Hallucinogens such as LSD and DOM increase extracellular glutamate in the prefrontal cortex of rats, as shown by in vivo microdialysis. LSD (0.1 mg/kg) caused a time-dependent rise in glutamate that was blocked by a 5-HT(2A) antagonist. DOM (0.6 mg/kg) raised glutamate to 206% above controls. Direct application of LSD to the prefrontal cortex via reverse dialysis also rapidly increased glutamate, which remained elevated after infusion stopped. These findings suggest that enhanced glutamate release is a shared mechanism in the action of hallucinogens.
In rats trained to distinguish LSD from saline, several N-substituted tryptamines produced intermediate levels of LSD-like responding: MDMT (76.4%), DMT (77.9%), and DET (48.7%). 6-F-DET elicited 41.3% LSD-appropriate responding at 6.0 mg/kg, but only 4 of 8 subjects completed the session, precluding statistical analysis. Bufotenine (25.8%) failed to substitute. None of the tryptamines substituted completely for LSD, though the pattern aligns with their known human hallucinogenic activity. Among beta-carbolines tested, only harmane showed intermediate substitution (49.5%); others, including harmaline and THBC, showed no significant generalization. The tryptamines overall showed greater similarity to the LSD stimulus than the beta-carbolines did.