Cannabis only increased psychosis risk in people who already had elevated inflammation, supporting a "two-hit" model | Research

The takeaway

Daily cannabis use and early onset (before age 17) were only associated with psychosis among individuals with medium-to-high systemic inflammation, providing the first human evidence for a two-hit hypothesis.

Psychosis researchers, immunopsychiatry specialists, people concerned about cannabis and mental health risks

Daily cannabis use only linked to psychosis in those with medium-to-high inflammation

What the researchers found

Cannabis did not increase inflammation (ruling out a mediating pathway). Instead, daily cannabis use and onset before age 17 only increased psychosis odds among those with medium-to-high inflammatory composite scores. This interaction effect went beyond the individual effects of either cannabis or inflammation alone.

Why it matters

This suggests not everyone who uses cannabis faces equal psychosis risk. Pre-existing immune dysregulation may be a necessary biological vulnerability that cannabis then triggers, explaining why most users never develop psychosis.

The numbers in context

153 first-episode psychosis patients; 256 controls; 7 cytokines measured; daily use and onset <17 interacted with inflammation; cannabis did not increase inflammation directly

How the study worked

Cross-sectional study of 153 first-episode psychosis patients and 256 community controls. Cannabis use assessed via Cannabis Experience Questionnaire. Seven plasma cytokines measured to create an inflammatory composite score. Mediation and moderation analyses performed.

What this study cannot tell us

Cross-sectional design cannot confirm temporal ordering. Single blood inflammatory measurement. Cannot rule out unmeasured confounders. First-episode psychosis patients may differ from the broader at-risk population.

How to read the evidence

Well-designed cross-sectional study with biological measures, though cannot establish temporal causation

When this study was published

Published in 2021. The two-hit hypothesis for cannabis and psychosis is an emerging area of research.

The bigger picture

The two-hit hypothesis could eventually enable personalized risk assessment: measuring inflammatory markers might identify individuals for whom cannabis poses a genuine psychosis risk versus those for whom it does not.

Questions still open

Could inflammatory biomarkers be used to screen for cannabis-psychosis vulnerability? Would anti-inflammatory treatments reduce psychosis risk in cannabis users with high inflammation? Is the inflammation genetic, environmental, or both?

Common questions

Why do some cannabis users develop psychosis and others do not?

This study found cannabis only increased psychosis risk in people with pre-existing elevated inflammation. Those with low inflammation who used cannabis did not show increased risk, supporting the idea that a biological vulnerability is needed.

Does cannabis cause inflammation that leads to psychosis?

No. This study found cannabis did not increase inflammation. Instead, pre-existing immune dysregulation appeared to be the vulnerability that cannabis then interacted with to increase psychosis risk.

Read the original research

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

Psychological medicine, 1-11

View on PubMed ↗Publisher’s paper ↗

Citation

Corsi-Zuelli, Fabiana; Marques, Leonardo; da Roza, Daiane Leite; Loureiro, Camila Marcelino; Shuhama, Rosana; Di Forti, Marta; Menezes, Paulo Rossi; Louzada-Junior, Paulo; Del-Ben, Cristina Marta. (2021). The independent and combined effects of cannabis use and systemic inflammation during the early stages of psychosis: exploring the two-hit hypothesis.. Psychological medicine, 1-11. https://doi.org/10.1017/S0033291721000726