A systematic review of 41 studies found the endocannabinoid and HPA stress systems show interconnected alterations in psychosis, with THC affecting the stress axis and childhood trauma affecting endocannabinoid signaling.
People interested in the biological mechanisms linking cannabis use, stress, and psychosis risk.
Bidirectional interaction between endocannabinoid and stress systems in psychosis
What the researchers found
Both systems show independent contributions to psychosis risk, but they also interact bidirectionally: cannabis use affects endocannabinoid tone, stress exposure alters the HPA axis, and crucially, THC also affects the HPA axis while childhood trauma affects endocannabinoid signaling, revealing cross-system perturbation.
Why it matters
The stress-diathesis model and cannabinoid hypothesis of schizophrenia have been studied independently. This review reveals they are deeply interconnected, suggesting that cannabis risk for psychosis cannot be understood without considering stress, and vice versa.
The numbers in context
41 studies reviewed. 9 HPA-related biological studies. 2 endocannabinoid-related biological studies. 29 environmental-measure studies. 1 genetic study. CNR1 genetic variation identified as a cross-system factor.
How the study worked
PRISMA-compliant systematic review searching PubMed, Web of Science, and Scopus. 41 eligible studies extracted, including biological interventional and non-interventional studies, environmental-measure studies, and genetic studies examining the interplay of HPA and endocannabinoid systems in psychosis.
What this study cannot tell us
Heterogeneous study designs limit direct comparisons. Many included studies measured environmental factors (cannabis use, stress) rather than biological endocannabinoid or HPA markers. The mechanistic evidence is stronger for within-system than cross-system effects.
How to read the evidence
PRISMA-compliant systematic review synthesizing 41 studies. Evidence is consistent but mostly correlational, with limited interventional data for cross-system effects.
When this study was published
Published in 2024 in Current Neuropharmacology.
The bigger picture
Understanding psychosis risk requires looking at the interplay between genetic vulnerability, cannabis use, stress exposure, and biological systems. This review argues for a unified model rather than studying cannabis and stress as separate risk factors.
Questions still open
- Could interventions targeting both the HPA axis and endocannabinoid system simultaneously reduce psychosis risk? Does the timing of stress relative to cannabis exposure matter for the cross-system interaction? Are there genetic profiles that make the interaction particularly dangerous?
Common questions
How do cannabis and stress interact to affect psychosis risk?
Can you separate cannabis risk from stress risk for psychosis?
Read the original research
Biobehavioral Interactions between Endocannabinoid and Hypothalamicpituitary- adrenal Systems in Psychosis: A Systematic Review.
Current neuropharmacology, 22(3), 495-520
Citation
Colizzi, Marco; Bortoletto, Riccardo; Antolini, Giulia; Bhattacharyya, Sagnik; Balestrieri, Matteo; Solmi, Marco. (2024). Biobehavioral Interactions between Endocannabinoid and Hypothalamicpituitary- adrenal Systems in Psychosis: A Systematic Review.. Current neuropharmacology, 22(3), 495-520. https://doi.org/10.2174/1570159X21666230801150032
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