Low doses of the hallucinogens ketamine and psilocybin, too small to cause perceptual effects, modestly improved motivation, attention, and impulse control in low-performing male rats. In two food-rewarded tasks, acute doses of ketamine (1–3 mg/kg) and psilocybin (0.05–0.1 mg/kg) increased break point for food and improved attentional accuracy. The benefits were small and mainly seen in rats that initially performed poorly. Both drugs produced similar patterns of effect. These findings support the idea that low, sub-perceptual doses of these drugs may have therapeutic potential for depression-related symptoms like anhedonia and cognitive dysfunction, though further research is needed.
Drug discrimination procedures in rats confirm that hallucinogenic effects of psychedelics like psilocybin, LSD, DMT, and 5-MeO-DMT are mediated primarily by 5-HT2A and 5-HT1A receptors. Plasma levels of psilocin required for generalization in rats (5–52 ng/mL) overlapped with human perceptual effects, while DMT and LSD needed higher exposures in rats than in humans. The duration of drug-lever generalization followed LSD > psilocybin > 5-MeO-DMT ≥ DMT, matching clinical experience. LSD showed a disconnect between plasma exposure and generalization, similar to clinical findings. These results support the translational value of drug discrimination assays for studying psychedelics.