Several drugs of abuse have recently been shown clinically to have long-lasting antidepressant effects. Psilocybin and ketamine induce antidepressant effects which last for days or weeks after a single dose, yet their pharmacology is distinct. Psilocybin is a classical psychedelic which acts via 5-HT2A receptor agonism, and ketamine is a NMDA receptor antagonist with dissociative hallucinatory properties. Our goal was to increase our understanding of acute drug effects in mice. We treated wildtype mice with psilocybin (1 mg/kg, i.p.) or ketamine (30 mg/kg, i.p.) and analyzed their behavior in an open field. In a separate group of mice, we immunostained c-Fos to identify brain areas responsive to the drugs. Cocaine was included as a positive control. Similar to cocaine, ketamine increased locomotion, but with obvious differences in movements. Psilocybin increased head-twitching. For all three drugs the behavioral changes lasted for maximal one hour. Compared to saline treatment, psilocybin and ketamine increased the number of c-Fos-positive cells in the prelimbic, orbitofrontal and cingulate cortex, like cocaine. Ketamine and cocaine also increased c-Fos expression in the infralimbic cortex. Acute psilocybin and ketamine effects were behaviorally distinct and the drugs also differed in their c-Fos induction pattern. Our ongoing research further investigates the acute behavioral signatures, which may ultimately refine testing of new psychedelic-like substances.