The influence of second-generation antipsychotics and cannabidiol on sphingolipid metabolism

Abstract

Schizophrenia is a severe psychiatric disorder marked by positive, negative, and cognitive symptoms, resulting in substantial disability and socioeconomic burden. Second-generation antipsychotics (SGAs) are the mainstay of treatment but are limited by adverse metabolic effects such as weight gain, dyslipidaemia, and glucose dysregulation, highlighting the need for safer alternatives. Cannabidiol (CBD) has shown antipsychotic efficacy comparable to SGAs but without these metabolic side effects. Although the mechanisms behind CBD’s effects remain unclear, emerging evidence points to a role for lipid signalling pathways.

To date, no clinical studies have examined lipidomic changes in healthy volunteers treated with SGAs, nor the lipid profile effects of CBD alone or in combination with SGAs. This study investigated CBD’s impact on lipid responses triggered by SGAs in a randomized phase I safety trial. Serum samples were collected at baseline, after three days of SGA monotherapy (amisulpride 150 mg/day, quetiapine 300 mg/day, olanzapine 10 mg/day, or risperidone 3 mg/day), and following six days of combined SGA and CBD (800 mg/day) treatment.

Our findings highlight sphingolipid metabolism as a key pathway in SGA-induced metabolic disturbances and CBD’s potential ameliorative effects. Results suggest that SGAs may enhance sphingolipid catabolism, while adjunctive CBD promotes sphingolipid synthesis, potentially countering metabolic dysregulation. Additionally, we developed and validated an LC-MS/MS method for quantifying amisulpride, olanzapine, quetiapine, risperidone, and their metabolites in serum, supporting future studies on pharmacokinetics and drug interactions.