433. Psilocybin reveals diverse antidepressant efficacies across different preclinical models of depression
Z Wang, W Chen, C Hu, X Ji, M Li, Q Chen, C Li, Q Du, L Wang, J Tan, W Gao, G Russo
International Journal of Neuropsychopharmacology September 9, 2026 DOI: 10.1093/ijnp/pyag040.302 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice and rats in chronic unpredictable mild stress and lipopolysaccharide-induced depression models |
| Intervention | Psilocybin |
| Duration | 21-day chronic treatment (q.o.d.), 6-day sub-chronic treatment (q.d.), and acute single or multi-dose administrations |
| Measures | head twitch response test (HTR), sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), forced swim test (FST) |
| Topics | Depression Psilocybin |
| Key points | Psilocybin's behavioral effects varied by model, dose schedule, and outcome: chronic and acute multi-dose treatment improved sucrose preference and anxiety-like measures in the mouse chronic stress model, while acute single doses showed limited or no effects in the rat stress and mouse lipopolysaccharide models, suggesting that standard tests and models differ in sensitivity to psilocybin's antidepressant-like effects. |
Abstract
Abstract Background Within the rapidly expanding field of psychedelic research, psilocybin, along with its active metabolite psilocin, has emerged as a highly promising candidate in the search for innovative treatments for neuropsychiatric disorders. In this context, preclinical research using animal disease models has produced somewhat inconsistent results when employing standard tests to assess depressive- and anxiety-like behavioral phenotypes following psilocybin administration. Aims & Objectives This study aims to validate and identify target sensitive behavioral paradigms and animal models of depression, to accurately elucidate the potential antidepressant effects of psilocybin.
Method: First, the hallucinogenic effects of psilocybin were validated in mice using the head twitch response test (HTR). Then the antidepressant effects of psilocybin were investigated in several etiology related animal models of depression. First, the effects of both acute and chronic doses of psilocybin were assessed in the mouse chronic unpredictable mild stress (CUMS) induced depression model. Then, the effects of acute doses of psilocybin were evaluated in a rat model of CUMS. Furthermore, the effects of both acute single dose or sub-chronic dose of psilocybin were evaluated in the mouse Lipopolysaccharide (LPS)-induced depression model.
Results: Acute single dose of psilocybin effectively elicited head twitch responses in mice. Both a 21-day chronic treatment (q.o.d) and an acute multi-dose of psilocybin increased sucrose preference in the sucrose preference test (SPT), prolonged time spent in the central zone of the open field test (OFT), and extended time in the open arms of the elevated plus maze (EPM) in the mouse CUMS induced depression model. An acute single dose of psilocybin showed a trend of sucrose preference improvement in the SPT, but did not significantly affect central area exploration in the OFT, yet notably reduced stereotypy namely grooming and rotating behaviors during the OFT in the rat CUMS induced depression model. An acute single dose of psilocybin after the LPS induction significantly increased the number of central zone entries in the OFT, however showed no effect on the immobility time in the FST nor the sucrose preference in the SPT, in the mouse LPS induced depression model. A 6-day sub-chronic treatment (q.d.) of psilocybin prior to the LPS induction produced no significant changes in sucrose preference in the SPT, immobility time in the FST, nor central zone entries in the OFT, in the mouse LPS induced depression model. Discussion & Conclusions