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

Fabiana Corsi-Zuelli*, Leonardo Marques, Daiane Leite Da Roza, Camila Marcelino Loureiro, Rosana Shuhama, Marta Di Forti, Paulo Rossi Menezes, Paulo Louzada-Junior, Cristina Marta Del-Ben

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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-γ3), 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.

Original languageEnglish
JournalPsychological Medicine
Publication statusAccepted/In press - 2021


  • adaptive immunity
  • anti-inflammatory cytokines
  • inflammation
  • innate immunity
  • marijuana
  • pro-inflammatory cytokines
  • schizophrenia


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