Psilocybin and the glutamatergic pathway: implications for the treatment of neuropsychiatric diseases.

Psilocybin, a 5-HT2A receptor agonist on cortical pyramidal cells, increases glutamate release in the frontal cortex and hippocampus. This elevated glutamate boosts activity of GABAergic interneurons, raising GABA levels, which appears to promote antidepressant effects. Psilocybin also interacts with glutamatergic pathways to support neuroplasticity. This mini-review discusses how psilocybin affects glutamatergic neurotransmission and its therapeutic potential for depression and other nervous system disorders.

Study at a glance

Abstract

In recent decades, psilocybin has gained attention as a potential drug for several mental disorders. Clinical and preclinical studies have provided evidence that psilocybin can be used as a fast-acting antidepressant. However, the exact mechanisms of action of psilocybin have not been clearly defined. Data show that psilocybin as an agonist of 5-HT2A receptors located in cortical pyramidal cells exerted a significant effect on glutamate (GLU) extracellular levels in both the frontal cortex and hippocampus. Increased GLU release from pyramidal cells in the prefrontal cortex results in increased activity of γ-aminobutyric acid (GABA)ergic interneurons and, consequently, increased release of the GABA neurotransmitter. It seems that this mechanism appears to promote the antidepressant effects of psilocybin. By interacting with the glutamatergic pathway, psilocybin seems to participate also in the process of neuroplasticity. Therefore, the aim of this mini-review is to discuss the available literature data indicating the impact of psilocybin on glutamatergic neurotransmission and its therapeutic effects in the treatment of depression and other diseases of the nervous system.