Preadministration of Lorazepam Negates the Long-Term Antidepressant-Like Effects of Psilocybin in Male Wistar Kyoto Rats

Psilocybin produced sustained antidepressant-like effects in male Wistar Kyoto rats for up to 9 weeks, as measured by the forced swim test. However, when lorazepam was administered 30 minutes before psilocybin, those antidepressant-like effects were completely prevented, and the rats performed similarly to controls given only saline. At 12 weeks post-treatment, lorazepam was associated with decreased Gria3 gene expression, and psilocybin with increased Gria4 expression in the prelimbic cortex, but the role of these gene changes in antidepressant effects remains unclear. The findings suggest that benzodiazepines may reduce the therapeutic benefits of psilocybin-assisted therapy.

Study at a glance

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.