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Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis

Published online by Cambridge University Press:  29 January 2020

Aisling O'Neill Open the ORCID record for Aisling O'Neill [Opens in a new window] ,
Robin Wilson ,
Grace Blest-Hopley ,
Luciano Annibale ,
Marco Colizzi ,
Mick Brammer ,
Vincent Giampietro  and
Sagnik Bhattacharyya
Aisling O'Neill
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Robin Wilson
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Grace Blest-Hopley
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Luciano Annibale
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Marco Colizzi
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
Mick Brammer
Affiliation:
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Vincent Giampietro
Affiliation:
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Sagnik Bhattacharyya*
Affiliation:
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
*
Author for correspondence: Sagnik Bhattacharyya, E-mail: [email protected]
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Abstract

Background

Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown.

Methods

Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest.

Results

Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients.

Conclusions

This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

Keywords

CannabidiolcannabinoidfMRIfunctional connectivitymemorypsychosisschizophrenia
Type
Original Article
Information
Psychological Medicine , Volume 51 , Issue 4 , March 2021 , pp. 596 - 606
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Copyright
Copyright © Cambridge University Press 2020

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References

Achim, A. M., & Lepage, M. (2005). Episodic memory-related activation in schizophrenia: Meta-analysis. British Journal of Psychiatry, 187, 500–509.CrossRefGoogle ScholarPubMed
Agurell, S., Carlsson, S., Lindgren, J. E., Ohlsson, A., Gillespie, H., & Hollister, L. (1981). Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man. Assay of cannabinol and cannabidiol by mass fragmentography. Experientia, 37, 1090–1092.CrossRefGoogle ScholarPubMed
Allen, P., Azis, M., Modinos, G., Bossong, M. G., Bonoldi, I., Samson, C., … Mcguire, P. (2018). Increased resting hippocampal and basal ganglia perfusion in people at ultra high risk for psychosis: Replication in a second cohort. Schizophrenia Bulletin, 44, 1323–1331.CrossRefGoogle ScholarPubMed
Allen, P., Chaddock, C. A., Egerton, A., Howes, O. D., Bonoldi, I., Zelaya, F., … Mcguire, P. (2016). Resting hyperperfusion of the hippocampus, midbrain, and basal ganglia in people at high risk for psychosis. American Journal of Psychiatry, 173, 392–399.CrossRefGoogle ScholarPubMed
American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association.Google Scholar
Bergamaschi, M. M., Queiroz, R. H., Zuardi, A. W., & Crippa, J. A. (2011). Safety and side effects of cannabidiol, a Cannabis sativa constituent. Current Drug Safety, 6, 237–249.CrossRefGoogle ScholarPubMed
Bhattacharyya, S., Atakan, Z., Martin-Santos, R., Crippa, J. A., Kambeitz, J., Prata, D., … Mcguire, P. K. (2012a). 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.CrossRefGoogle Scholar
Bhattacharyya, S., Crippa, J. A., Allen, P., Martin-Santos, R., Borgwardt, S., Fusar-Poli, P., … Mcguire, P. K. (2012b). Induction of psychosis by Delta9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Archives of General Psychiatry, 69, 27–36.CrossRefGoogle Scholar
Bhattacharyya, S., Fusar-Poli, P., Borgwardt, S., Martin-Santos, R., Nosarti, C., O'carroll, C., … Mcguire, P. (2009). Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: A neural basis for the effects of Cannabis sativa on learning and psychosis. Archives of General Psychiatry, 66, 442–451.CrossRefGoogle ScholarPubMed
Bhattacharyya, S., Morrison, P. D., Fusar-Poli, P., Martin-Santos, R., Borgwardt, S., Winton-Brown, T., … Mcguire, P. K. (2010). Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 35, 764–774.CrossRefGoogle ScholarPubMed
Bhattacharyya, S., Wilson, R., Appiah-Kusi, E., O'neill, A., Brammer, M., Perez, J., … Mcguire, P. (2018). Effect of cannabidiol on medial temporal, midbrain, and striatal dysfunction in people at clinical high risk of psychosis: A randomized clinical trial. JAMA Psychiatry, 75, 1107–1117.CrossRefGoogle ScholarPubMed
Bisogno, T., Hanus, L., De Petrocellis, L., Tchilibon, S., Ponde, D. E., Brandi, I., … Di Marzo, V. (2001). Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. British Journal of Pharmacology, 134, 845–852.CrossRefGoogle ScholarPubMed
Blasi, G., Popolizio, T., Taurisano, P., Caforio, G., Romano, R., Di Giorgio, A., … Bertolino, A. (2009). Changes in prefrontal and amygdala activity during olanzapine treatment in schizophrenia. Psychiatry Research, 173, 31–38.CrossRefGoogle Scholar
Blumenfeld, R. S., & Ranganath, C. (2007). Prefrontal cortex and long-term memory encoding: An integrative review of findings from neuropsychology and neuroimaging. Neuroscientist, 13, 280–291.CrossRefGoogle ScholarPubMed
Bonner-Jackson, A., Haut, K., Csernansky, J. G., & Barch, D. M. (2005). The influence of encoding strategy on episodic memory and cortical activity in schizophrenia. Biological Psychiatry, 58, 47–55.CrossRefGoogle Scholar
Bossong, M. G., Mehta, M. A., Van Berckel, B. N., Howes, O. D., Kahn, R. S., & Stokes, P. R. (2015). Further human evidence for striatal dopamine release induced by administration of 9-tetrahydrocannabinol (THC): Selectivity to limbic striatum. Psychopharmacology (Berl), 232, 2723–2729.CrossRefGoogle ScholarPubMed
Brammer, M. J., Bullmore, E. T., Simmons, A., Williams, S. C., Grasby, P. M., Howard, R. J., … Rabe-Hesketh, S. (1997). Generic brain activation mapping in functional magnetic resonance imaging: A nonparametric approach. Magnetic Resonance Imaging, 15, 763–770.CrossRefGoogle ScholarPubMed
Buckner, R. L., & Wheeler, M. E. (2001). The cognitive neuroscience of remembering. Nature Reviews Neuroscience, 2, 624–634.CrossRefGoogle ScholarPubMed
Bullmore, E., Long, C., Suckling, J., Fadili, J., Calvert, G., Zelaya, F., … Brammer, M. (2001). Colored noise and computational inference in neurophysiological (fMRI) time series analysis: Resampling methods in time and wavelet domains. Human Brain Mapping, 12, 61–78.3.0.CO;2-W>CrossRefGoogle ScholarPubMed
Bullmore, E. T., Suckling, J., Overmeyer, S., Rabe-Hesketh, S., Taylor, E., & Brammer, M. J. (1999). Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain. IEEE Transactions on Medical Imaging, 18, 32–42.CrossRefGoogle ScholarPubMed
Davachi, L. (2006). Item, context and relational episodic encoding in humans. Current Opinion in Neurobiology, 16, 693–700.CrossRefGoogle ScholarPubMed
Fogaca, M. V., Campos, A. C., Coelho, L. D., Duman, R. S., & Guimaraes, F. S. (2018). The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology, 135, 22–33.CrossRefGoogle ScholarPubMed
Fusar-Poli, P., Allen, P., Bhattacharyya, S., Crippa, J. A., Mechelli, A., Borgwardt, S., … Mcguire, P. (2010). Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. International Journal of Neuropsychopharmacology, 13, 421–432.CrossRefGoogle ScholarPubMed
Hofer, A., Weiss, E. M., Golaszewski, S. M., Siedentopf, C. M., Brinkhoff, C., Kremser, C., … Fleischhacker, W. W. (2003). Neural correlates of episodic encoding and recognition of words in unmedicated patients during an acute episode of schizophrenia: A functional MRI study. American Journal of Psychiatry, 160, 1802–1808.CrossRefGoogle ScholarPubMed
Howes, O., Bose, S., Turkheimer, F., Valli, I., Egerton, A., Stahl, D., … Mcguire, P. (2011). Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: A PET study. Molecular Psychiatry, 16, 885–886.CrossRefGoogle ScholarPubMed
Hutcheson, N. L., Reid, M. A., White, D. M., Kraguljac, N. V., Avsar, K. B., Bolding, M. S., … Lahti, A. C. (2012). Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging. Schizophrenia Research, 140, 136–142.CrossRefGoogle ScholarPubMed
IBM Corp. (2013). IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.Google Scholar
Iseger, T. A., & Bossong, M. G. (2015). A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophrenia Research, 162, 153–161.CrossRefGoogle ScholarPubMed
Jessen, F., Scheef, L., Germeshausen, L., Tawo, Y., Kockler, M., Kuhn, K. U., … Heun, R. (2003). Reduced hippocampal activation during encoding and recognition of words in schizophrenia patients. American Journal of Psychiatry, 160, 1305–1312.CrossRefGoogle ScholarPubMed
Katona, I. (2015). Cannabis and endocannabinoid signaling in epilepsy. Handbook of Experimental Pharmacology, 231, 285–316.CrossRefGoogle ScholarPubMed
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13, 261–276.CrossRefGoogle Scholar
Kirwan, C. B., & Stark, C. E. (2004). Medial temporal lobe activation during encoding and retrieval of novel face-name pairs. Hippocampus, 14, 919–930.CrossRefGoogle ScholarPubMed
Landau, S. M., Lal, R., O'neil, J. P., Baker, S., & Jagust, W. J. (2009). Striatal dopamine and working memory. Cerebral Cortex, 19, 445–454.CrossRefGoogle ScholarPubMed
Leweke, F. M., Piomelli, D., Pahlisch, F., Muhl, D., Gerth, C. W., Hoyer, C., … Koethe, D. (2012). Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational Psychiatry, 2, e94.CrossRefGoogle ScholarPubMed
Lewis, D. A., & Hashimoto, T. (2007). Deciphering the disease process of schizophrenia: The contribution of cortical GABA neurons. International Review of Neurobiology, 78, 109–131.CrossRefGoogle ScholarPubMed
Lodge, D. J., & Grace, A. A. (2011). Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends in Pharmacological Sciences, 32, 507–513.CrossRefGoogle ScholarPubMed
Martin-Santos, R., Crippa, J. A., Batalla, A., Bhattacharyya, S., Atakan, Z., Borgwardt, S., … Mcguire, P. K. (2012). Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Current Pharmaceutical Design, 18, 4966–4979.CrossRefGoogle ScholarPubMed
Mcguire, P., Robson, P., Cubala, W. J., Vasile, D., Morrison, P. D., Barron, R., … Wright, S. (2018). Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. American Journal of Psychiatry, 175, 225–231.CrossRefGoogle ScholarPubMed
Mcnab, F., & Klingberg, T. (2008). Prefrontal cortex and basal ganglia control access to working memory. Nature Neuroscience, 11, 103–107.CrossRefGoogle ScholarPubMed
Mesholam-Gately, R. I., Giuliano, A. J., Goff, K. P., Faraone, S. V., & Seidman, L. J. (2009). Neurocognition in first-episode schizophrenia: A meta-analytic review. Neuropsychology, 23, 315–336.CrossRefGoogle ScholarPubMed
Modinos, G., Simsek, F., Azis, M., Bossong, M., Bonoldi, I., Samson, C., … Mcguire, P. (2018). Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis. Neuropsychopharmacology, 43, 2652–2659.CrossRefGoogle ScholarPubMed
Montaldi, D., Spencer, T. J., Roberts, N., & Mayes, A. R. (2006). The neural system that mediates familiarity memory. Hippocampus, 16, 504–520.CrossRefGoogle ScholarPubMed
Murray, L. J., & Ranganath, C. (2007). The dorsolateral prefrontal cortex contributes to successful relational memory encoding. Journal of Neuroscience, 27, 5515–5522.CrossRefGoogle ScholarPubMed
Nielsen, M. O., Rostrup, E., Wulff, S., Bak, N., Broberg, B. V., Lublin, H., … Glenthoj, B. (2012). Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia. Archives of General Psychiatry, 69, 1195–1204.CrossRefGoogle Scholar
Pertwee, R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. British Journal of Pharmacology, 153, 199–215.CrossRefGoogle ScholarPubMed
Pirnia, T., Woods, R. P., Hamilton, L. S., Lyden, H., Joshi, S. H., Asarnow, R. F., … Narr, K. L. (2015). Hippocampal dysfunction during declarative memory encoding in schizophrenia and effects of genetic liability. Schizophrenia Research, 161, 357–366.CrossRefGoogle ScholarPubMed
Ragland, J. D., Gur, R. C., Raz, J., Schroeder, L., Kohler, C. G., Smith, R. J., … Gur, R. E. (2001). Effect of schizophrenia on frontotemporal activity during word encoding and recognition: A PET cerebral blood flow study. American Journal of Psychiatry, 158, 1114–1125.CrossRefGoogle ScholarPubMed
Ragland, J. D., Gur, R. C., Valdez, J., Turetsky, B. I., Elliott, M., Kohler, C., … Gur, R. E. (2004). Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia. American Journal of Psychiatry, 161, 1004–1015.CrossRefGoogle Scholar
Ragland, J. D., Gur, R. C., Valdez, J. N., Loughead, J., Elliott, M., Kohler, C., … Gur, R. E. (2005). Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition. American Journal of Psychiatry, 162, 1840–1848.CrossRefGoogle ScholarPubMed
Ragland, J. D., Laird, A. R., Ranganath, C., Blumenfeld, R. S., Gonzales, S. M., & Glahn, D. C. (2009). Prefrontal activation deficits during episodic memory in schizophrenia. American Journal of Psychiatry, 166, 863–874.CrossRefGoogle Scholar
Ragland, J. D., Ranganath, C., Harms, M. P., Barch, D. M., Gold, J. M., Layher, E., … Carter, C. S. (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. JAMA Psychiatry, 72, 909–916.CrossRefGoogle ScholarPubMed
Ranganath, C., Yonelinas, A. P., Cohen, M. X., Dy, C. J., Tom, S. M., & D'esposito, M. (2004). Dissociable correlates of recollection and familiarity within the medial temporal lobes. Neuropsychologia, 42, 2–13.CrossRefGoogle ScholarPubMed
Rohleder, C., Muller, J. K., Lange, B., & Leweke, F. M. (2016). Cannabidiol as a potential new type of an antipsychotic. A critical review of the evidence. Frontiers in Pharmacology, 7, 422.CrossRefGoogle Scholar
Santos, P. M., Lopez-Garcia, P., Navarro, J. S., Fernandez, A. S., Sadaba, B., & Vidal, J. P. (2007). False positive phencyclidine results caused by venlafaxine. American Journal of Psychiatry, 164, 349.CrossRefGoogle ScholarPubMed
Schobel, S. A., Chaudhury, N. H., Khan, U. A., Paniagua, B., Styner, M. A., Asllani, I., … Small, S. A. (2013). Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron, 78, 81–93.CrossRefGoogle Scholar
Spielberger, C. D., Gorsuch, R. L., & Lushene, R. E. (1970). STAI manual for the State-Trait Anxiety Inventory (“Self-Evaluation Questionnaire”). Palo Alto, Calif.: Consulting Psychologists Press.Google Scholar
Talairach, J., & Tournoux, P. (1988). Co-planar stereotaxic atlas of the human brain: 3-dimensional proportional system: An approach to cerebral imaging. Stuttgart; New York: Georg Thieme.Google Scholar
Wagner, A. D., Schacter, D. L., Rotte, M., Koutstaal, W., Maril, A., Dale, A. M., … Buckner, R. L. (1998). Building memories: Remembering and forgetting of verbal experiences as predicted by brain activity. Science, 281, 1188–1191.CrossRefGoogle ScholarPubMed
Wilson, M. (1988). Mrc psycholinguistic database – machine-usable dictionary, version 2.00. Behavior Research Methods Instruments & Computers, 20, 6–10.CrossRefGoogle Scholar
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