Justin Dugie

Introduction: MDD(Major Depressive Disorder) is the largest global burden on disease with a 15% lifetime prevalence.⁷ MDD is associated with increased resting FC(Functional Connectivity) in the medial frontal lobe, temporal lobe and basal ganglia to other regions, and decreased cerebellum FC.⁷ FC is used as one of the measurements for neuroplasticity, and demonstrates the communication between to brain structures⁷ During task-related conditions, the dynamic FC of the medial and lateral frontal lobes, cerebellum, and limbic regions have decreased connectivity in persons with MDD compared to normal.⁶ The 5HT2A Receptor (5HTR2A) is a serotonin receptor largely responsible for dopamine release in the brain.³ 5HTR2A is the main target of SSRIs, the most common antidepressant prescribed.³ Psilocybin, commonly referred to as magic mushrooms, is a schedule 1 psychedelic drug used recreationally to experience a “mystical” experience.³ However, in recent years it has been hypothesized to provide a long term antidepressant effect in patients with MDD and may be a practical, highly specific treatment for future patients.⁴  Methods: Psilocybin(.08 mg/kg IV) was administered to 25 pigs and 5HTR2A density and SV2A expression measured at one and seven days.² 25 female pigs administered Psilocybin (.08 mg/kg IV) had brains extracted and measure for receptor occupancy and changes in gene expression for 5HTR2A and immunoinflammatory genes.⁴ 23 healthy humans administered Psylocibin (.2 mg/kg orally) were measured at 20, 40, and 70 minutes for changes in FC for internal and between brain regions.¹ In 16 patients with treatment-resistant MDD, Psilocybin (10 mg followed by 25 mg after one week orally) administered concurrently with therapy was measured by changes in specific FC between regions associated with MDD.⁵ Patients took the QIDS-SR16 before and at one and five weeks post-treatment to measure their depression.⁵ Results: One dose was shown to acutely decrease 5HTR2A density and increased prolonged synaptogenesis measured with SV2A.² SV2A is used to represent neuroplasticity and FC.²  Psilocybin exhibited preferred receptor locations, notably the prefrontal cortex, Default Mode Network, and the amygdala.⁴ Psilocybin increased multiple gene’s expressions, especially those involved with anti-neuroinfammation.⁴ Psilocybin exhibited increased FC in a time-dependent manner that strongly correlates with 5HTR2A gene expression patterns, especially in sensory regions.¹ Patients showed a universal decrease in mean depression score at one week and 15 of 19 at five weeks.⁵ 47% met criteria for treatment response at five weeks.⁵ Changes in DMN resting FC and vmPFC-ilPC FC were predictive of treatment success, and long term decreases in amygdala and temporal lobe FC were positively associated with treatment response. Conclusions: Psilocybin acts on 5HT2A Receptors in a highly specific and predictable pattern. The changes in functional connectivity between specific brain regions, notably the Prefrontal Cortex, Default Mode Network, and Amygdala, indicates the possibility for Psilocybin to create long lasting, positive changes in neural plasticity in regions highly associated with MDD. The changes in neuroplasticity may account for the increased efficacy when combined with therapy for treatment resistant MDD patients. These studies suggest Psilocybin can be used to provide targeted treatments for patients with specific patterns of abnormal FC, possibly opening the door for higher treatment responses for MDD.

1. Preller KH, Duerler P, Burt JB, et al. Psilocybin Induces Time-Dependent Changes in Global Functional Connectivity [published correction appears in Biol Psychiatry. 2020 Jul 15;88(2):208]. Biol Psychiatry. 2020;88(2):197-207. doi:10.1016/j.biopsych.2019.12.027
2. Raval NR, Johansen A, Donovan LL, et al. A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain. Int J Mol Sci. 2021;22(2):835. Published 2021 Jan 15. doi:10.3390/ijms22020835
3. Grandjean J, Buehlmann D, Buerge M, et al. Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice. Neuroimage. 2021;225:117456. doi:10.1016/j.neuroimage.2020.117456
4. Donovan LL, Johansen JV, Ros NF, et al. Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig. Eur Neuropsychopharmacol. 2021;42:1-11. doi:10.1016/j.euroneuro.2020.11.013
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8. Ivanova SA, Loonen AJ, Bakker PR, et al. Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations. SAGE Open Med. 2016;4:2050312116643673. Published 2016 Apr 11. doi:10.1177/2050312116643673