In helpless mice, the psychedelic compound N,N-dimethyltryptamine (DMT) produced rapid and long-lasting antidepressant effects comparable to the fast-acting antidepressant S-ketamine. DMT at 10 mg/kg reversed escape deficits and reduced immobility in several behavioral tests, with effects lasting up to 8 days, whereas S-ketamine's effects lasted up to 30 hours. DMT also showed anxiolytic-like effects, reversing stress-induced hypolocomotion and increasing open-arm exploration, while S-ketamine did not. Neither drug altered behavior in the novelty-suppressed feeding test. These findings suggest DMT has transdiagnostic therapeutic potential for stress-related disorders.
In stressed mice, neither (R,S)-ketamine nor (S)-ketamine affected the retrieval of avoidance memory, but (S)-ketamine, and to a lesser extent (R,S)-ketamine, reduced avoidance responses during re-exposure to an aversive stimulus. Both forms equally produced antidepressant effects in the tail suspension test. However, only the racemic mixture (R,S)-ketamine induced anxiolytic actions in the open field test. These results suggest that (R,S)-ketamine may be more effective than (S)-ketamine for simultaneously reducing avoidance responses and producing antidepressant and anxiolytic effects in stressed mice.