Among people with schizophrenia, those with lifetime cannabis use had significantly lower blood levels of the endocannabinoid 2-AG, and non-clozapine antipsychotics altered CB2 receptor levels.
Psychiatrists, schizophrenia researchers, endocannabinoid system scientists
What the researchers found
In a study of 93 individuals (29 treatment-resistant schizophrenia on clozapine, 31 on other antipsychotics, 33 controls), those reporting lifetime cannabis use had significantly lower plasma 2-AG levels (p=0.011), and this remained the only significant factor in models controlling for confounders. Patients on non-clozapine antipsychotics showed altered CB2 receptor levels compared to controls (p=0.022). AEA levels and CB2 levels did not differ between patients and controls overall.
Why it matters
This provides the first evidence that cannabis use and antipsychotic medication type independently modulate different components of the peripheral endocannabinoid system in schizophrenia. The distinction between clozapine and other antipsychotics on CB2 levels suggests ECS interactions may partly explain different treatment responses.
The numbers in context
93 participants (29 clozapine, 31 other antipsychotics, 33 controls); cannabis users had lower 2-AG (p=0.011); non-clozapine antipsychotics altered CB2 (p=0.022); cannabis use was the only significant factor for 2-AG in adjusted models
How the study worked
Cross-sectional study measuring blood levels of AEA, 2-AG, and CB2 receptor in 93 participants divided into three groups: clozapine-treated schizophrenia (treatment-resistant), other antipsychotic-treated schizophrenia, and healthy controls. Generalized linear models controlled for confounders.
What this study cannot tell us
Small sample size. Cross-sectional design cannot establish causation. Peripheral blood measurements may not reflect brain endocannabinoid activity. Lifetime cannabis use is a crude measure that does not capture recency, frequency, or type.
How to read the evidence
Preliminary: small cross-sectional study with peripheral biomarkers that may not reflect central nervous system activity.
When this study was published
2025 publication
The bigger picture
Understanding how cannabis use modifies the endocannabinoid system in schizophrenia could inform both treatment selection and risk assessment for patients who use cannabis alongside antipsychotic medication.
Questions still open
- Does lower 2-AG in cannabis-using schizophrenia patients reflect downregulation from chronic exposure?
- Could 2-AG levels serve as a biomarker for cannabis exposure in psychiatric populations?
Read the original research
Endocannabinoid system alterations in schizophrenia: association with cannabis use and antipsychotic medication.
European archives of psychiatry and clinical neuroscience, 275(2), 545-553
Citation
Haddad, Natalia Mansur; De Jesus, Leonardo Peroni; Serpa, Mauricio; Van De Bilt, Martinus; Talib, Leda; Costa, Alana; Gattaz, Wagner; Loch, Alexandre Andrade. (2025). Endocannabinoid system alterations in schizophrenia: association with cannabis use and antipsychotic medication.. European archives of psychiatry and clinical neuroscience, 275(2), 545-553. https://doi.org/10.1007/s00406-024-01788-x
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