Uncovering metabolic dysregulation in schizophrenia and cannabis use disorder through untargeted plasma lipidomics

Cannabis use disorder affects up to 42% of individuals with schizophrenia, correlating with earlier onset, increased positive symptoms, and more frequent hospitalizations. This study employed an untargeted lipidomics approach to identify biomarkers in plasma samples from subjects with schizophrenia, cannabis use disorder, or both (dual diagnosis), aiming to elucidate the metabolic underpinnings of cannabis abuse and schizophrenia development. The use of liquid chromatography-high resolution mass spectrometry enabled the annotation of 119 metabolites, with the highest identification confidence level achieved for 16 compounds. Notably, a marked reduction in acylcarnitines, including octanoylcarnitine and decanoylcarnitine, was observed across all patient groups compared to controls. In cannabis use disorder patients, N-acyl amino acids (NAAAs), particularly N-palmitoyl threonine and N-palmitoyl serine, showed a strong downregulation, a pattern also seen in schizophrenia and dual diagnosis patients. Conversely, elevated levels of 7-dehydrodesmosterol were detected in schizophrenia and dual diagnosis patients relative to controls. These findings suggest a potential link between metabolic disruptions and the pathophysiology of both disorders. The untargeted lipidomics approach offers a powerful tool to identify novel biomarkers, enhancing our understanding of the biological relationship between cannabis abuse and schizophrenia, and paving the way for future therapeutic strategies targeting metabolic pathways in these conditions.