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The independent and combined effects of cannabis use and systemic inflammation during the early stages of psychosis: exploring the two-hit hypothesis

Published online by Cambridge University Press:  19 March 2021

Fabiana Corsi-Zuelli Open the ORCID record for Fabiana Corsi-Zuelli [Opens in a new window] ,
Leonardo Marques ,
Daiane Leite da Roza Open the ORCID record for Daiane Leite da Roza [Opens in a new window] ,
Camila Marcelino Loureiro Open the ORCID record for Camila Marcelino Loureiro [Opens in a new window] ,
Rosana Shuhama Open the ORCID record for Rosana Shuhama [Opens in a new window] ,
Marta Di Forti Open the ORCID record for Marta Di Forti [Opens in a new window] ,
Paulo Rossi Menezes Open the ORCID record for Paulo Rossi Menezes [Opens in a new window] ,
Paulo Louzada-Junior Open the ORCID record for Paulo Louzada-Junior [Opens in a new window]  and
Cristina Marta Del-Ben Open the ORCID record for Cristina Marta Del-Ben [Opens in a new window]
Fabiana Corsi-Zuelli*
Affiliation:
Department of Neuroscience and Behaviour, Division of Psychiatry, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil Center for Research on Inflammatory Diseases – CRID, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
Leonardo Marques
Affiliation:
Department of Neuroscience and Behaviour, Division of Psychiatry, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
Daiane Leite da Roza
Affiliation:
Department of Neuroscience and Behaviour, Division of Psychiatry, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
Camila Marcelino Loureiro
Affiliation:
Center for Research on Inflammatory Diseases – CRID, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil Department of Internal Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil Population Mental Health Center – NAP-SaMP, University of São Paulo, São Paulo, Brazil
Rosana Shuhama
Affiliation:
Department of Neuroscience and Behaviour, Division of Psychiatry, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil Population Mental Health Center – NAP-SaMP, University of São Paulo, São Paulo, Brazil
Marta Di Forti
Affiliation:
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
Paulo Rossi Menezes
Affiliation:
Population Mental Health Center – NAP-SaMP, University of São Paulo, São Paulo, Brazil Department of Preventive Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
Paulo Louzada-Junior
Affiliation:
Center for Research on Inflammatory Diseases – CRID, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil Department of Internal Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
Cristina Marta Del-Ben
Affiliation:
Department of Neuroscience and Behaviour, Division of Psychiatry, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil Population Mental Health Center – NAP-SaMP, University of São Paulo, São Paulo, Brazil
*
Author for correspondence: Fabiana Corsi-Zuelli, E-mail: fabiana.zuelli@usp.br
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Abstract

Background

Cannabis consumption is a modifiable risk factor associated with psychosis, but not all cannabis users develop psychosis. Animal studies suggest that an antecedent active immune system interacts with subsequent cannabis exposure and moderates the cannabis–psychosis association, supporting the two-hit hypothesis. The clinical investigations are few, and it is unclear if the immune system is a biological candidate moderating the cannabis–psychosis association or whether cannabis increases inflammation, which in turn, augments psychosis likelihood.

Methods

We explored the mediating and moderating role of blood inflammation using PROCESS macro. We used data from a cross-sectional study, including 153 first-episode psychosis patients and 256 community-based controls. Participants answered the Cannabis Experience Questionnaire (cannabis frequency, age of onset, and duration), and plasma cytokines were measured [interleukin (IL)-1β, IL-6, IL-4, IL-10, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), transforming growth factor-β (TGF-β); multiplex]. We computed an inflammatory composite score (ICS) to represent the systemic inflammatory state. Confounders included sex, age, ethnicity, educational level, body mass index, tobacco smoking, lifetime use of other drugs, and antipsychotic treatment.

Results

Mediation: Cannabis consumption was not associated with increased inflammation, thus not supporting a mediating effect of inflammation. Moderation: Daily use and age of onset <17 interacted significantly with the ICS to increase the odds of psychosis beyond their individual effects and were only associated with psychosis among those scoring medium–high in the ICS.

Conclusions

Immune dysregulation might be part of the pathophysiology of psychosis, not explained by cannabis use or other confounders. We provide the first and initial evidence that immune dysregulation modifies the cannabis–psychosis association, in line with a two-hit hypothesis.

Keywords

marijuanainflammationschizophreniapro-inflammatory cytokinesanti-inflammatory cytokinesinnate immunityadaptive immunity
Type
Original Article
Information
Psychological Medicine , Volume 52 , Issue 16 , December 2022 , pp. 3874 - 3884
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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