Psilocybin Promotes Neuroplasticity through 5-HT2A Receptor agonism: Implications for Treatment of Depression
Introduction. Depression is a state of low mood with a lifetime prevalence of about 20% globally.1 Potential etiologies include the monoamine hypothesis which describes a decrease in molecules like serotonin.1,2 Loss or alteration of neuroplasticity may also play a role in pathogenesis, as suggested by the decreased BDNF observed in patients with major depression.1,3 Excitatory receptor 5-HT2A is thought to mediate neuroplasticity in the prefrontal cortex and has been observed as upregulated in unmedicated depressed patients and suicide victims.3 Current treatments include psychotherapy, such as cognitive behavioral therapy, and pharmacotherapy.1 Pharmacotherapy includes first-line SSRIs,1,3 tricyclic antidepressants, and monoamine oxidase inhibitors.1 Patients with a suboptimal response to these treatments may be diagnosed with treatment-resistant depression, suggesting a need for new treatment options.4 Psilocybin, a tryptamine and prodrug for active component psilocin,5 is a potential treatment under research and is thought to mediate neuroplasticity through 5-HT2A receptor agonism.3 Methods. 5-HT2A receptor downregulation and synaptic vesicle protein 2A (SV2A) were measured in the prefrontal cortex of rats one- and seven-days following psilocybin injection.6 Pigs administered psilocybin were observed for behaviors associated with 5-HT2A receptor agonism and brain tissue was assessed for psilocin occupancy of 5-HT2A receptors.5 Psilocybin was administered to eighty rats in one of seven doses and changes in neuroplastic genes were observed in prefrontal cortical and hippocampal tissue.7 Rat cortical neurons were treated with various psychedelics and antagonists including ANA-12, rapamycin, and ketanserin to determine morphological effects and the roles of mTOR and TrkB.8 Rats treated with psilocybin were subjected to a forced swim test to examine behavioral and environmental effects of treatment.9 Results. Rat 5-HT2A receptors were downregulated one day post-injection and SV2A was increased seven days post-injection.6 An increase in pig behaviors associated with 5-HT2A receptor agonism was observed along with a psilocin occupancy of 67% of 5-HT2A receptors, greater in the neocortex.5 Dose-dependent increases in neurogenic genes C-Fos, Arc, Egr2, and Ikb–a were observed, particularly in the prefrontal cortex.7 Spinogenesis and neuritogenesis observed with psychedelics were blocked by antagonist co-administration.8 Rats administered psilocybin demonstrated increased swimming and climbing in forced swim test compared with control.9 Conclusions. Psilocybin acts as a 5-HT2A agonist through pathways involving mTOR and TrkB to upregulate neuroplastic genes, particularly in the prefrontal cortex. Neuroplasticity alters behavioral flexibility to allow patients to develop better coping skills when faced with a stressful environment. These studies suggest that psilocybin is a potentially viable treatment for depression.
- Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299-2312. doi:10.1016/S0140-6736(18)31948-2
- Yohn CN, Gergues MM, Samuels BA. The role of 5-HT receptors in depression. Mol Brain. 2017;10(1):28. Published 2017 Jun 24. doi:10.1186/s13041-017-0306-y
- Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors. J Psychopharmacol. 2017;31(9):1091-1120. doi:10.1177/0269881117725915
- Liu W, Ge T, Leng Y, et al. The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex. Neural Plast. 2017;2017:6871089. doi:10.1155/2017/6871089
- Lundgaard Donovan L, Vilstrup Johansen J, Fernandez Ros N, et al. Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig. Neuropsychopharmacol. 2021;42:1-11. https://doi.org/10.1016/j.euroneuro.2020.11.013. Accessed April 11, 2021.
- Raval NR, Johansen A, Lundgaard Donovan L, et al. A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. J. Mol. Sci. 2021;22(2):835. doi: 10.3390/ijms22020835. Accessed April 11, 2021.
- Jefsen OH, Elfving B, Wegener G, Müller HK. Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin [published online ahead of print, 2020 Nov 4]. J Psychopharmacol. 2020;269881120959614. doi:10.1177/0269881120959614
- Ly C, Greb AC, Cameron LP, et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 2018;23(11):3170-3182. doi: 10.1016/j.celrep.2018.05.022. Accessed April 11, 2021.
- Hibicke M, Landry AN, Kramer HM, Talman ZK, Nichols CD. Psychedelics, but not ketamine, produce persistent antidepressant-like effects in a rodent experimental system for the study of depression. ACS Chem. Neurosci. 2020;11(6):864-871. https://doi.org/10.1021/acschemneuro.9b00493. Accessed April 11, 2021.