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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 powder for sale 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.

Currently marketed antidepressants are poorly efficacious, requiring weeks of chronic dosing for symptomatic relief, and many of those who suffer from major depressive disorder fail to achieve complete remission.(1,2) First-line pharmacotherapies, frequently selective serotonin reuptake inhibitors, are poorly efficacious, and nonpharmacological approaches such as bright light therapy actually may have a greater antidepressant effect.(3) Alternative pharmacotherapies such as tricyclic antidepressants are associated with greater risk of adverse effects, including weight gain, gastrointestinal and urinary retention, sexual dysfunction, and cardiovascular problems. Furthermore, no currently available antidepressants produce long-term antidepressant effects without chronic administration.

Recently, ketamine has been shown to have extremely rapid antidepressant effects.(4−7) Ketamine is an NMDA receptor antagonist used as a sedative and anesthetic in human and veterinary medicine. Ketamine infusion can produce symptomatic relief for major depression and suicidal ideation within minutes,(6) and it has been used off-label and in clinics across the country to treat depression. Unfortunately, for patients with treatment-resistant depression, ketamine is an efficacious antidepressant only for approximately half of the people infused, and the mean time to relapse of another depressive episode is only 17 days.(8) To prolong the antidepressant effect, ketamine requires repeated clinical visits (typically 6 visits over 12 days),(6) but symptomatic relief lasts only for about 5 weeks before another round of infusion therapy is needed.

Significantly, in March 2019, the U.S. Food and Drug Administration (FDA) approved clinical administration of intranasal esketamine (the S-(+) enantiomer of ketamine) through a restricted distribution system, and in conjunction with standard antidepressants, for treatment-resistant depression.(9) Although shown to be efficacious for treatment-resistant depression, intranasal administration is similar to intravenous infusion in that it requires repeated clinical administration. Regardless, ketamine has provided a powerful context in which to study pharmacological mechanisms that contribute to rapid antidepressant effects of drugs.

Ketamine’s antidepressant effects are associated with increased synaptic density in the hippocampus(7) and medial prefrontal cortex of rats(7,10) and in rat cortical cell culture.(11) These effects are consistent with neuroproliferation observed with traditional antidepressants(12−14) that has been associated with antidepressant effects. Additional recent studies indicate that ketamine-related neuroproliferation and plasticity are dependent on the mammalian target of rapamycin (mTOR) signaling cascade,(15,16) which is dysfunctional in humans suffering from major depressive disorder.(17) Like ketamine, certain psychedelic compounds such as lysergic acid diethylamide (LSD)(18) and N,N-dimethyltryptamine (DMT)(19) have been reported to have some antidepressant-like behavioral effects in rodents, as well as to promote neuroplasticity in rat cortical cell culture via a tropomyosin receptor kinase B (TrkB) and mTOR-dependent mechanism.(11) All classic psychedelic compounds activate the serotonin 5-HT2A receptor,(20) several of which have been shown to activate the Akt/mTOR pathway.