Psychedelics Improve the Mental Health of Rats

Introduction Psilocybin has recently demonstrated profound efficacy to alleviate depression and anxiety in several clinical trials and has received Breakthrough Status by the FDA. Symptomatic relief after only one or two therapeutic treatments last for at least several months in the vast majority of individuals. It is unclear whether the persistent antidepressant and anxiolytic effects are a psychological integration of the subject's personal experience while under the influence of the drug, or are a consequence of neurochemical changes induced by psilocybin that correct abnormalities leading to a healthier brain state. To distinguish between these possibilities, we investigated the antidepressant and anxiolytic effects of psilocybin in a rat model of treatment resistant depression, Wistar-Kyoto (WKY) rats. Rats do not, as we currently believe, have a sense of self to reflect upon during a psychedelic experience. Therefore, if the effects are purely psychological, psilocybin should not occasion long lasting therapeutic effects as are seen in humans. Objective To evaluate the long-term effects of psychedelics on depressive-like and anxiety-like behaviors in a rat model of depression. Methods Two experiments were performed in which rats were administered a single bolus dose of saline or treatment in saline vehicle: psilocybin (1 mg/kg), lysergic acid diethylamide (LSD, 0.15 mg/kg), or ketamine (5.0 mg/kg) intraperitoneally at a volume of 1 mL/kg. Saline (experiment 1, n =8) and repeat measures psilocybin (experiment 1, n =8) groups were evaluated in the Forced Swim Test (FST) weekly for five weeks, and then the Evaluated Plus Maze (EPM) on the sixth week. Interval psilocybin (experiment 1, n =8), saline (experiment 2, n =6), LSD (experiment 2, n =6), and ketamine (experiment 2, n =6) were evaluated in the FST a single time on the fifth week, and then in the EPM on the sixth week. All measures were evaluated with one-way ANOVA using Holm-Sidak post hoc, or with t-test as appropriate. Results Remarkably, we have found that a single treatment with psilocybin produces context-dependent, long lasting antidepressant-like ( p =0.046, p =0.026, and p