Skip to main content

Advertisement

SpringerLink
Log in

Role of cannabis and endocannabinoids in the genesis of schizophrenia

  • Review
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Cannabis abuse and endocannabinoids are associated to schizophrenia.

Objectives

It is important to discern the association between schizophrenia and exogenous Cannabis sativa, on one hand, and the endogenous cannabinoid system, on the other hand.

Results

On one hand, there is substantial evidence that cannabis abuse is a risk factor for psychosis in genetically predisposed people, may lead to a worse outcome of the disease, or it can affect normal brain development during adolescence, increasing the risk for schizophrenia in adulthood. Regarding genetic predisposition, alterations affecting the cannabinoid CNR1 gene could be related to schizophrenia. On the other hand, the endogenous cannabinoid system is altered in schizophrenia (i.e., increased density of cannabinoid CB1 receptor binding in corticolimbic regions, enhanced cerebrospinal fluid anandamide levels), and dysregulation of this system can interact with neurotransmitter systems in such a way that a “cannabinoid hypothesis” can be integrated in the neurobiological hypotheses of schizophrenia. Finally, there is also evidence that some genetic alterations of the CNR1 gene can act as a protectant factor against schizophrenia or can induce a better pharmacological response to atypical antipsychotics.

Conclusions

Cannabis abuse is a risk factor for psychosis in predisposed people, it can affect neurodevelopment during adolescence leading to schizophrenia, and a dysregulation of the endocannabinoid system can participate in schizophrenia. It is also worth noting that some specific cannabinoid alterations can act as neuroprotectant for schizophrenia or can be a psychopharmacogenetic rather than a vulnerability factor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R (1982) Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 17(6):639–654

    PubMed  CAS  Google Scholar 

  • Adler LE, Rose G, Freedman R (1986) Neurophysiological studies of sensory gating in rats: effects of amphetamine, phencyclidine, and haloperidol. Biol Psychiatry 21(8–9):787–798

    PubMed  CAS  Google Scholar 

  • Adriani W, Laviola G (2004) Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model. Behav Pharmacol 15:341–352

    PubMed  CAS  Google Scholar 

  • Ajdacic-Gross V, Lauber C, Warnke I, Haker H, Murray RM, Rössler W (2007) Changing incidence of psychotic disorders among the young in Zurich. Schizophr Res 95(1–3):9–18

    PubMed  Google Scholar 

  • Andreasson S, Allebeck P, Engstrom A, Rydberg U (1987) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 2:1483–1486

    PubMed  CAS  Google Scholar 

  • Angrist B, Van Kammen DP (1984) CNS stimulants as tools in the study of schizophrenia. Trends Neurosci 7:388–390

    Google Scholar 

  • Arendt M, Rosenberg R, Foldager L, Perto G, Munk-Jørgensen P (2005) Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases. Br J Psychiatry 187:510–515

    PubMed  Google Scholar 

  • Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE (2002) Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 325:1212–1213

    PubMed  Google Scholar 

  • Auclair N, Otani S, Soubrie P, Crepel F (2000) Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. J Neurophysiol 83:3287–3293

    PubMed  CAS  Google Scholar 

  • Azad SC, Eder M, Marsicano G, Lutz B, Zieglansberger W, Rammes G (2003) Activation of the cannabinoid receptor type 1 decreases glutamatergic and GABAergic synaptic transmission in the lateral amygdala of the mouse. Learn Mem 10:116–128

    PubMed  Google Scholar 

  • Ballmaier M, Bortolato M, Rizzetti C et al (2007) Cannabinoid receptor antagonists counteract sensorimotor gating deficits in the phencyclidine model of psychosis. Neuropsychopharmacology 32(10):2098–2107

    PubMed  CAS  Google Scholar 

  • Bangalore SS, Prasad KM, Montrose DM, Goradia DD, Diwadkar VA, Keshavan MS (2008) Cannabis use and brain structural alterations in first episode schizophrenia—a region of interest, voxel based morphometric study. Schizophr Res 99(1–3):1–6

    PubMed  Google Scholar 

  • Barnett JH, Werners U, Secher SM et al (2007) Substance use in a population-based clinic sample of people with first-episode psychosis. Br J Psychiatry 190:515–520

    PubMed  Google Scholar 

  • Beinfeld MC, Connolly K (2001) Activation of CB1 cannabinoid receptors in rat hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible mechanism contributing to the spatial memory defects produced by cannabinoids. Neurosci Lett 301:69–71

    PubMed  CAS  Google Scholar 

  • Beltramo M, Rodriguez de Fonseca F, Navarro M et al (2000) Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor. J Neurosci 20:3401–3407

    PubMed  CAS  Google Scholar 

  • Berk M, Brook S, Trandafir AI (1999) A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial. Int Clin Psychopharmacol 14(3):177–180

    PubMed  CAS  Google Scholar 

  • Bersani G, Orlandi V, Kotzalidis GD, Pancheri P (2002) Cannabis and schizophrenia: impact on onset, course, psychopathology and outcomes. Eur Arch Psychiatry Clin Neurosci 252(2):86–92

    PubMed  CAS  Google Scholar 

  • Biscaia M, Marín S, Fernández B, Marco E, Rubio M, Guaza C, Ambrosio E, Viveros MP (2003) Chronic treatment with CP 55, 940 during the periadolescent period differentially affects the behavioural responses of male and female rats in the adulthood. Psychopharmacology 170:301–308

    PubMed  CAS  Google Scholar 

  • Block RI, O’Leary DS, Ehrhardt JC, Augustinack JC, Ghoneim MM, Arndt S, Hall JA (2000) Effects of frequent marijuana use on brain tissue volume and composition. NeuroReport 11(3):491–496

    PubMed  CAS  Google Scholar 

  • Bortolato M, Campolongo P, Mangieri RA et al (2006) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:2652–2659

    PubMed  CAS  Google Scholar 

  • Bossong MG, van Berckel BN, Boellaard R, Zuurman L, Schuit RC, Windhorst AD, van Gerven JM, Ramsey NF, Lammertsma AA, Kahn RS (2009) Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 34(3):759–766

    PubMed  CAS  Google Scholar 

  • Boucher AA, Arnold JC, Duffy L, Schofield PR, Micheau J, Karl T (2007a) Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. Psychopharmacology (Berl) 192(3):325–336

    CAS  Google Scholar 

  • Boucher AA, Hunt GE, Karl T, Micheau J, McGregor IS, Arnold JC (2007b) Heterozygous neuregulin 1 mice display greater baseline and Delta(9)-tetrahydrocannabinol-induced c-Fos expression. Neuroscience 149(4):861–870

    PubMed  CAS  Google Scholar 

  • Boydell J, Van Os J, Caspi A, Kennedy N, Giouroukou E, Fearon P, Farrell M, Murray RM (2006) Trends in cannabis use prior to first presentation with schizophrenia, in South-East London between 1965 and 1999. Psychol Med 36(10):1441–1446

    PubMed  CAS  Google Scholar 

  • Cadenhead KS, Light GA, Geyer MA, Braff DL (2000) Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder. Am J Psychiatry 157(1):55–59

    PubMed  CAS  Google Scholar 

  • Cahn W, Hulshoff Pol HE, Caspers E, van Haren NE, Schnack HG, Kahn RS (2004) Cannabis and brain morphology in recent-onset schizophrenia. Schizophr Res 67(2–3):305–307

    PubMed  CAS  Google Scholar 

  • Caspi A, Moffitt TE, Cannon M et al (2005) Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene x environment interaction. Biol Psychiatry 57:1117–1127

    PubMed  CAS  Google Scholar 

  • Castle DJ, Ames FR (1996) Cannabis and the brain. Aust N Z J Psychiatry 30(2):179–183

    PubMed  CAS  Google Scholar 

  • Chavarría-Siles I, Contreras-Rojas J, Hare E, Walss-Bass C, Quezada P, Dassori A, Contreras S, Medina R, Ramírez M, Salazar R, Raventos H, Escamilla MA (2008) Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia. Am J Med Genet B Neuropsychiatr Genet 147(3):279–284

    PubMed  Google Scholar 

  • De Irala J, Ruiz-Canela M, Martínez-González MA (2005) Causal relationship between cannabis use and psychotic symptoms or depression. Should we wait and see? A public health perspective. Med Sci Monit 11:RA355–RA358

    PubMed  Google Scholar 

  • De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V (2003) Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis 19:5

    Google Scholar 

  • Dean B, Sundram S, Bradbury R, Scarr E, Copolov D (2001) Studies on [3H]CP-55490 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103:9–15

    PubMed  CAS  Google Scholar 

  • Dean B, Bradbury R, Copolov DL (2003) Cannabis-sensitive dopaminergic markers in postmortem central nervous system: changes in schizophrenia. Biol Psychiatry 53:585–592

    PubMed  CAS  Google Scholar 

  • Derkinderen P, Toutant M, Burgaya F, Lebert M, Siciliano JC, Defranciscis V, Gelman M, Girault JA (1996) Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273:1719–1722

    PubMed  CAS  Google Scholar 

  • Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613

    PubMed  CAS  Google Scholar 

  • Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinge A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    PubMed  CAS  Google Scholar 

  • Di Marzo V (2008) Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 7:438–455

    PubMed  Google Scholar 

  • Di Marzo V, Maccarrone M (2008) FAAH and anandamide: is 2-AG really the odd one out? Trends Neurosci 29:229–233

    Google Scholar 

  • Diana MA, Marty A (2004) Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol 142:9–19

    PubMed  CAS  Google Scholar 

  • Dissanayake DW, Zachariou M, Marsden CA, Mason R (2008) Auditory gating in rat hippocampus and medial prefrontal cortex: effect of the cannabinoid agonist WIN55,212-2. Neuropharmacology 55(8):1397–1404

    PubMed  CAS  Google Scholar 

  • Doniger GM, Foxe JJ, Murray MM, Higgins BA, Javitt DC (2002) Impaired visual object recognition and dorsal/ventral stream interaction in schizophrenia. Arch Gen Psychiatry 59:1011–1020

    PubMed  Google Scholar 

  • Drake RE, Xie H, McHugo GJ, Green AI (2000) The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull 26(2):441–449

    PubMed  CAS  Google Scholar 

  • D’Souza DC, Perry E, MacDougall L et al (2004) The psychomimetic effects of intravenous delta9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29:1558–1572

    PubMed  Google Scholar 

  • D’Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G, Gueorguieva R, Cooper TB, Krystal JH (2005) Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry 57(6):594–608

    PubMed  Google Scholar 

  • D’Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, Perry E, Krystal J (2008a) Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology 33(10):2505–2516

    PubMed  Google Scholar 

  • D’Souza DC, Braley G, Blaise R, Vendetti M, Oliver S, Pittman B, Ranganathan M, Bhakta S, Zimolo Z, Cooper T, Perry E (2008b) Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Delta-9-tetrahydrocannabinol in humans. Psychopharmacology (Berl) 198(4):587–603

    Google Scholar 

  • Ellenbroek BA (2003) Animal models in the genomic era: possibilities and limitations with special emphasis on schizophrenia. Behav Pharmacol 14:409–417

    PubMed  CAS  Google Scholar 

  • Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284(1):14–30

    PubMed  CAS  Google Scholar 

  • Favrat B, Ménétrey A, Augsburger M, Rothuizen LE, Appenzeller M, Buclin T, Pin M, Mangin P, Giroud C (2005) Two cases of “cannabis acute psychosis” following the administration of oral cannabis. BMC Psychiatry 5:17

    PubMed  Google Scholar 

  • Feinberg I (1982) Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 17(4):319–334

    PubMed  Google Scholar 

  • Feinberg I (1987) Adolescence and mental illness. Science 236(4801):507–508

    PubMed  CAS  Google Scholar 

  • Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ, Cullinan GJ, Hunden DC, Johnson DW, Chaney MO, Koppel GA, Brownstein M (1998) LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J Pharmacol Exp Ther 284:291–297

    PubMed  CAS  Google Scholar 

  • Ferdinand RF, Sondeijker F, van der Ende J, Selten JP, Huizink A, Verhulst FC (2005) Cannabis use predicts future psychotic symptoms, and vice versa. Addiction 100(5):612–618

    PubMed  Google Scholar 

  • Fergusson DM, Horwood LJ, Ridder EM (2005) Tests of causal linkages between cannabis use and psychotic symptoms. Addiction 100(3):354–366

    PubMed  Google Scholar 

  • Fernandez-Espejo E, Galan-Rodriguez B (2004) Sensorimotor gating in mice is disrupted after AM404, an anandamide reuptake and degradation inhibitor. Psychopharmacology 175:220–224

    PubMed  CAS  Google Scholar 

  • Ferrer B, Gorriti MA, Palomino A, Gornemann I, de Diego Y, Bermudez-Silva FJ, Bilbao A, Fernandez-Espejo E, Moratalla R, Navarro M, Rodríguez de Fonseca F (2007) Cannabinoid CB1 receptor antagonism markedly increases dopamine receptor-mediated stereotypies. Eur J Pharmacol 559:180–183

    PubMed  CAS  Google Scholar 

  • French ED, Dillon K, Wu X (1997) Cannabinoids excite dopamine neurons in the ventral tegmental area and substantia nigra. NeuroReport 8:649–652

    PubMed  CAS  Google Scholar 

  • Fujiwara M, Egashira N (2004) New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. J Pharmacol Sci 96:326–366

    Google Scholar 

  • Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61

    PubMed  Google Scholar 

  • Gallagher HL, Happé F, Brunswick N, Fletcher PC, Frith U, Frith CD (2003) Reading the mind in cartoons and stories: an fMRI study of ‘theory of mind’ in verbal and nonverbal tasks. Neuropsychologia 38(1):11–21

    Google Scholar 

  • Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647

    CAS  Google Scholar 

  • Gardner EL, Vorel RH (1998) Cannabinoid transmission and reward-related events. Neurobiol Dis 5:502–533

    PubMed  CAS  Google Scholar 

  • Gardner EL, Paredes W, Smith D et al (1988) Facilitation of brain stimulation reward by d9-tetrahydrocannabinol. Psychopharmacology 341:39–44

    Google Scholar 

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade of review. Psychopharmacology 156:117–154

    PubMed  CAS  Google Scholar 

  • Geyer MA, McIlwain KL, Paylor R (2002) Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry 7:1039–1053

    PubMed  CAS  Google Scholar 

  • Giuffrida A, Leweke FM, Gerth CW et al (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29:2108–2114

    PubMed  CAS  Google Scholar 

  • Giuliani D, Ferrari F (1997) Involvement of dopamine receptors in the antipsychotic profile of (−) eticlopride. Physiol Behav 61(4):563–567

    PubMed  CAS  Google Scholar 

  • Gorriti MA, Rodriguez de Fonseca F, Navarro M, Palomo T (1999) Chronic (−)-delta9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats. Eur J Pharmacol 365:133–142

    PubMed  CAS  Google Scholar 

  • Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1–24

    PubMed  CAS  Google Scholar 

  • Graham FK (1975) The more or less startling effects of weak prestimuli. Psychophysiology 12:238–248

    PubMed  CAS  Google Scholar 

  • Grant BF, Chou SP, Goldstein RB et al (2008) Prevalence, correlates, disability, and comorbidity of DSM-IV borderline personality disorder: results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 69(4):533–545

    Article  PubMed  Google Scholar 

  • Hajós M, Hoffmann WE, Kocsis B (2008) Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia. Biol Psychiatry 63(11):1075–1083

    PubMed  Google Scholar 

  • Hall WD (1998) Cannabis use and psychosis. Drug Alcohol Rev 17:433–444

    PubMed  CAS  Google Scholar 

  • Hall W, Degenhardt L (2007) Prevalence and correlates of cannabis use in developed and developing countries. Curr Opin Psychiatr 20:393–397

    Google Scholar 

  • Hall W, Solowij N (1997) Long-term cannabis use and mental health. Br J Psychiatry 171:107–108

    PubMed  CAS  Google Scholar 

  • Hamdani N, Tabeze JP, Ramoz N, Ades J, Hamon M, Sarfati Y, Boni C, Gorwood P (2008) The CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia. Eur Neuropsychopharmacol 18(1):34–40

    PubMed  CAS  Google Scholar 

  • Hart WG (1978) Reply to a case report by Ian Sale and Henry Kristall-March issue. Aust N Z J Psychiatry 12(2):136–137

    PubMed  CAS  Google Scholar 

  • Heckers S, Curran T, Goff D, Rauch SL, Fischman AJ, Alpert NM, Schacter DL (2000) Abnormalities in the thalamus and prefrontal cortex during episodic object recognition in schizophrenia. Biol Psychiatry 48:651–657

    PubMed  CAS  Google Scholar 

  • Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J (2005) Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 330(7481):11

    PubMed  Google Scholar 

  • Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583

    PubMed  CAS  Google Scholar 

  • Hirvonen J, Van Erp TG, Huttunen J et al (2005) Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia. Arch Gen Psychiatry 62(4):371–378

    PubMed  CAS  Google Scholar 

  • Hoffman HS, Ison JR (1980) Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev 87:175–189

    PubMed  CAS  Google Scholar 

  • Howlett AC, Bidaut-Russell M, Devane WA, Melvin LS, Johnson MR, Herkenham M (1990) The cannabinoid receptor: biochemical, anatomical and behavioral characterization. Trends Neurosci 13:420–423

    PubMed  CAS  Google Scholar 

  • Jarrahian A, Watts VJ, Barker E (2004) D2 dopamine receptors modulate Gα-subunit coupling of the CB1 cannabinoid receptor. J Pharmacol Exp Ther 308:880–886

    PubMed  CAS  Google Scholar 

  • Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    PubMed  CAS  Google Scholar 

  • Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR (2007) Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav 6(7):677–687

    PubMed  CAS  Google Scholar 

  • Katona I, Uran GM, Wallace M, Ledent C, Jung KM, Piomelli D, Mackie K, Freund TF (2006) Molecular composition of the endocannabinoid system at glutamatergic synapses. J Neurosci 26:5628–5637

    PubMed  CAS  Google Scholar 

  • Keshavan MS, Anderson S, Pettegrew JW (1994) Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. J Psychiatr Res 28(3):239–265

    PubMed  CAS  Google Scholar 

  • Konings M, Henquet C, Maharajh HD, Hutchinson G, Van Os J (2008) Early exposure to cannabis and risk for psychosis in young adolescents in Trinidad. Acta Psychiatr Scand 118(3):209–213

    PubMed  CAS  Google Scholar 

  • Laruelle M, Abi-Dargham A, van Dyck CH et al (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93(17):9235–9240

    PubMed  CAS  Google Scholar 

  • Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D (1999) Elevated endogenous cannabinoids in schizophrenia. NeuroReport 10:1665–1669

    PubMed  CAS  Google Scholar 

  • Leweke FM, Giuffrida A, Koethe D et al (2007) Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. Schizophr Res 94:29–36

    PubMed  Google Scholar 

  • Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, Keefe RS, Green AI, Gur RE, McEvoy J, Perkins D, Hamer RM, Gu H, Tohen M, HGDH Study Group (2005) Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 62(4):361–370

    PubMed  CAS  Google Scholar 

  • Maccarrone M, Rossi S, Bari M, De Chiara V, Fezza F, Musella A, Gasperi V, Prosperetti C, Bernardi G, Finazzi-Agrò A, Cravatt BF, Centonze D (2008) Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat Neurosci 11(2):152–159

    PubMed  CAS  Google Scholar 

  • Macleod J, Oakes R, Copello A, Crome I, Egger M, Hickman M, Oppenkowski T, Stokes-Lampard H, Davey Smith G (2004) Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. Lancet 363(9421):1579–1588

    PubMed  Google Scholar 

  • Malone DT, Taylor DA (2006) The effect of Delta9-tetrahydrocannabinol on sensorimotor gating in socially isolated rats. Behav Brain Res 166(1):101–109

    PubMed  CAS  Google Scholar 

  • Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology 94:507–514

    PubMed  CAS  Google Scholar 

  • Mansbach RS, Rovetti CC, Winston EN, Lowe JA (1996) Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats. Psychopharmacology 124:315–322

    PubMed  CAS  Google Scholar 

  • Marek G, Merchant K (2005) Developing therapeutics for schizophrenia and other psychotic disorders. NeuroRx 2:579–589

    PubMed  Google Scholar 

  • Marsicano G, Wotjak CT, Azad SC, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534

    PubMed  CAS  Google Scholar 

  • Marsicano G, Goodenough S, Monory K et al (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88

    PubMed  CAS  Google Scholar 

  • Martin RS, Secchi RL, Sung E et al (2003) Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat. Psychopharmacology 165:128–135

    PubMed  CAS  Google Scholar 

  • Matochik JA, Eldreth DA, Cadet JL, Bolla KI (2005) Altered brain tissue composition in heavy marijuana users. Drug Alcohol Depend 77(1):23–30

    PubMed  CAS  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    PubMed  CAS  Google Scholar 

  • Maynard TM, Sikich L, Lieberman JA, LaMantia AS (2001) Neural development, cell–cell signaling, and the “two-hit” hypothesis of schizophrenia. Schizophr Bull 27:457–476

    PubMed  CAS  Google Scholar 

  • McGuire P, Jones P, Murray R (1993) Psychiatric symptoms in cannabis users. Br J Psychiatry 163:698

    PubMed  CAS  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewithch M, Barg J, Vogel Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    PubMed  CAS  Google Scholar 

  • Mendhiratta SS, Varma VK, Dang R, Malhotra AK, Das K, Nehra R (1988) Cannabis and cognitive functions: a re-evaluation study. Br J Addict 83(7):749–753

    PubMed  CAS  Google Scholar 

  • Mewell KA, Deng C, Huang XF (2006) Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Exp Brain Res 172:550–560

    Google Scholar 

  • Miettunen J, Törmänen S, Murray GK, Jones PB, Mäki P, Ebeling H, Moilanen I, Taanila A, Heinimaa M, Joukamaa M, Veijola J (2008) Association of cannabis use with prodromal symptoms of psychosis in adolescence. Br J Psychiatry 192:470–471

    PubMed  Google Scholar 

  • Moore H, West A, Grace AA (1999) The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 46:40–55

    PubMed  CAS  Google Scholar 

  • Moore THM, Zammit S, Lingford-Hughes A, Barnes TRE, Jones PB, Burke M, Lewis G (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–328

    PubMed  Google Scholar 

  • Moreno M, Lopez-Moreno JA, Rodríguez de Fonseca F, Navarro M (2005) Behavioural effects of quinpirole following withdrawal of chronic treatment with the CB1 agonist, HU-210, in rats. Behav Pharmacol 16:441–446

    PubMed  CAS  Google Scholar 

  • Müller-Vahl KR, Emrich HM (2008) Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia. Expert Rev Neurother 8(7):1037–1048

    PubMed  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    PubMed  CAS  Google Scholar 

  • Negrete JC (1983) Effect of cannabis use on health. Acta Psiquiatr Psicol Am Lat 29(4):267–276

    PubMed  CAS  Google Scholar 

  • Nordentoft M, Hjorthøj C (2007) Cannabis use and risk of psychosis in later life. Lancet 370:293–294

    PubMed  Google Scholar 

  • Núñez LA, Gurpegui M (2002) Cannabis-induced psychosis: a cross-sectional comparison with acute schizophrenia. Acta Psychiatr Scand 105:151–157

    Google Scholar 

  • Onaivi ES (2006) Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain. Neuropsychobiology 54(4):231–246

    PubMed  CAS  Google Scholar 

  • O’Shea M, Singh ME, McGregor IS, Mallet PE (2004) Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats. J Psychopharmacol 18:502–508

    PubMed  Google Scholar 

  • O’Shea M, McGregor IS, Mallet PE (2006) Repeated cannabinoid exposure during perinatal, adolescent or early adult ages produces similar long-lasting deficits in object recognition and reduced social interaction in rats. J Psychopharmacol 20:611–621

    PubMed  Google Scholar 

  • Ouagazzal AM, Jenck F, Moreau JL (2001) Drug-induced potentiation of prepulse inhibition of acoustic startle in mice: a model for detecting antipsychotic activity? Psychopharmacology 156:273–283

    PubMed  CAS  Google Scholar 

  • Pertwee RG (2005) The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J 7:E625–E654

    PubMed  CAS  Google Scholar 

  • Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884

    PubMed  CAS  Google Scholar 

  • Piomelli D, Giuffrida A, Calignano A, Rodriguez de Fonseca F (2000) The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci 21:218–224

    PubMed  CAS  Google Scholar 

  • Pistis M, Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL (2004) Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biol Psychiatry 56:86–94

    PubMed  CAS  Google Scholar 

  • Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, Kahn R (2008) Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry 165(4):490–496

    PubMed  Google Scholar 

  • Ralph-Williams RJ, Paulus MP, Geyer MA (2001) Strain-specific effects of amphetamine on prepulse inhibition and patterns of locomotor behavior in mice. J Pharmacol Exp Ther 298:148–155

    Google Scholar 

  • Ralph-Williams RJ, Lehmann-Masten V, Otero-Corchon V, Low MJ, Geyer MA (2002) Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice. J Neurosci 22:9604–9611

    PubMed  CAS  Google Scholar 

  • Robbe D, Alonso G, Duchamp F, Bockaert J, Manzoni OJ (2001) Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J Neurosci 21:109–116

    PubMed  CAS  Google Scholar 

  • Robbe D, Alonso G, Manzoni OJ (2003) Exogenous and endogenous cannabinoids control synaptic transmission in mice nucleus accumbens. Ann N Y Acad Sci 1003:212–225

    PubMed  CAS  Google Scholar 

  • Robertson GS, Hori SE, Powell KJ (2006) Schizophrenia: an integrative approach to modelling a complex disorder. J Psychiatry Neurosci 31:157–167

    PubMed  Google Scholar 

  • Rodriguez de Fonseca F, Ramos JA, Bonnin A, Fernandez-Ruiz JJ (1993) Presence of cannabinoid binding sites in the brain from early postnatal ages. NeuroReport 4:135–138

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez de Fonseca F, Carrera MR, Navarro M, Koob GF, Weiss F (1997) Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050–2054

    PubMed  CAS  Google Scholar 

  • Rodriguez de Fonseca F, Del Arco I, Martin-Calderon JL, Gorriti MA, Navarro M (1998) Role of the endogenous cannabinoid system in the regulation of motor activity. Neurobiol Dis 5:483–501

    PubMed  CAS  Google Scholar 

  • Rodriguez de Fonseca F, Navarro M, Gomez R, Escuredo L, Nava F, Fu J, Murillo-Rodriguez E, Giuffrida A, LoVerme J, Gaetani S, Kathuria S, Gall C, Piomelli D (2001) An anorexic lipid mediator regulated by feeding. Nature 414:209–212

    PubMed  CAS  Google Scholar 

  • Rössler W, Riecher-Rössler A, Angst J, Murray R, Gamma A, Eich D, van Os J, Gross VA (2007) Psychotic experiences in the general population: a twenty-year prospective community study. Schizophr Res 92(1–3):1–14

    PubMed  Google Scholar 

  • Rueda D, Navarro B, Martinez-Serrano A, Guzman M, Galve-Roperh I (2002) The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway. J Biol Chem 277:46645–46650

    PubMed  CAS  Google Scholar 

  • Scheepers FE, Gispen de Wied CC, Hulshoff Pol HE, Kahn RS (2001) Effect of clozapine on caudate nucleus volume in relation to symptoms of schizophrenia. Am J Psychiatry 158(4):644–646

    PubMed  CAS  Google Scholar 

  • Schlieker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptor. Trends Pharmacol Sci 22:565–572

    Google Scholar 

  • Schneider M, Koch M (2002) The cannabinoid agonist WIN 55,212-2 reduces sensorimotor gating and recognition memory in rats. Behav Pharmacol 13:29–37

    PubMed  CAS  Google Scholar 

  • Schneider M, Koch M (2003) Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmacology 28:1760–1769

    PubMed  CAS  Google Scholar 

  • Schneider M, Koch M (2005) Deficient social and play behavior in juvenile and adult rats after neonatal cortical lesion: effects of chronic pubertal cannabinoid treatment. Neuropsychopharmacology 30:944–957

    PubMed  CAS  Google Scholar 

  • Schneider M, Koch M (2007) The effect of chronic peripubertal cannabinoid treatment on deficient object recognition memory in rats after neonatal mPFC lesion. Eur Neuropsychopharmacol 17:180–186

    PubMed  CAS  Google Scholar 

  • Schneier FR, Siris SG (1987) A review of psychoactive substance use and abuse in schizophrenia. Patterns of drug choice. J Nerv Ment Dis 175(11):641–652

    PubMed  CAS  Google Scholar 

  • Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188(4194):1217–1219

    PubMed  CAS  Google Scholar 

  • Sekine Y, Minabe Y, Ouchi Y et al (2003) Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms. Am J Psychiatr 160(9):1699–1701

    PubMed  Google Scholar 

  • Semple DM, McIntosh AM, Lawrie SM (2005) Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 19(2):187–194

    PubMed  Google Scholar 

  • Smit F, Bolier L, Cuijpers P (2004) Cannabis use and the risk of later schizophrenia: a review. Addiction 99:425–430

    PubMed  Google Scholar 

  • Solowij N, Michie PT (2007) Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci 32:30–52

    PubMed  Google Scholar 

  • Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, Christiansen K, McRee B, Vendetti J, Marijuana Treatment Project Research Group (2002) Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA 287:1123–1131

    PubMed  Google Scholar 

  • Soria G, Mendizabal V, Touriño C et al (2005) Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 30:1670–1680

    PubMed  CAS  Google Scholar 

  • Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463

    PubMed  CAS  Google Scholar 

  • Stanley-Cary CC, Harris C, Martin-Iverson MT (2002) Differing effects of the cannabinoid agonist CP55, 940, in an alcohol or Tween 80 solvent, on prepulse inhibition of the acoustic startle reflex in the rat. Behav Pharmacol 13:15–28

    PubMed  CAS  Google Scholar 

  • Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J (2004) Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 99:1333–1341

    PubMed  CAS  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinthorsdottir V et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71(4):877–892

    PubMed  Google Scholar 

  • Suárez J, Bermúdez-Silva FJ, Mackie K, Ledent C, Zimmer A, Cravatt BF, Rodriguez de Fonseca F (2008) Immunohistochemical description of the endogenous cannabinoid system in the rat cerebellum and functionally related nuclei. J Comp Neurol 509(4):400–421

    PubMed  Google Scholar 

  • Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97

    PubMed  CAS  Google Scholar 

  • Sundram S, Copolov D, Dean B (2005) Clozapine decreases [3H] CP 55940 binding to the cannabinoid 1 receptor in the rat nucleus accumbens. Naunyn Schmiedebergs Arch Pharmacol 371(5):428–433

    PubMed  CAS  Google Scholar 

  • Thacore VR, Sukhla SRP (1976) Cannabis psychosis and paranoid schizophrenia. Arch Gen Psychiatry 33:383–386

    PubMed  CAS  Google Scholar 

  • Thornicroft G (1990) Cannabis and psychosis. Is there epidemiological evidence for an association? Br J Psychiatry 157:25–33

    PubMed  CAS  Google Scholar 

  • Tien AY, Anthony JC (1990) Epidemiological analysis of alcohol and drug use as risk factors for psychotic experiences. J Nerv Ment Dis 178(8):473–480

    PubMed  CAS  Google Scholar 

  • Ujike H, Takaki M, Nakata K et al (2002) CNR1, a central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 7:515–518

    PubMed  CAS  Google Scholar 

  • Van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H (2002) Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 156(4):319–327

    PubMed  Google Scholar 

  • Varma SL, Sharma I (1993) Psychiatric morbidity in the first-degree relatives of schizophrenic patients. Br J Psychiatry 162:672–678

    PubMed  CAS  Google Scholar 

  • Verdoux H, Tournier M (2004) Cannabis use and risk of psychosis: an etiological link? Epidemiol Psichiatr Soc 13(2):113–119

    PubMed  Google Scholar 

  • Verdoux H, Tournier M, Cougnard A (2005) Impact of substance use on the onset and course of early psychosis. Schizophr Res 79:69–75

    PubMed  Google Scholar 

  • Vogt BA (2005) Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci 6:533–544

    PubMed  CAS  Google Scholar 

  • Walss-Bass C, Liu W, Lew DF et al (2006a) A novel missense mutation in the transmembrane domain of neuregulin 1 is associated with schizophrenia. Biol Psychiatry 60(6):548–553

    PubMed  CAS  Google Scholar 

  • Walss-Bass C, Raventos H, Montero AP, Armas R, Dassori A, Contreras S, Liu W, Medina R, Levinson DF, Pereira M, Leach RJ, Almasy L, Escamilla MA (2006b) Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population. Acta Psychiatr Scand 113(4):314–321

    PubMed  CAS  Google Scholar 

  • Wenger T, Gerendai I, Fezza F, Gonzalez S, Bisoqno T, Fernandez-Ruiz JJ, Di Marzo V (2002) The hypothalamic levels of the endocannabinoid, anandamide, peak immediately before the onset of puberty in female rats. Life Sci 70:1407–1414

    PubMed  CAS  Google Scholar 

  • Wicker B, Perrett DI, Baron-Cohen S, Decety J (2003) Being the target of another’s emotion: a PET study. Neuropsychologia 41(2):139–146

    PubMed  Google Scholar 

  • Wiley JL, Kendler SH, Burston JJ, Howard DR, Selley DE, Sim-Selley LJ (2008) Antipsychotic-induced alterations in CB1 receptor-mediated G-protein signaling and in vivo pharmacology in rats. Neuropharmacology 55(7):1183–1190

    PubMed  CAS  Google Scholar 

  • Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592

    PubMed  CAS  Google Scholar 

  • Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682

    PubMed  CAS  Google Scholar 

  • Wilson RI, Kunos G, Nicoll RA (2001) Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31:453–462

    PubMed  CAS  Google Scholar 

  • Zachariou M, Dissanayake DW, Coombes S, Owen MR, Mason R (2008) Sensory gating and its modulation by cannabinoids: electrophysiological, computational and mathematical analysis. Cogn Neurodyn 2(2):159–170

    PubMed  Google Scholar 

  • Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G (2002) Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ 325(7374):1199

    PubMed  Google Scholar 

  • Zavitsanou K, Garrick T, Huang XF (2004) Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28:355–360

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants to EFE, MPV, and FRF from RED de Trastornos Adictivos (Instituto Carlos III, RD06/0001), to EFE from Delegacion del Gobierno para el Plan Nacional Sobre Drogas (3SI/05/4), and to MPV from MEC SAF2006-07523.

Conflict of interest

There is no actual or potential conflict of interest in relation to this article.

Author information

Authors and Affiliations

  1. Departamento de Fisiología Médica, Facultad de Medicina, Universidad de Sevilla, 41009, Seville, Spain

    Emilio Fernandez-Espejo

  2. Departamento de Fisiología (Fisiología Animal II), Universidad Complutense de Madrid, 28040, Madrid, Spain

    Maria-Paz Viveros

  3. Centro Médico, Calle Hermanos Imaz 8, 31002, Pamplona, Spain

    Luis Núñez

  4. Evotec Neurosciences GmbH, Neuropharmacology, CiM, Falkenried 88, 20251, Hamburg, Germany

    Bart A. Ellenbroek

  5. Fundación IMABIS, Hosp. Reg. Univ. Carlos Haya, 29010, Málaga, Spain

    Fernando Rodriguez de Fonseca

Authors
  1. Emilio Fernandez-Espejo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria-Paz Viveros
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luis Núñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bart A. Ellenbroek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fernando Rodriguez de Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Emilio Fernandez-Espejo or Fernando Rodriguez de Fonseca.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernandez-Espejo, E., Viveros, MP., Núñez, L. et al. Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology 206, 531–549 (2009). https://doi.org/10.1007/s00213-009-1612-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1612-6

Keywords

Search

Navigation