Psilocybin shows efficacy to alleviate depression in human clinical trials for six or more months after only one or two treatments. Another hallucinogenic drug, esketamine, has recently been U.S. Food and Drug Administration (FDA)-approved as a rapid-acting antidepressant. The mechanistic basis for the antidepressant effects of psilocybin and ketamine appear to be conserved. The efficacy of these two medications has not, however, been directly compared either clinically or preclinically. Further, whether or not a profound subjective existential experience is necessary for psilocybin to have antidepressant effects is unknown. To address these questions, we tested psilocybin, lysergic acid diethylamide (LSD), and ketamine in a rat model for depression. As in humans, a single administration of psilocybin or LSD produced persistent antidepressant-like effects in our model. In contrast, ketamine produced only a transient antidepressant-like effect. Our results indicate that classic psychedelics may have therapeutic efficacy that is more persistent than that of ketamine, and also suggest that a subjective existential experience may not be necessary for therapeutic effects.

A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.

IntroductionPsilocybin 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.ObjectiveTo evaluate the long‐term effects of psychedelics on depressive‐like and anxiety‐like behaviors in a rat model of depression.MethodsTwo 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.ResultsRemarkably, we have found that a single treatment with psilocybin produces context‐dependent, long lasting antidepressant‐like (p=0.046, p=0.026, and p<0.0001) and anxiolytic effects (p=0.039) in male WKY rats as measured by the FST and EPM. We have also found that LSD, a related psychedelic, produces a long lasting antidepressant‐like effect in male WKY rats (p=0.003), while ketamine does not.ConclusionsThese results indicate that at least a substantial portion of the ability of psychedelics to produce long lasting therapeutic effects has a biological basis and can be studied in animal models.Support or Funding InformationThis work was supported by Eleusis, PBC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Introduction Psilocybin (PSI) has persistent antidepressant efficacy in human trials. We have shown one dose of PSI to significantly decrease depressive‐like behavior in male Wistar‐Kyoto (WKY) rats for at least five weeks without losing efficacy. However, the outcome assay we used to evaluate depressive‐like behavior, the forced swim test (FST), has been criticized for not providing circuit‐specific endpoint data. Further, rodent strains like WKY selectively bred for face validity in modeling depression have lower translational value than chronic/developmental stress models. Pattern separation is a function of the dentate gyrus (DG) and CA3 region of the hippocampus. Pattern separation deficits are measurable in a number of psychological and neurological disorders where the DG‐CA3 circuit is impaired, including major depressive disorder, schizophrenia, and age‐related dementias. The object pattern separation (OPS) task is a new paradigm to measure DG‐CA3 function in rodents, proposed as a cognitive‐based outcome measure for depression‐like phenotypes, but so far only used in healthy male animals. Whether OPS performance correlates with established measures of behavioral despair, or can be normalized by human pharmacotherapies, is unknown. Objectives Evaluate long‐term antidepressant‐like effects of PSI in the stress‐based adolescent chronic restraint stress (aCRS) model for depression, establish face and predictive validity of the OPS task, and determine whether OPS correlates with FST immobility in aCRS rats. Methods Adolescent female Sprague Dawley rats were assigned to groups: not restrained‐saline (NRS), not restrained‐PSI (NRP), restrained‐saline (RS), and restrained‐PSI (RP). RS and RP rats were restrained 1 hr/day post‐natal days (PND) 32–45. Rats received IP PSI (1 mg/kg) or saline PND 52. The OPS task was performed nightly PND 82 (0 cm) – 86 (24 cm) in a 66 cm diameter arena containing two identical objects, one of which was moved from 0 cm to 6, 12, 18, and 24 cm from 0 following an hour intertrial interval. FST was performed PND 89–90. Results Significant discrimination in the OPS at 24 cm was observed in NRS (p<0.001), NRP (p<0.0001), and RP (p<0.01), but RS rats were unable to discriminate between moved and stationary objects. RS rats were significantly more immobile in the FST than NRS rats (p<0.0001). No differences were observed between NRS, NRP, and RP rats. Immobility in the FST was inversely correlated to discrimination in the OPS at 24 cm (r=−0.402, p=0.023). Conclusions The OPS is a translationally relevant outcome with face and predictive validity, correlates with an established measure of depressive‐like behavior, and can be used in female rats. One dose of PSI in late adolescence mitigates cognitive and behavioral deficiencies characteristic of the developmentally‐stressed adult aCRS rat model for depression. Our aCRS model is uniquely suitable for elucidating the antidepressant mechanisms of PSI, which has translationally relevant antidepressant‐like effects that can be measured using th...

Stress during times of rapid development is a risk factor for Major Depressive Disorder, a mood disorder that disproportionately affects women. We developed an adolescent chronic restraint stress (aCRS) protocol using female rats to address the impact of adolescent stress on female adult depressive-like behavior. Animals were divided into 4 treatment groups: not restrained:saline (NRSAL), not restrained:desipramine (NRDES), restrained:saline (RSAL), and restrained:desipramine (RDES). NRSAL and NRDES rats were housed in a separate colony room from RSAL and RDES rats. All animals were weighed and handled daily. Beginning postnatal day (PND) 34(±1), RSAL and RDES rats were restrained for 1 hour daily for 14 consecutive days. Beginning PND 55(±1), NRDES and RDES rats were given subcutaneous desipramine (5 mg/kg), which served as a positive control, daily for 14 consecutive days. During that same time period, NRSAL and RSAL rats were given subcutaneous saline daily. aCRS (RSAL and RDES) rats showed significantly attenuated weight gain compared with nonrestrained (NRSAL and NRDES) rats during the restraint period. Weight gain normalized after the final restraint session. Behavioral testing took place PND 68-69(±1), and included open field testing, the elevated plus maze, locomotor activity, and the forced swim test (FST). RSAL rats showed significantly more immobility in the FST versus all other groups, indicating depressive-like behavior. No differences between groups were observed in the other behavioral measures. These results indicate that aCRS elicits depressive-like behavioral characteristics in adult female rats without increasing anxiety-like behaviors. (PsycINFO Database Record