The 5-HT2A receptor (“5-HT” = 5-hydroxytryptamine, also known as serotonin) is a widely-expressed Gq-coupled protein receptor (GCPR) that triggers a range of intracellular pathways.
Psilocybin and major depression
Increased network modularity is a symptom of major depression that is directly correlated with symptom severity.4 A recent Nature study exploring the effects of this drug in patients with major depression found that treatment with psilocybin caused a significant increase in global network integration.4 Results were observed just one day after oral administration of psilocybin and were not observed in the control group treated with the selective serotonin reuptake inhibitor (SSRI) escitalopram. The researchers noticed that psilocybin dysregulated activity and caused functional changes in areas of the brain with high 5-HT2A density,4 supporting the hypothesis that psilocybin is a selective 5-TH2A agonist. On the other hand, SSRIs did not affect network modularity.4
While the sample size of this study was small, the results were significant. It represents one of the few clinical trials using 5-HT2A agonists and could help treat severely depressed individuals where other therapeutics have failed.4 The authors concluded that the liberating effect on cortical activity induced by psilocybin could lead to a long-term reduction in network modularity and improvements in depression severity4 but that further clinical studies were needed to explore its full therapeutic potential.