Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-26T06:00:56.508Z Has data issue: false hasContentIssue false
  • English
  • Français

Increased hippocampal engagement during learning as a marker of sensitivity to psychotomimetic effects of δ-9-THC

Published online by Cambridge University Press:  05 March 2018

Sagnik Bhattacharyya ,
Thomas Sainsbury ,
Paul Allen ,
Chiara Nosarti ,
Zerrin Atakan ,
Vincent Giampietro ,
Michael Brammer  and
P K McGuire
Sagnik Bhattacharyya*
Affiliation:
Department of Psychosis Studies, King's College London, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK
Thomas Sainsbury
Affiliation:
Department of Psychosis Studies, King's College London, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK
Paul Allen
Affiliation:
Department of Psychology, University of Roehampton, UK
Chiara Nosarti
Affiliation:
Department of Psychosis Studies, King's College London, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, London, UK
Zerrin Atakan
Affiliation:
Department of Psychosis Studies, King's College London, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK
Vincent Giampietro
Affiliation:
Department of Neuroimaging, King's College London, Institute of Psychiatry, PO Box 089, De Crespigny Park, London, SE5 8AF, UK
Michael Brammer
Affiliation:
Department of Neuroimaging, King's College London, Institute of Psychiatry, PO Box 089, De Crespigny Park, London, SE5 8AF, UK
P K McGuire
Affiliation:
Department of Psychosis Studies, King's College London, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK
*
Author for correspondence: Dr Sagnik Bhattacharyya, E-mail: sagnik.2.bhattacharyya@kcl.ac.uk
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Cannabis and its main psychoactive ingredient δ-9-tetrahydrocannibidiol (THC) can induce transient psychotic symptoms in healthy individuals and exacerbate them in those with established psychosis. However, not everyone experience these effects, suggesting that certain individuals are particularly susceptible. The neural basis of this sensitivity to the psychotomimetic effects of THC is unclear.

Methods

We investigated whether individuals who are sensitive to the psychotomimetic effects of THC (TP) under experimental conditions would show differential hippocampal activation compared with those who are not (NP). We studied 36 healthy males under identical conditions under the influence of placebo or THC (10 mg) given orally, on two separate occasions, in a pseudo-randomized, double-blind, repeated measures, within-subject, cross-over design, using psychopathological assessments and functional MRI while they performed a verbal learning task. They were classified into those who experienced transient psychotic symptoms (TP; n = 14) following THC administration and those who did not (NP; n = 22).

Results

Under placebo conditions, there was significantly greater engagement of the left hippocampus (p < 0.001) in the TP group compared with the NP group during verbal encoding, which survived leave-one-out analysis. The level of hippocampal activation was directly correlated (Spearman's ρ = 0.44, p = 0.008) with the severity of transient psychotic symptoms induced by THC. This difference was not present when we compared two subgroups from the same sample that were defined by sensitivity to anxiogenic effects of THC.

Conclusions

These results suggest that altered hippocampal activation during verbal encoding may serve as a marker of sensitivity to the acute psychotomimetic effects of THC.

Keywords

Cannabisδ-9-tetrahydrocannabinolfMRIhippocampuspsychosisverbal learning
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 16 , December 2018 , pp. 2748 - 2756
Copyright
Copyright © Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Allen, P, Chaddock, CA, Egerton, A, Howes, OD, Bonoldi, I, Zelaya, F et al. (2016) Resting hyperperfusion of the hippocampus, midbrain, and basal ganglia in people at high risk for psychosis. American Journal of Psychiatry 173, 392–399.Google Scholar
Atakan, Z, Bhattacharyya, S, Allen, P, Martin-Santos, R, Crippa, JA, Borgwardt, SJ et al. (2013) Cannabis affects people differently: inter-subject variation in the psychotogenic effects of delta-9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers. Psychological Medicine 43, 1255–1267.Google Scholar
Bhattacharyya, S, Atakan, Z, Martin-Santos, R, Crippa, JA, Kambeitz, J, Malhi, S et al. (2015 a) Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis. European Neuropsychopharmacology 25, 26–37.Google Scholar
Bhattacharyya, S, Atakan, Z, Martin-Santos, R, Crippa, JA, Kambeitz, J, Prata, D et al. (2012 a) Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: aKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function. Molecular Psychiatry 17, 1152–1155.Google Scholar
Bhattacharyya, S, Crippa, JA, Allen, P, Martin-Santos, R, Borgwardt, S, Fusar-Poli, P et al. (2012 b) Induction of psychosis by delta-9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Archives of General Psychiatry 69, 27–36.Google Scholar
Bhattacharyya, S, Egerton, A, Kim, E, Rosso, L, Riano Barros, D, Hammers, A et al. (2017) Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors. Scientific Reports 7, 15025–15039.Google Scholar
Bhattacharyya, S, Falkenberg, I, Martin-Santos, R, Atakan, Z, Crippa, JA, Giampietro, V et al. (2015 b) Cannabinoid modulation of functional connectivity within regions processing attentional salience. Neuropsychopharmacology 40, 1343–1352.Google Scholar
Bhattacharyya, S, Fusar-Poli, P, Borgwardt, S, Martin-Santos, R, Nosarti, C, O'Carroll, C et al. (2009) Modulation of mediotemporal and ventrostriatal function in humans by delta-9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Archives of General Psychiatry 66, 442–451.Google Scholar
Bhattacharyya, S, Iyegbe, C, Atakan, Z, Martin-Santos, R, Crippa, JA, Xu, X et al. (2014) Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control. Psychological Medicine 44, 3315–3328.Google Scholar
Bhattacharyya, S, Morrison, PD, Fusar-Poli, P, Martin-Santos, R, Borgwardt, S, Winton-Brown, T et al. (2010) Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35, 764–774.Google Scholar
Callicott, JH, Bertolino, A, Mattay, VS, Langheim, FJ, Duyn, J, Coppola, R et al. (2000) Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cerebral Cortex 10, 1078–1092.Google Scholar
Curran, HV, Brignell, C, Fletcher, S, Middleton, P and Henry, J (2002) Cognitive and subjective dose-response effects of acute oral delta-9-tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology (Berl) 164, 61–70.Google Scholar
D'Souza, DC, Abi-Saab, WM, Madonick, S, Forselius-Bielen, K, Doersch, A, Braley, G et al. (2005) Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biological Psychiatry 57, 594–608.Google Scholar
D'Souza, DC, Perry, E, MacDougall, L, Ammerman, Y, Cooper, T, Wu, YT et al. (2004) The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29, 1558–1572.Google Scholar
Di Forti, M, Iyegbe, C, Sallis, H, Kolliakou, A, Falcone, MA, Paparelli, A et al. (2012) Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biological Psychiatry 72, 811–816.Google Scholar
Eggan, SM and Lewis, DA (2007) Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. Cerebral Cortex 17, 175–191.Google Scholar
Eichenbaum, H, Yonelinas, AP and Ranganath, C (2007) The medial temporal lobe and recognition memory. Annual Review of Neuroscience 30, 123–152.Google Scholar
Eldreth, DA, Matochik, JA, Cadet, JL and Bolla, KI (2004) Abnormal brain activity in prefrontal brain regions in abstinent marijuana users. Neuroimage 23, 914–920.Google Scholar
Elphick, MR and Egertova, M (2001) The neurobiology and evolution of cannabinoid signalling. Philosophical Transactions of Royal Society London B Biological Science 356, 381–408.Google Scholar
Hannula, DE and Ranganath, C (2008) Medial temporal lobe activity predicts successful relational memory binding. Journal of Neuroscience 28, 116–124.Google Scholar
Henquet, C, Krabbendam, L, Spauwen, J, Kaplan, C, Lieb, R, Wittchen, HU et al. (2005) Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. The British Medical Journal 330, 11–15.Google Scholar
Henquet, C, Rosa, A, Krabbendam, L, Papiol, S, Fananas, L, Drukker, M et al. (2006) An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 31, 2748–2757.Google Scholar
Heyser, CJ, Hampson, RE and Deadwyler, SA (1993) 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. Journal of Pharmacology & Experimental Therapeutics 264, 294–307.Google Scholar
Jacobson, NS and Truax, P (1991) Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting & Clinical Psychology 59, 12–19.Google Scholar
Kay, SR, Fiszbein, A and Opler, LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276.Google Scholar
Lepage, M, Hawco, C and Bodnar, M (2015) Relational memory as a possible neurocognitive marker of schizophrenia. Journal of the American Medical Association Psychiatry 72, 946–947.Google Scholar
Lodge, DJ and Grace, AA (2007) Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. Journal of Neuroscience 27, 11424–11430.Google Scholar
Lodge, DJ and Grace, AA (2011) Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends in Pharmacological Science 32, 507–513.Google Scholar
Mathew, RJ, Wilson, WH, Humphreys, DF, Lowe, JV and Wiethe, KE (1992) Regional cerebral blood flow after marijuana smoking. Journal of Cerebral Blood Flow & Metabolism 12, 750–758.Google Scholar
McGuire, PK, Jones, P, Harvey, I, Williams, M, McGuffin, P and Murray, RM (1995) Morbid risk of schizophrenia for relatives of patients with cannabis-associated psychosis. Schizophrenia Research 15, 277–281.Google Scholar
McLellan, AT, Luborsky, L, Woody, GE and O'Brien, CP (1980) An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index. Journal of Nervous & Mental Disease 168, 26–33.Google Scholar
Moore, TH, Zammit, S, Lingford-Hughes, A, Barnes, TR, Jones, PB, Burke, M et al. (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. The Lancet 370, 319–328.Google Scholar
Morrison, PD, Nottage, J, Stone, JM, Bhattacharyya, S, Tunstall, N, Brenneisen, R et al. (2011) Disruption of frontal theta coherence by delta-9-tetrahydrocannabinol is associated with positive psychotic symptoms. Neuropsychopharmacology 36, 827–836.Google Scholar
Nelson, MD, Saykin, AJ, Flashman, LA and Riordan, HJ (1998) Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Archives of General Psychiatry 55, 433–440.Google Scholar
Patel, R, Wilson, R, Jackson, R, Ball, M, Shetty, H, Broadbent, M et al. (2016) Association of cannabis use with hospital admission and antipsychotic treatment failure in first episode psychosis: an observational study. British Medical Journal Open 6, e009888.Google Scholar
Pertwee, RG (2008) Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addiction Biology 13, 147–159.Google Scholar
Ragland, JD, Ranganath, C, Harms, MP, Barch, DM, Gold, JM, Layher, E et al. (2015) Functional and neuroanatomic specificity of episodic memory dysfunction in schizophrenia: a functional magnetic resonance imaging study of the relational and item-specific encoding task. Journal of the American Medical Association Psychiatry 72, 909–916.Google Scholar
Ranganathan, M and D'Souza, DC (2006) The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl) 188, 425–444.Google Scholar
Robbe, D, Montgomery, SM, Thome, A, Rueda-Orozco, PE, McNaughton, BL and Buzsaki, G (2006) Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nature Neuroscience 9, 1526–1533.Google Scholar
Schaefer, J, Giangrande, E, Weinberger, DR and Dickinson, D (2013) The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophrenia Research 150, 42–50.Google Scholar
Schoeler, T and Bhattacharyya, S (2013) The effect of cannabis use on memory function: an update. Substance Abuse & Rehabilitation 4, 11–27.Google Scholar
Schoeler, T, Kambeitz, J, Behlke, I, Murray, R and Bhattacharyya, S (2016 a) The effects of cannabis on memory function in users with and without a psychotic disorder: findings from a combined meta-analysis. Psychological Medicine 46, 177–188.Google Scholar
Schoeler, T, Monk, A, Sami, MB, Klamerus, E, Foglia, E, Brown, R et al. (2016 b) Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis. The Lancet Psychiatry 3, 215–225.Google Scholar
Schoeler, T, Petros, N, Di Forti, M, Klamerus, E, Foglia, E, Ajnakina, O et al. (2016 c) Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study. The Lancet Psychiatry 3, 947–953.Google Scholar
Schoeler, T, Petros, N, Di Forti, M, Pingault, JB, Klamerus, E, Foglia, E et al. (2016 d) Association between continued cannabis use and risk of relapse in first-episode psychosis: a quasi-experimental investigation within an observational study. Journal of the American Medical Association Psychiatry 73, 1173–1179.Google Scholar
Shergill, SS, Brammer, MJ, Williams, SC, Murray, RM and McGuire, PK (2000) Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Archives of General Psychiatry 57, 1033–1038.Google Scholar
Simons, JS and Spiers, HJ (2003) Prefrontal and medial temporal lobe interactions in long-term memory. Nature Review Neuroscience 4, 637–648.Google Scholar
Solowij, N, Stephens, RS, Roffman, RA, Babor, T, Kadden, R, Miller, M et al. , Marijuana Treatment Project Research, G. (2002). Cognitive functioning of long-term heavy cannabis users seeking treatment. Journal of the American Medical Association 287, 1123–1131.Google Scholar
Spielberger, CD (1983) Manual for the State/Trait Anxiety Inventory (form Y): (Self Evaluation Questionnaire). Palo Alto: Consulting Psychologists Press.Google Scholar
Stirling, J, Barkus, EJ, Nabosi, L, Irshad, S, Roemer, G, Schreudergoidheijt, B et al. (2008) Cannabis-induced psychotic-like experiences are predicted by high schizotypy. Confirmation of preliminary results in a large cohort. Psychopathology 41, 371–378.Google Scholar
Tapert, SF, Schweinsburg, AD, Drummond, SP, Paulus, MP, Brown, SA, Yang, TT et al. (2007) Functional MRI of inhibitory processing in abstinent adolescent marijuana users. Psychopharmacology (Berl) 194, 173–183.Google Scholar
Thirion, B, Pinel, P, Meriaux, S, Roche, A, Dehaene, S and Poline, JB (2007) Analysis of a large fMRI cohort: statistical and methodological issues for group analyses. Neuroimage 35, 105–120.Google Scholar
Valli, I, Stone, J, Mechelli, A, Bhattacharyya, S, Raffin, M, Allen, P et al. (2011) Altered medial temporal activation related to local glutamate levels in subjects with prodromal signs of psychosis. Biological Psychiatry 69, 97–99.Google Scholar
van Winkel, R, Genetic, R , Outcome of Psychosis, I. (2011). Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Archives of General Psychiatry 68, 148–157.Google Scholar
Weinstein, A, Brickner, O, Lerman, H, Greemland, M, Bloch, M, Lester, H et al. (2008) Brain imaging study of the acute effects of delta-9-tetrahydrocannabinol (THC) on attention and motor coordination in regular users of marijuana. Psychopharmacology (Berl) 196, 119–131.Google Scholar
Zammit, S, Allebeck, P, Andreasson, S, Lundberg, I and Lewis, G (2002) Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. The British Medical Journal 325, 1199–1203.Google Scholar
Supplementary material: File

Bhattacharyya et al. supplementary material

Bhattacharyya et al. supplementary material 1

Download Bhattacharyya et al. supplementary material(File)
File 2.2 MB