An exploratory study of metabolomics in endogenous and cannabis-use-associated psychotic-like experiences in adolescence

In adolescence, psychotic-like experiences (PLE) may indicate potential prodromal symptoms preceding the onset of psychosis. Metabolomic studies have shown promise in providing valuable insights into predicting psychosis with enhanced precision compared to conventional clinical features. This study investigated metabolomic alterations associated with PLE in 76 depressed adolescents aged 14-20 years. Serum concentrations of 92 metabolites were analyzed with liquid chromatography-mass spectrometry. PLE were assessed using the Youth Experiences and Health (YEAH) questionnaire. The associations between PLE symptom dimensions (delusions, paranoia, hallucinations, negative symptoms, thought disorder, and dissociation) and metabolite concentrations were analyzed in linear regression models adjusted for different covariates. The symptom dimensions consistently correlated with the metabolome in different models, except those adjusted for cannabis use. Specifically, the hallucination dimension was associated with 13 metabolites (acetoacetic acid, allantoin, asparagine, decanoylcarnitine, D-glucuronic acid, guanidinoacetic acid, hexanoylcarnitine, homogentisic acid, leucine, NAD⁺, octanoylcarnitine, trimethylamine-N-oxide, and valine) in the various linear models. However, when adjusting for cannabis use, eight metabolites were associated with hallucinations (adenine, AMP, cAMP, chenodeoxycholic acid, cholic acid, L-kynurenine, neopterin, and D-ribose-5-phosphate). The results suggest diverse mechanisms underlying PLE in adolescence; hallucinatory experiences may be linked to inflammatory functions, while cannabis use may engage an alternative metabolic pathway related to increased energy demand and ketogenesis in inducing PLE. The limited sample of individuals with depression restricts the generalizability of these findings. Future research should explore whether various experiences and related metabolomic changes jointly predict the onset of psychoses and related disorders.