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Endocannabinoid system alterations in schizophrenia: association with cannabis use and antipsychotic medication

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Abstract

Determining peripheral modulation of the endocannabinoid system (ECS) may be important for differentiating individuals with schizophrenia. Such differentiation can also be extended to subgroups of individuals, those who use cannabis and antipsychotic medications, particularly those who are treatment resistant. Patients and controls were recruited from the outpatient clinic of the Psychosis Group of the University of São Paulo, Brazil. A final sample of 93 individuals was divided into 3 groups: patients with schizophrenia using clozapine (treatment-resistant) (n = 29), patients with schizophrenia using another antipsychotic (n = 31), and controls (n = 33). By measuring the proteins and metabolites involved in the ECS pathways in the peripheral blood, AEA (anandamide), 2-AG (2-arachidonoyl ethanolamine), and CB2 receptor (peripheral) were quantified. Individuals reporting lifetime cannabis use had lower 2-AG plasma levels (p = 0.011). Regarding the CB2 receptor, the values of patients with schizophrenia and controls were similar, but those of patients using antipsychotics other than clozapine differed (p = 0.022). In generalized linear models to control for confounders, the use of cannabis remained the only factor that significantly influenced 2-AG levels. The relationship for non-clozapine antipsychotics as the only factor related to CB2 changes was marginally significant. We found for the first time that cannabis use and non-clozapine antipsychotic medication are potentially involved in the modulation of the ECS, specifically influencing 2-AG endocannabinoid and CB2 receptor levels. More studies regarding the ECS are needed since it has been increasingly related to the physiopathology of schizophrenia.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The Laboratory of Neuroscience LIM27 receives financial support from the Associacao Beneficente Alzira Denise Hertzog da Silva.

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP (Grant Number 2014/50873-3), Brazil. The sponsor had no influence on the design of the study; on the collection, analysis and interpretation of data; on the writing of the manuscript; or on the decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Laboratório de Neurociências (LIM 27), Instituto de Psiquiatria, Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de Sao Paulo, Rua Dr. Ovidio Pires de Campos 785, 4 Andar Ala Norte Sala 4N60, Sao Paulo, SP, CEP 05403-010, Brazil

    Natalia Mansur Haddad, Leonardo Peroni De Jesus, Mauricio Serpa, Martinus Van De Bilt, Leda Talib, Alana Costa, Wagner Gattaz & Alexandre Andrade Loch

  2. Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasília, Brazil

    Mauricio Serpa, Martinus Van De Bilt, Leda Talib, Wagner Gattaz & Alexandre Andrade Loch

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  1. Natalia Mansur Haddad
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All authors designed the study and wrote the protocol. Author NMHOS managed the literature searches and wrote the first draft of the manuscript, author AAL undertook the statistical analysis. All authors contributed to and have approved the final manuscript.

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Haddad, N.M., De Jesus, L.P., Serpa, M. et al. Endocannabinoid system alterations in schizophrenia: association with cannabis use and antipsychotic medication. Eur Arch Psychiatry Clin Neurosci (2024). https://doi.org/10.1007/s00406-024-01788-x

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