Psilocybin produces a complex internal cue in rats that depends partly, but not entirely, on the 5-HT2A serotonin receptor. Blocking the 5-HT2A receptor with M100907 only partially reduced the drug's effect, while blocking the 5-HT1A/7 receptor or the dopamine D2 receptor had no effect. Rats trained to recognize psilocybin also recognized other hallucinogens such as LSD, psilocin, and DOM, and partially recognized mescaline and 2C-T-7. LSD and MDMA partly substituted for psilocybin, and those effects were fully blocked by M100907. Unlike the related hallucinogen 5-MeO-DMT, psilocybin's effects do not involve the 5-HT1A receptor.
In mice genetically modified to express human CYP2D6 (Tg-CYP2D6) and wild-type mice, the psychedelic 5-MeO-DMT produced similar rates of learning a drug discrimination task. Bufotenine did not substitute for 5-MeO-DMT, while its lipid-soluble analog acetylbufotenine produced intermediate substitution. Combining harmaline with 5-MeO-DMT significantly increased drug-appropriate responding in both mouse types, indicating harmaline enhances 5-MeO-DMT's stimulus effects. Harmaline alone also produced significant 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice, suggesting metabolic interactions. No differences between wild-type and Tg-CYP2D6 mice were found in acquisition or responses to bufotenine and acetylbufotenine.