Preadministration of Lorazepam Negates the Long-Term Antidepressant-Like Effects of Psilocybin in Male Wistar Kyoto Rats
Sophie Woodruff, Meghan Hibicke, Charles D. Nichols
Psychedelic Medicine December 16, 2025 DOI: 10.1177/28314425251393186 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Male Wistar Kyoto rats |
| Interventions | Psilocybin Lorazepam |
| Duration | 12-week follow-up |
| Topics | Psilocybin |
| Keywords | Lorazepam Pharmacology Prefrontal cortex Anesthesia Anterior cingulate cortex Infralimbic cortex Saline Antidepressant Hallucinogen |
| Key points | Preadministration of lorazepam prevented psilocybin's sustained antidepressant-like effects in rats for up to 9 weeks. |
Abstract
Introduction:Psilocybin, a classical psychedelic, has shown to produce persistent antidepressant effects, including in patients with treatment-resistant depression. In clinical practice, it is common to coprescribe benzodiazepines (BZDs) alongside antidepressants. However, our preliminary study indicated that preadministration of lorazepam diminished the antidepressant-like efficacy and longevity of psilocin. These results raise concern about the potential reduction of therapeutic benefits in psilocybin-assisted therapy for patients concurrently prescribed BZDs. The current study aimed to confirm these results while exploring psilocybin’s long-term effects on neuroplasticity-related gene expression in the medial prefrontal cortex. Methods:Male Wistar Kyoto rats were given saline (S/S), lorazepam (L/S), psilocybin (S/P), or lorazepam followed by psilocybin (L/P). Treatments were delivered as two intraperitoneal injections separated by 30 min. Rats were tested in the forced swim test at 3, 5, 7, 9, and 11 weeks post-treatment. Tissue punches from the anterior cingulate cortex, prelimbic cortex (PL), and infralimbic cortex were collected for quantitative PCR analysis of 17 targets normalized to Ywhaz. Results:S/P rats exhibited sustained antidepressant-like effects for up to 9 weeks compared with control (S/S). L/P rats did not exhibit antidepressant-like effects at any time point, similarly to S/S. Lorazepam was associated with a decrease in Gria3 expression, and psilocybin was associated with an increase in Gria4 expression at 12 weeks post-treatment in the PL. Conclusions:Psilocybin produced long-lasting antidepressant-like effects, and administration of a BZD prior to psilocybin prevented these effects. Two genes were altered in response to treatment; however, their implications in antidepressant-like effects remain elusive.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cites 24
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 19 more in the library