Preadministration of Lorazepam Reduces Efficacy and Longevity of Antidepressant-Like Effect from a Psychedelic

Introduction: Psychedelics such as psilocybin have been shown to have persistent antidepressant effects, but with considerable individual variability in optimal dosing. Intravenous (IV) dosing is rapid onset and quickly titrated, possibly preceded by an anxiolytic for patient comfort. We explored the viability of IV psilocin with and without preadministration of lorazepam for possible future inpatient therapeutic utility. Methods: Male Wistar-Kyoto rats were given saline (S), psilocin (P), or psilocin and lorazepam (P+L). Saline was given intraperitoneally (IP), psilocin was given IV to a second group, and lorazepam was given IP, then psilocin was given IV30 min later to a final group. Rats were tested in the forced swim test (FST) 3 and 14 weeks after injection. Results: P rats were more active than S rats at both time points. P + L rats were more active in the FST than S rats at 3, but not 14, weeks. P + L rats were less active than P rats at 14 weeks, and less active than themselves at 3 weeks. S rats' behavior was not different at 3 and 14 weeks. Similarly, P rats behaved the same at both time points. Conclusions: IV psilocin persistently decreased immobility in the FST, but lorazepam reduced psilocin's antidepressant-like efficacy and longevity.