A single dose of the NMDA receptor antagonist ketamine, but not the GSK-3 inhibitor SB216763, produced long-lasting antidepressant effects in a mouse model of chronic mild stress (CMS). In CMS mice, ketamine reversed the drop in sucrose intake and reduced immobility in the tail suspension and forced swimming tests, effects that persisted for 8 days after a single dose. The GSK-3 inhibitor did not produce these effects. Ketamine also reduced immobility in non-stressed control mice. These results suggest that ketamine's rapid and sustained antidepressant action may not depend on GSK-3 inhibition.
4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT, psilacetin) is a synthetic psychedelic that may act as a precursor to psilocin, but its metabolism was poorly understood. Incubating 4-AcO-DMT with pooled human liver microsomes produced 15 metabolites: 12 from phase I and 3 from phase II reactions. Transformations included hydrolysis, hydroxylation, N-demethylation, oxidation, and glucuronic acid conjugation. The hydrolysis product was the most abundant. For forensic detection of 4-AcO-DMT use, the beta-hydroxylation metabolite (M2-1) is recommended as a biomarker. These findings may help predict in vivo metabolism and assist drug testing.