How Prenatal Infections May Interact With Cannabis to Affect Schizophrenia Risk | Research

The takeaway

A review of the two-hit hypothesis of schizophrenia finds that the expected worsening of symptoms from adolescent cannabis use after prenatal immune activation is not consistently supported by animal studies.

Neuroscientists, psychiatry researchers, and those interested in how prenatal exposures and cannabis interact in brain development.

What the researchers found

Despite theoretical expectations, several preclinical studies failed to show that adolescent cannabinoid exposure worsened behavioral or neurological outcomes in animals exposed to maternal immune activation, challenging the straightforward two-hit model.

Why it matters

The idea that prenatal infection plus adolescent cannabis creates a 'double hit' for schizophrenia risk is widely cited. This review reveals that the animal evidence is more complicated than the theory predicts, which has implications for how we communicate risk.

The numbers in context

No specific quantitative data; this is a narrative review synthesizing findings from multiple preclinical studies on MIA and adolescent cannabinoid exposure.

How the study worked

Narrative review of preclinical and clinical literature on maternal immune activation (MIA), the endocannabinoid system, and the two-hit hypothesis of schizophrenia, with emphasis on 2-AG signaling in synaptic plasticity and neuroinflammation.

What this study cannot tell us

Narrative review without systematic methodology. Relies heavily on animal models that may not fully capture human neurodevelopmental complexity. Most preclinical studies use synthetic cannabinoids rather than whole-plant cannabis. Publication bias may affect the literature reviewed.

How to read the evidence

Narrative review of preclinical literature with no systematic search or meta-analysis. Findings are hypothesis-generating rather than definitive.

When this study was published

Published 2025, reviewing literature through 2024.

The bigger picture

The endocannabinoid system plays a fundamental role in brain development, and its disruption by prenatal immune activation could create vulnerability. However, the inconsistent results from two-hit animal studies suggest that the relationship between prenatal infection, cannabis, and psychosis risk is more complex than a simple additive model.

Questions still open

Why adolescent cannabinoid exposure does not consistently worsen MIA outcomes in animal models
Whether 2-AG-specific interventions could reduce schizophrenia risk in people with prenatal immune activation

Common questions

What is the two-hit hypothesis of schizophrenia?

It proposes that schizophrenia requires two insults: a first hit during early development (like prenatal infection) that creates vulnerability, and a second hit later (like adolescent cannabis use or stress) that triggers the disorder.

Does this mean cannabis is safe after prenatal infection exposure?

No. The review found inconsistent results in animal models, which means the relationship is more complicated than expected. It does not mean cannabis use is without risk in this context.

Read the original research

Maternal Immune Activation and the Endocannabinoid System: Focus on Two-Hit Models of Schizophrenia.

Biological psychiatry, 98(2), 105-115

View on PubMed ↗Publisher’s paper ↗

Citation

Santoni, Michele; Pistis, Marco. (2025). Maternal Immune Activation and the Endocannabinoid System: Focus on Two-Hit Models of Schizophrenia.. Biological psychiatry, 98(2), 105-115. https://doi.org/10.1016/j.biopsych.2024.11.015