How Prenatal Infections May Interact With Cannabis to Affect Schizophrenia Risk

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.

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.

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 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.

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.