Twenty-two rats were trained to discriminate either 1.5 mg/kg or 3.0 mg/kg of 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT) from saline in a standard two-lever operant procedure. Once responding was stable, various doses of several serotonin (5-HT) antagonists, i.e., cyproheptadine (CYP), methysergide (UML), cinanserin (CIN), and methergoline (MCE), were administered in combination with 5-OMe DMT, to assess the ability of each antagonist to attenuate each 5-OMe DMT-stimulus. The 5-OMe DMT-stimulus at 1.5 rng/kg was completely antagonized by CYP, and was partially attenuated by CIN and MCE. UML had negligible effects on 5-OMe DMT-appropriate responding. In the 3.0 mg/kg 5-OMe DMT-trained rats, UML and MCE partially blocked the 5-OMe DMT-stimulus; CYP and CIN had no significant effect on 5-OMe DMT-appropriate responding. The results suggest that until the in vivo effects and mechanism of action of 5-OMe DMT and certain 5-HT antagonists are better understood, caution is advised when conclusions are drawn from studies employing these agents. 5-OMe DMT, Serotonin, Serotonin antagonists, Drug discrimination