5-MeO-AMT, a tryptamine used recreationally for its hallucinogenic and mood-elevating effects, triggers head-twitch response (HTR) in mice through activation of serotonin receptor 2a (5-HTR2a) in the prefrontal cortex. Acute administration at doses 0.3–10 mg/kg produced HTR, but repeated dosing led to tolerance. The 5-HTR2a antagonist ketanserin blocked the response. The drug increased 5-HTR2a mRNA and induced PKC-γ phosphorylation in the prefrontal cortex. 5-MeO-AMT did not produce locomotor sensitization, conditioned place preference, or self-administration, suggesting low abuse potential.
Both enantiomers of methoxetamine (MXE), a ketamine analog, produce rapid antidepressant effects in mice, but the R-enantiomer causes fewer behavioral side effects. S-MXE and R-MXE both bind to NMDA receptors and inhibit serotonin transporters. At 10 mg/kg, each enantiomer reduced depression-like behavior and increased gamma brain waves, effects blocked by an AMPA receptor antagonist. They also boosted mTOR signaling and AMPA receptor subunit proteins in the hippocampus or prefrontal cortex, and increased serotonin receptor mRNA levels; a serotonin receptor antagonist blocked their antidepressant effects. Unlike S-MXE, R-MXE did not cause prepulse inhibition deficits, hyperactivity, conditioned place preference, or locomotor sensitization, though it briefly impaired motor coordination. R-MXE may be a safer antidepressant candidate.
Methoxetamine (MXE) is a dissociative drug similar to ketamine and phencyclidine that acts as an NMDA receptor antagonist. While MXE has known abuse liability, can stimulate dopamine in the brain's reward pathway, and has been linked to adverse effects and deaths, recent preclinical studies suggest it also possesses antidepressant and analgesic properties. These potential therapeutic effects are thought to involve the glutamatergic and serotonergic systems. This review compiles evidence on both the harmful effects—toxicity, psychotomimetic effects, and abuse potential—and the promising therapeutic qualities of MXE, discussing the mechanisms that may explain these paradoxical effects.