The metabolic signature of acute psychosocial stress in humans.

Acute psychological stress triggers rapid physiological adjustments, but the full scope of associated metabolic changes in humans remains poorly characterized. Prior studies have typically examined a limited set of candidate metabolites or pathways. We used untargeted metabolomics to characterize the plasma metabolite response to acute psychosocial stress induced by the Trier Social Stress Test (TSST) in 33 adults (10 men, 21 women, 2 non-binary; age M = 41.7, SD = 10.8). Blood was sampled at baseline, 5-min, and 90-min post-stress. A total of 561 metabolites were quantified using LC/GC-MS. Linear mixed models tested time-dependent (quadratic) effects while controlling for age, sex, BMI, and time since last meal. Acute psychosocial stress induced widespread metabolic changes, with 250 metabolites showing significant non-linear time effects. Most metabolites increased 5-min after stress and returned toward baseline at 90-min, reflecting transient activation and recovery. Three distinct clusters emerged: (1) Fatty acid-dominated cluster including long-chain and hydroxylated fatty acids, and cortisol, reflecting upregulated lipid mobilization and energy metabolism; (2) Phospholipid and sphingolipid-dominated cluster implicating membrane remodeling and signaling; and (3) Amino acid/nucleotide-dominated cluster, characterized by reduced essential amino acids and nucleotide intermediates. Pathway analysis revealed enrichment in steroid hormone biosynthesis, α-linolenic acid, and carbohydrate metabolism. Acute psychosocial stress elicits coordinated and reversible changes across multiple biochemical systems, primarily involving lipid mobilization and amino acid catabolism. Many of the identified metabolites overlap with those previously linked to depression, anxiety, and PTSD, suggesting that stress-induced metabolic responses may engage biological pathways relevant to psychiatric disorders and represent an initial step toward understanding how acute stress responses relate to these conditions.