The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research?

Psychedelics may have revolutionary potential in psychiatry, but until recently their pharmacodynamic properties seemed similar to serotonin, whose levels are raised by SSRIs. Unlike antidepressants, psychedelics can induce long-lasting neuroplasticity. New molecular findings show that neuroplasticity is triggered by stimulation of intracellular 5-HT2A receptors. Psychedelics reach these receptors because their lipophilic properties allow them to cross the neuronal membrane, whereas serotonin cannot. The specific mechanisms are not yet fully understood, but better understanding could lead to new drugs or therapeutic strategies that sustain neuroplasticity while minimizing side effects.

Study at a glance

Abstract

Psychedelics could have revolutionary potential in psychiatry, although, until recently, the pharmacodynamic properties of such compounds have not seemed to differ much from those of serotonin, whose levels are raised by Serotonin Reuptake Inhibitors (SSRI). The cardinal point is that serotonergic compounds, such as antidepressive drugs, do not have the potential to induce long-lasting neuroplasticity as psychedelics do. Therefore, the biological underpinnings of the peculiar effect of such compounds had not been fully understood until new astonishing molecular findings came out this year to shed new light on them. Specifically, the phenomena of neuroplasticity are triggered by the stimulation of a peculiar type of receptors: the intracellular 5-HT2A receptors. Interestingly, psychedelics can reach this pool of intracellular receptors due to their lipophilic properties, as they can cross the lipophilic neuronal membrane while serotonin cannot. The importance of such a discovery should not be underestimated as the specific mechanisms involved have not yet been elucidated and a better understanding of them could pave the way to the development of new drugs (and/or new tailored therapeutic strategies) able to sustain neuroplasticity while minimizing side effects.