Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression

Abstract

Therapeutic deficiencies with monoaminergic antidepressants invites the need to identify and develop novel rapid-acting antidepressants. Hitherto, ketamine and esketamine are identified as safe, well-tolerated rapid-acting antidepressants in adults with treatment-resistant depression, and also mitigate measures of suicidality. Psilocybin is a naturally occurring psychoactive alkaloid and non-selective agonist at many serotonin receptors, especially at serotonin 5-HT 2A receptors, and is found in the Psilocybe genus of mushrooms. Preliminary studies with psilocybin have shown therapeutic promise across diverse populations including major depressive disorder. The pharmacodynamic mechanisms mediating the antidepressant and psychedelic effects of psilocybin are currently unknown but are thought to involve the modulation of the serotonergic system, primarily through agonism at the 5-HT 2A receptors and downstream changes in gene expression. It is also established that indirect effects on dopaminergic and glutamatergic systems are contributory, as well as effects at other lower affinity targets. Along with the direct effects on neurochemical systems, psilocybin alters neural circuitry and key brain regions previously implicated in depression, including the default mode network and amygdala. The aim of this review is to synthesize the current understanding of the receptor pharmacology and neuronal mechanisms underlying the psychedelic and putative antidepressant properties of psilocybin. Key PointsPsilocybin is a psychoactive alkaloid with psychedelic and putative antidepressant effects. Its actions are proposed to be primarily mediated by agonism at serotonin 5-HT 2A receptors and downstream changes in gene expression.Psilocybin modulates the serotonergic system and indirectly affects the dopaminergic and glutamatergic systems.Psilocybin alters neural circuitry between areas such as the default mode network and amygdala, which may mediate antidepressant effects.

Potential Therapeutic Effects of Psilocybin: A Systematic Review

“…Comparative pharmacological attributes as far as ligand-restricting examples were found in examinations utilizing cloned 5-HT2ARs communicated in heterologous frameworks when contrasted with in situ-created receptors. High measures of 5-HT2AR courier ribonucleic corrosive (mRNA) were recognized in the mind using the Northern smudge examination, like prior examinations utilizing radioligand restricting techniques [12].…”

“…Then, at that point, 5-HT2AR desensitization and various downstream effector pathways are incited by initiated PKC. All researched hallucinogenic substances to date are 5-HT2AR agonists, which open this route [11][12][13].…”

“…Various examinations utilizing receptor autoradiography have shown that cortical layer V in various species contains an improved populace of 5-HT2ARs. Various examinations utilizing receptor autoradiography have shown that cortical layer V in various species contains an upgraded populace of 5-HT2ARs [12][13][14].…”

“…FIGURE 3: Relevance of 5-HT2AR signaling to psychedelic drug effects* *[13](a) Diagram illustrating the intracellular signaling networks connected to the activation of the 5-hydroxytryptamine 2A receptor (5-HT2AR) and its effectors[11][12][13]. (b) Biased agonist activity of 5-HT2AR[11][12][13] …”

Unraveling the Mysteries of Mental Illness With Psilocybin

“…The structural similarity to serotonin would seem to make understanding the molecular events of psilocin more tractable, but even serotonin neurotransmission is complicated [ 60 ]. The molecular mechanisms of psilocin have recently been reviewed in more detail elsewhere [ 61 , 62 ]. To avoid redundancy, they will be briefly described here.…”