Acute and Chronic Effects of Cannabinoids on Learning and Memory Functions

Yıl 2018, Cilt: 19 Sayı: 4, 123 - 135, 30.12.2018

Burcu Alkan , Tevfik Alıcı

Öz

Cannabinoids have been associated with a wide range of pharmacological effects, some of which have potential therapeutic benefit while others result in negative outcomes, such as dependence and impaired cognition. The most robust finding with respect to cognition is a deficit in working or short-term memory, which is a function requiring an intact hippocampus and prefrontal cortex, two brain regions richly expressing CB1 receptors. Starting with the discovery of an endogenous brain cannabinoid system with specific receptors, and their endogenous ligands and through the use of the tools such as specific CB1 receptor antagonist, and various transgenic models, considerable advances have been made in understanding the mechanisms underlying the effects of cannabinoids on memory. In studies that excluded the acute cannabis intoxication, chronic cannabis users’ poor performance on verbal learning and memory tasks reflect the potential chronic negatif effect of cannabinoids on learning and memory functions. Studies indicate the potential permanent side effects of cannabis use, especially during adolescence. The aim of this article is to review the current findings about the nature, size and reversibility of acute and chronic effects of cannabinoids on learning and memory functions and to discuss its relation with substance use characteristics.

Anahtar Kelimeler

dependence, elderly, alcohol use disorder, substance use disorder

Kannabinoidlerin Öğrenme ve Bellek İşlevleri Üzerindeki Akut ve Kronik Etkileri

Öz

Kannabinoidler klinik amaçlı
kullanımlarının yanı sıra bilişsel işlevler üzerinde bozucu etki yaratmakta ve
bağımlılık yapıcı potansiyelleriyle bilinmektedir.  Kannabinoidlerin bilişsel işlevler üzerindeki
en belirgin ve tutarlı negatif etkisi kısa süreli bellek veya çalışma belleği
alanlarında görülmektedir. Bellek işlevlerinden sorumlu olan hipokampüs ve
prefrontal korteks gibi alanların her ikisi de CB1 reseptörleri
açısından zengin alanlardır. Özgül kannabinoid reseptörlerinin, bu reseptörlere
bağlanan endojen ligandların ve seçici CB1 reseptör antagonisti ile
transgenik modellerin sağladığı olanaklarla kannabinoidlerin öğrenme ve bellek
işlevleri üzerindeki bozucu etkilerinin altında yatan nöral mekanizma konusunda
önemli gelişmeler kaydedilmiştir. Akut madde intoksikasyonunun dışlandığı
çalışmalarda ise kronik esrar kullanıcılarının sözel öğrenme ve bellek
görevlerinde düşük performans göstermesi, kannabinoidlerin öğrenme ve bellek
işlevleri üzerindeki potansiyel kronik negatif etkisini yansıtmaktadır. Çalışmalar
özellikle ergenlik döneminde esrar kullanımının potansiyel kalıcı yan
etkilerine işaret etmektedir. Bu makalenin amacı, kannabinoidlerin öğrenme ve
bellek fonksiyonları üzerindeki hem akut hem de kronik etkisinin doğasını
mevcut insan ve hayvan çalışmaları kapsamında olabildiğince kapsamlı bir
şekilde incelemektir. Mevcut negatif etkinin boyutu, esrar kullanım
özellikleriyle olan ilişkisi, esrar kullanımın sonlandırılmasıyla birlikte
geriye döndürülebilir bir doğası olup olmadığı gibi sorular mevcut bulgular ışığında
cevaplandırılmaya çalışılacaktır. Konunun özellikle ergenlik dönemindeki
bireyler için eğitimsel doğurguları bulunmakla birlikte, dünyada esrar
kullanımının yasallaştırılması yönündeki girişimler açısından da toplumsal
önemi bulunmaktadır.

Anahtar Kelimeler

kannabinoid, sözel öğrenme, kısa süreli bellek, çalışma belleği, bağımlılık

Kaynakça

• United Nations Office on Drugs and Crime, World Drug Report 2017 (ISBN: 978-92-1-148291-1, eISBN: 978-92-1-060623-3, United Nations publication, Sales No. E.17.XI.6).
• Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015; 313(24):2456-2473.
• ElSohly MA, Mehmedic Z, Foster S, et al. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States. Biol Psychiatry 2016; 79(7):613-619.
• Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964; 86(8):1646-1647.
• Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013; 64:21-47.
• Curran HV, Freeman TP, Mokrysz C, et al. Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 2016; 17(5):293-306.
• Hillard CJ, Harris RA, Bloom AS. Effects of the cannabinoids on physical properties of brain membranes and phospholipid vesicles: fluorescence studies. J Pharmacol Exp Ther 1985; 232(3):579-588.
• Howlett AC. Cannabinoid inhibition of adenylate cyclase: biochemistry of the response in neuroblastoma cell membranes. Mol Pharmacol 1985; 27(4):429-436.
• Howlett AC, Qualy JM, Khachatrian LL. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol 1986; 29(3):307-313.
• Devane WA, Dysarz FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34(5):605-613.
• Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346(6284):561-564.
• Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993; 365(6441):61-65.
• Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005; 310(5746):329-332.
• Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tethrahydrocannabinol, cannabidiol and delta9-tethrahydrocannabinovarin. Br J Pharmacol 2008; 153(2):199-215.
• 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.
• Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990; 87(5):1932-1936.
• 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(1607):3254-3263.
• Katona I, Urban GM, Wallace M, et al. Molecular composition of the endocannabinoid system at glutamatergic synapses. J Neurosci 2006; 26(21):5628-5637.
• Tsou K, Mackie K, Sanudo-Pena MC, Walker JM. Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing gabaergic interneurons in the rat hippocampal formation. Neuroscience 1999; 93(3):969-975.
• Hajos N, Katona I, Naiem SS, et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci 2000; 12(9):3239-3249.
• Raver SM, Haughwout SP, Keller A. Adolescent cannabinoid exposure permanently suppresses cortical oscillations in adult mice. Neuropsychopharmacology 2013; 38(12):2338-2347.
• Robbe D, Montgomery SM, Thome A, et al. Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nat Neurosci 2006; 9(12):1526-1533.
• 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(5):1039-1050.
• Hill MN, Froc DJ, Fox CJ, et al. Prolonged cannabinoid treatment results in spatial working memory deficits and impaired long-term potentiation in the CA1 region of the hippocampus in vivo. Eur J Neurosci 2004; 20(3):859-863.
• Hoffman AF, Oz M, Yang RQ, et al. Opposing actions of chronic Δ9- tethrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learn Mem 2007; 14(1-2):63-74.
• Goonawardena AV, Robinson L, Hampson RE, Riedel G. Cannabinoid and cholinergic systems interact during performance of a short-term memory task in the rat. Learn Mem 2010; 17(10):502-511.
• Theunissen EL, Heckman P, de Sousa Fernandes Perna EB, et al. Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans. Psychopharmacology 2015; 232(2):343-353.
• Diana M, Melis M, Gessa GL. Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids. Eur J Neurosci 1998; 10(9):2825-2830.
• Jentsch JD, Andrusiak E, Tran A, et al. Delta9-tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: blockade of dopaminergic effects with HA966. Neuropsychopharmacology 1997; 16(6):426-432.
• Jentsch JD, Verrico CD, Le D, Roth RH. Repeated exposure to delta-9-tetrahydrocannabinol reduces prefrontal cortical dopamine metobolism in the rat. Neurosci Lett 1998; 246(3):169-172.
• Lichtman AH, Martin BR. Delta 9-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. Psychopharmacology 1996; 126(2):125-131.
• Reibaud M, Obinu MC, Ledent C, et al. Enhancement of memory in cannabinoid CB1 receptor knock-out mice. Eur J Pharmacol 1999; 379:R1-R2.
• Heyser CJ, Hampson RE, Deadwyler SA. Effects of delta-9-tetrahydrocannabinol on delayed match to sample performance in rats: alterations in short-term memory associated with changes in task specific firing of hippocampal cells. J Pharmacol Exp Ther 1993; 264(1):294-307.
• Hampson RE, Deadwyler SA. Cannabinoids, hippocampal function and memory. Life Sci 1999; 65(6-7):715-723.
• Schneider M, Schömig E, Leweke FM. Acute and chronic cannabinoid treatment differentially affects recognition memory and social behavior in pubertal and adult rats. Addict Biol 2008; 13(3-4):345-357.
• Molina-Holgada F, Gonzalez MI, Leret ML. Effect of delta9-tetrahydrocannabinol on short-term memory in the rat. Physiol Behav 1995; 57(1):177-179.
• Ferrari F, Ottani A, Vivoli R, Giuliani D. Learning impairment produced in rats by the cannabinoid agonist HU 210 in a water maze task. Pharmacol Biochem Behav 1999; 64(3):555-561.
• Varvel SA, Hamm RJ, Martin BR, Lichtman AH. Differential effects of delta 9¬ THC on spatial reference and working memory in mice. Psychopharmacology 2001; 157(2):142-150.
• Tselnicker I, Karen O, Hefetz A, et al. A single low dose of tethrahydrocannabinol induces long-term cognitive deficits. Neurosci Lett 2007; 411(2):108-111.
• Curran HV, Brignell C, Fletcher S. Cognitive and subjective dose-response effects of acute oral Delta9-tethrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology 2002; 164(1):61-70.
• D’Souza DC, Perry E, MacDougall L, et al. The psychotomimetic effects of intravenous delta-9-tethrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 2004; 29(8), 1558-1572.
• Heishman SJ, Arasteh K, Stitzer ML. Comparative effects of alcohol and marijuana on mood, memory and performance. Pharmacol Biochem Behav 1997; 58(1):93-101.
• Morrison PD, Zois V, McKeown DA, et al. The acute effects of synthetic intravenous Delta9-tethrahydrocannabinol on psychosis, mood, and cognitive functioning. Psychol Med 2009; 39(10):1607-1616.
• Ilan AB, Smith ME, Gevins A. Effects of marijuana on neurophysiological signals of working and episodic memory. Psychopharmacology 2004; 176(2):214-222.
• Böcker KB, Hunault CC, Gerritsen J, et al. Cannabinoid modulations of resting state EEG theta power and working memory are correlated in humans. J Cogn Neurosci 2010; 22(9):1906-1916.
• Bossong MG, Jansma JM, van Hell HH, et al. Effects of Δ9-tethrahydrocannabinol on human working memory function. Biol Psychiatry 2012; 71(8):693-699.
• Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 2013; 27(1):19-27.
• Hart CL, von Gorp W, Haney M, et al. Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology 2001; 25(5):757-765.
• Hart CL, Ilan AB, Gevins A, et al. Neurophysiological and cognitive effects of smoked marijuana in frequent users. Pharmacol Biochem Behav 2010; 96(3):333-341.
• D’Souza DC, Ranganathan M, Braley G, et al. Blunted psychotomimetic and amnestic effects of delta-9-tethrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology 2008; 33(10):2505-2516.
• Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study. Br J Psychiatry 2010; 197(4):285-290.
• Broyd SJ, van Hell HH, Beale C, et al. Acute and chronic effects of cannabinoids on human cognition-a systematic review. Biol Psychiatry 2016; 79(7):557-567.
• Grant I, Gonzalez R, Carey CL, et al. Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol Soc 2003; 9(5):679-689.
• Schreiner AM, Dunn ME. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychopharmacol 2012; 20(5):420-429.
• Schoeler T, Kambeitz J, Behlke I, et al. The effects of cannabis on memory function in users with and without a psychotic disorder: findings from a combined meta-analysis. Psychol Med 2016; 46(1):177-188.
• McDaniel MA, Einstein GO. Prospective memory. An overview and synthesis of an emerging field. California: Sage, 2007.
• Fisk JE, Montgomery C. Real-world memory and executive processes in cannabis users and non-users. J Psychopharmacol 2008; 22(7):727-736.
• Bartholomew J, Holroyd S, Heffernan TM. Does cannabis use affect prospective memory in young adults. J Psychopharmacol 2010; 24(2):241-246.
• Montgomery C, Seddon AL, Fisk JE, et al. Cannabis-related deficits in real-world memory. Hum Psychopharmacol 2012; 27(2):217-225.
• Cuttler C, McLaughlin RJ, Graf P. Mechanisms underlying the link between cannabis use and prospective memory. PloS One 2012; 7(5):1-10.
• Hanson KL, Winward JL, Schweinsburg AD, et al. Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence. Addict Behav 2010; 35(11):970-976.
• Thames AD, Arbid N, Sayegh P. Cannabis use and neurocognitive functioning in a non-clinical sample of users. Addict Behav 2014; 39(5):994-999.
• Fried PA, Watkinson B, Gray R. Neurocognitive consequences of marihuana – a comparison with pre-drug performance. Neurotoxicol Teratol 2005; 27(2):231-239.
• Tait RJ, Mackinnon A, Christensen H. Cannabis use and cognitive function: 8-year trajectory in a young adult cohort. Addiction 2011; 106(12), 2195-2203.
• Bossong MG, Jager G, Bhattacharyya S, Allen P. Acute and non-acute effects of cannabis on human memory function: a critical review of neuroimaging studies. Curr Pharm Des 2014; 20(13):2114-2125.
• Kanayama G, Rogowska J, Pope, HG, et al. Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study. Psychopharmacology 2004; 176(3-4):239-247.
• Bolla KI, Brown K, Eldreth D, et al. Dose-related neurocognitive effects of marijuana use. Neurology 2002; 59(9):1337-1343.
• Messinis L, Kyprianidou A, Malefaki S, Papathanasopoulos P. Neuropsychological deficits in long-term frequent cannabis users. Neurology 2006; 66(5):737-739.
• Solowij N, Stephens RS, Roffman RA, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA 2002; 287(9):1123-1131.
• Yücel M, Solowij N, Respondek C, et al. Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry 2008; 65(6):694-701.
• Becker B, Wagner D, Gouzoulis-Mayfrank E, et al. The impact of early-onset cannabis use on functional brain correlates of working memory. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(6):837-845.
• Dougherty DM, Mathias CW, Dawes MA, et al. Impulsivity, attention, memory and decision-making among adolescent marijuana users. Psychopharmacology 2013; 226(2):307-319.
• Solowij N, Jones KA, Rozman ME, et al. Verbal learning and memory in adolescent cannabis users, alcohol users and non-users. Psychopharmacology 2011; 216(1):131-144.
• Pope HG, Gruber AJ, Hudson JI, et al. Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug Alcohol Depend 2003; 69(3):303-310.
• Schuster RM, Hoeppner SS, Evins AE, Gilman JM. Early onset marijuana use is associated with learning inefficiencies. Neuropsychology 2016; 30(4):405-415.
• Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sc U S A 2012; 109(40):2657-2664.
• Pope HG, Gruber AJ, Yurgelun-Todd D. The residual neuropsychological effects of cannabis: the current status of research. Drug Alcohol Depend 1995; 38(1):25-34.
• Pope HG, Gruber AJ, Hudson JI et al. Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry 2001; 58(10):909-915.
• Weinstein A, Livny A, Weizman A. Brain imaging studies on the cognitive, pharmacological and neurobiological effects of cannabis in humans: evidence from studies of adult users. Curr Pharm Des 2016; 22(42):6366-6379.
• O’Shea M, Singh ME, McGregor IS, Mallet PE. Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats. J Psychopharmacology 2004; 18(4):502-508.
• Quinn HR, Matsumoto I, Callaghan PD, et al. Adolescent rats find repeated ¬Delta(9) THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 2008; 33(5):1113-1126.
• 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(8):763-772.
• Block RI, O’Leary DS, Hichwa RC, et al. Effects of frequent marijuana use on memory-related regional cerebral blood flow. Pharmacol Biochem Behav 2002; 72:237-250
• Crane NA, Schuster RM, Fusar-Poli P, Gonzalez R. Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences. Neuropsychol Rev 2013; 23(2):117-137.
• Macher RB, Earleywine M. Enhancing neuropsychological performance in chronic cannabis users: the role of motivation. J Clin Exp Neuropsychol 2012; 34(4):405-415.
• Becker MP, Collins PF, Luciana M. Neurocognition in college-aged daily marijuana users. J Clin Exp Neuropsychol 2014; 36(4):379-398.