberghe, C., Van Broeckhoven, C., and Sleegers, K., “The genetic landscape of Alzheimer disease: clinical implications and perspectives,” Genet. Med., 18, 421–430 (2015).
Van der Stelt, M. and Di Marzo, V., “Cannabinoid receptors and their role in neuroprotection,” Neuromolecular Med., 7, 37–50 (2005).
Van der Stelt, M., Mazzola, C., Esposito, G., et al., “Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: Effect of pharmacological elevation of endocannabinoid levels,” Cell. Mol. Life Sci., 63, 1410–1424 (2006).
Van Esbroeck, A. C. M., Janssen, A. P. A., Cognetta, A. B., III, et al., “Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474,” Science, 356, 1084–1087 (2017).
Van Sickle, M. D., Duncan, M., Kingsley, P. J., et al., “Identification and functional characterization of brainstem cannabinoid CB2 receptors,” Science, 310, 329–332 (2005).
Van Wingerden, M., Vinck, M., Lankelma, J., and Pennartz, C. M., “Thetaband phase locking of orbitofrontal neurons during reward expectancy,” J. Neurosci., 30, 7078–7087 (2010).
Varvel, S. A. and Lichtman, A. H., “Evaluation of CB1 receptor knockout mice in the Morris water maze,” J. Pharmacol. Exp. Ther., 301, 915–924 (2002).
Varvel, S. A., Anum, E. A., and Lichtman, A. H., “Disruption of CB1 receptor signaling impairs extinction of spatial memory in mice,” Psychopharmacology (Berlin), 179, 863–872 (2005).
Varvel, S. A., Wise, L. E., Niyuhire, F., et al., “Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task,” Neuropsychopharmacology, 32, 1032–1041 (2007).
Verrico, C. D., Gu, H., Peterson, M. L., et al., “Repeated Δ9-tetrahydrocannabinol exposure in adolescent monkeys: persistent effects selective for spatial working memory,” Am. J. Psychiatry, 171, 416–425 (2014).
Verrico, C. D., Jentsch, J. D., and Roth, R. H., “Persistent and anatomically selective reduction in prefrontal cortical dopamine metabolism after repeated, intermittent cannabinoid administration to rats,” Synapse, 49, 61–66 (2003).
Vilela, L. R., Medeiros, D. C., de Oliveira, A. C. P., et al., “Anticonvulsant effects of N-arachidonoyl-serotonin, a dual fatty acid amide hydrolase enzyme and transient receptor potential vanilloid type-1 (TRPV1) channel blocker, on experimental seizures: the roles of cannabinoid CB1 receptors and TRPV1 channels,” Basic Clin. Pharmacol. Toxicol, 115, 330–334 (2014).
Von Ruden, E. L., Jafari, M., Bogdanovic, R. M., et al., “Analysis in conditional cannabinoid 1 receptor-knockout mice reveals neuronal subpopulation specific effects on epileptogenesis in the kindling paradigm,” Neurobiol. Dis., 73, 334–347 (2015).
Wadsworth, E. J., Moss, S. C., Simpson, S. A., and Smith, A. P., “Cannabis use, cognitive performance and mood in a sample of workers,” J. Psychopharmacol., 20, 14–23 (2006).
Wallace, M. J., Blair, R. E., Falenski, K. W., et al., “The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy,” J. Pharmacol. Exp. Ther., 307, 129–137 (2003).
Weil, A. T. and Zinberg, N. E., “Acute effects of marihuana on speech,” Nature, 222, 434–437 (1969).
Wheeler, D. S., Chang, S. E., and Holland, P. C., “Odor-mediated taste learning requires dorsal hippocampus, but not basolateral amygdala activity,” Neurobiol. Learn. Mem., 101, 1–7 (2013).
Wiley, J. L., Marusich, J. A., and Huffman, J. W., “Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids,” Life Sci., 97, 55–63 (2014).
Wilson, R. I. and Nicoll, R. A., “Endocannabinoid signaling in the brain,” Science, 296, 678–682 (2002).
Wimmer, G. E and Shohamy, D., “Preference by association: how memory mechanisms in the hippocampus bias decisions,” Science, 338, No. 6104, 270–273 (2012).
Wise, L. E., Long, K. A., Abdullah, R. A., et al., “Dual fatty acid amide hydrolase and monoacylglycerol lipase blockade produces THC-like Morris water maze deficits in mice,” ACS Chem. Neurosci, 3, 369– 378 (2012).
Xu, D., Miller, S. D., and Koh, S., “Immune mechanisms in epileptogenesis,” Front. Cell. Neurosci., 7, 195 (2013).
Yanes, J. A., Riedel, M. C., Ray, K. L., et al., “Neuroimaging meta-analysis of cannabis use studies reveals convergent functional alterations in brain regions supporting cognitive control and reward processing,” J. Psychopharmacol., 32, 283–295 (2018).
Yucel, M., Solowij, N., Respondek, C., et al., “Regional brain abnormalities associated with long-term heavy cannabis use,” Arch. Gen. Psychiatry, 65, 694–701 (2008).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 71, No. 1, pp. 3–38, January–February, 2021.
Rights and permissions
About this article
Cite this article
Kitchigina, V.F. Cannabinoids, the Endocannabinoid System, and Cognitive Functions: Enemies or Friends?. Neurosci Behav Physi 51, 893–914 (2021). https://doi.org/10.1007/s11055-021-01148-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11055-021-01148-5