A theoretical framework is proposed to distinguish the hallucinogenic effects of psychedelics from their antidepressant effects. The authors argue that hallucinations and mood improvement may arise through separable neural mechanisms, and they outline a translational approach—spanning cellular, circuit, and behavioral levels—to test this dissociation. The framework suggests that antidepressant benefits could be achieved without the hallucinatory side effects, potentially leading to safer treatments. The paper synthesizes evidence from preclinical and clinical studies to support the idea that the two phenomena are not inevitably linked, though it acknowledges that further research is needed to confirm this separation.
Digging behavior in mice is a stable and consistent compulsive-like behavior that can be reduced by both behavioral and pharmacological stressors, producing a depression-like state. A single swim stress significantly reduced digging for at least three days, with recovery by day seven. Repeated treatment with fluoxetine (10 mg/kg/day), but not ketamine, partially reversed swim stress-induced digging suppression on days three and seven. The pharmacological stressor yohimbine dose-dependently decreased digging, and repeated ketamine (10 mg/kg/day), but not fluoxetine, reversed yohimbine-induced digging suppression. These results indicate that stress-induced suppression of digging behavior is stimulus- and drug-dependent, requiring further investigation.