Serum metabolic alterations associated with Chaihu-Longgu-Muli decoction in adolescents with insomnia: An exploratory untargeted metabolomics study

Adolescent insomnia is common and is frequently accompanied by anxiety and depressive symptoms. Chaihu-Longgu-Muli decoction (CLMD) is used in traditional Chinese medicine prescriptions for insomnia; however, the biological changes associated with CLMD treatment in adolescents remain poorly characterized. This exploratory study investigated clinical symptom changes and corresponding serum metabolomic alterations associated with CLMD treatment in adolescents with chronic insomnia. Adolescents with chronic insomnia received either CLMD or cognitive behavioral therapy (CBT) according to the predefined treatment-allocation procedure. A healthy control group was included for baseline metabolic comparison. Sleep quality and emotional symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS). Fasting serum samples collected before and after the intervention underwent untargeted metabolomic profiling using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Candidate differential metabolites were identified using multivariate analysis together with a variable importance in projection score > 1.0 and nominal P < .05, followed by pathway enrichment analysis. Given the exploratory nature of the study, metabolomic findings were considered hypothesis-generating. Thirty adolescents were included in each intervention group, with an additional 10 healthy controls. Both CLMD and CBT groups showed improvements in PSQI, SAS, and SDS measures after treatment (all P < .05). Untargeted metabolomic profiling identified differences between adolescents with insomnia and healthy controls. Among the exploratory candidate metabolites, sphinganine and 3-indoleacetonitrile were higher in adolescents with insomnia, whereas ethylmethylacetic acid, choline, L-lysine 1,6-lactam, (R)-2-O-sulfolactate, cis-aconitic acid, and sorbitol were lower (all P < .05). Following CLMD treatment, these metabolites shifted toward levels observed in healthy controls. Exploratory pathway analysis implicated the intestinal immune network for IgA production, sphingolipid signaling, PPAR signaling, and bile secretion. CLMD treatment was associated with improvements in insomnia-related symptoms and concurrent changes in serum metabolic profiles in adolescents with chronic insomnia. The identified metabolites and pathways represent preliminary biological signals rather than validated biomarkers or established mechanisms. Larger studies with targeted quantitative metabolomics and independent validation are needed.