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Importance: The endocannabinoid system (ECS) is a lipid-based endogenous signaling system. Its relevance to psychosis is through the association between cannabis use and the onset and course of illness and through the antipsychotic properties of cannabidiol, a potential ECS enhancer. Objective: To conduct a systematic review and meta-analysis of the blood and cerebrospinal fluid (CSF) measures of the ECS in psychotic disorders. Data Sources: Web of Science and PubMed were searched from inception through June 13, 2018. The articles identified were reviewed, as were citations to previous publications and the reference lists of retrieved articles. Study Selection: Original articles were included that reported blood or CSF measures of ECS activity in patients with psychotic illnesses and in healthy controls. Data Extraction and Synthesis: PRISMA guidelines, independent extraction by multiple observers, and random-effects meta-analysis were used. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested the robustness of the results. Main Outcomes and Measures: The clinical relevance of ECS modifications in psychotic disorders was investigated by (1) a quantitative synthesis of the differences in blood and CSF markers of the ECS between patients and healthy controls, and (2) a qualitative synthesis of the association of these markers with symptom severity, stage of illness, and response to treatment. Results: A total of 18 studies were included. Three individual meta-analyses were performed to identify the differences in ECS markers between people with schizophrenia and healthy controls. Five studies, including 226 patients and 385 controls, reported significantly higher concentrations of anandamide in the CSF of patients than controls (standardized mean difference [SMD], 0.97; 95% CI, 0.67-1.26; P < .001; I2 = 54.8%). In 9 studies, with 344 patients and 411 controls, significantly higher anandamide levels in blood were found in patients, compared with controls (SMD, 0.55; 95% CI, 0.05-1.04; P = .03; I2 = 89.6%). In 3 studies, involving 88 patients and 179 controls, a significantly higher expression of type 1 cannabinoid receptors on peripheral immune cells was reported in patients compared with controls (SMD, 0.57; 95% CI, 0.31-0.84; P < .001; I2 = 0%). Higher ECS tone was found at an early stage of illness in individuals who were antipsychotic naïve or free, and it had an inverse association with symptom severity and was normalized after successful treatment. Moderate to high level of heterogeneity in methods was found between studies. Conclusions and Relevance: Testing clinically relevant markers of the ECS in the blood and CSF of people with psychotic illness appears possible, and these markers provide useful biomarkers for the psychotic disorder; however, not all studies accounted for important variables, such as cannabis use. Trial Registration: PROSPERO identifier: CRD42018099863.

Original publication




Journal article


JAMA Psychiatry

Publication Date