Research progress on the antidepressant effect of psilocybin_West China Medical Journal

Authors：

XIE Xuxin ^1,2 , PENG Aihua ^1,2 ,  CAO Yu ^1,2

1. Department of Emergency Medicine and Institute of Disaster Medicine, Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Disaster Medical Center, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

CAO Yu, Email: yuyuer@126.com

Keywords：

Psilocybin; psilocin; molecular mechanism; depression; treatment

DOI：

10.7507/1002-0179.202409139

Video：

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Abstract Full text Figures/Tables Video References Cited by

Psilocybin is a hallucinogenic indole alkaloid derived from mushrooms, which is metabolized into psilocin in vivo and exerts biological effects. Clinical studies have shown that psilocybin has the effect of relieving anxiety and depression in cancer patients. Due to its fast onset, significant therapeutic effect, and low addictive nature, psilocybin has the potential to break through the bottleneck of slow action and poor efficacy of existing depression drugs, bringing new hope for the treatment of severe depression and refractory depression. This article will review the pharmacokinetics, antidepressant mechanisms, and research progress of psilocybin, providing a reference for subsequent research.

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11.	Manevski N, Kurkela M, Höglund C, et al. Glucuronidation of psilocin and 4-hydroxyindole by the human UDP-glucuronosyltransferases. Drug Metab Dispos, 2010, 38(3): 386-395.
12.	Hasler F, Bourquin D, Brenneisen R, et al. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. J Pharm Biomed Anal, 2002, 30(2): 331-339.
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1. Liu Q, He H, Yang J, et al. Changes in the global burden of depression from 1990 to 2017: findings from the global burden of disease study. J Psychiatr Res, 2020, 126: 134-140.
2. DeFilippis M, Wagner KD. Management of treatment-resistant depression in children and adolescents. Paediatr Drugs, 2014, 16(5): 353-361.
3. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med, 2022, 387(18): 1637-1648.
4. Passie T, Seifert J, Schneider U, et al. The pharmacology of psilocybin. Addict Biol, 2002, 7(4): 357-364.
5. Lowe H, Toyang N, Steele B, et al. The therapeutic potential of psilocybin. Molecules, 2021, 26(10): 2948.
6. Hopf A, Eckert H. Distribution patterns of 14-C-psilocin in the brains of various animals. Act Nerv Super (Praha), 1974, 16(1): 64-66.
7. Kalberer F, Kreis W, Rutschmann J. The fate of psilocin in the rat. Biochem Pharmacol, 1962, 11: 261-269.
8. Eivindvik K, Rasmussen KE, Sund RB. Handling of psilocybin and psilocin by everted sacs of rat jejunum and colon. Acta Pharm Nord, 1989, 1(5): 295-302.
9. Hasler F, Bourquin D, Brenneisen R, et al. Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. Pharm Acta Helv, 1997, 72(3): 175-184.
10. Dinis-Oliveira RJ. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Drug Metab Rev, 2017, 49(1): 84-91.
11. Manevski N, Kurkela M, Höglund C, et al. Glucuronidation of psilocin and 4-hydroxyindole by the human UDP-glucuronosyltransferases. Drug Metab Dispos, 2010, 38(3): 386-395.
12. Hasler F, Bourquin D, Brenneisen R, et al. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. J Pharm Biomed Anal, 2002, 30(2): 331-339.
13. Sticht G, Käferstein H. Detection of psilocin in body fluids. Forensic Sci Int, 2000, 113(1/2/3): 403-407.
14. Grieshaber AF, Moore KA, Levine B. The detection of psilocin in human urine. J Forensic Sci, 2001, 46(3): 627-630.
15. Fries GR, Saldana VA, Finnstein J, et al. Molecular pathways of major depressive disorder converge on the synapse. Mol Psychiatry, 2023, 28(1): 284-297.
16. Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuropsychopharmacol Biol Psychiatry, 2013, 45: 54-63.
17. Roseman L, Nutt DJ, Carhart-Harris RL. Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol, 2018, 8: 974.
18. Yaden DB, Griffiths RR. The subjective effects of psychedelics are necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci, 2020, 4(2): 568-572.
19. Pytliak M, Vargová V, Mechírová V, et al. Serotonin receptors - from molecular biology to clinical applications. Physiol Res, 2011, 60(1): 15-25.
20. Xu P, Huang S, Zhang H, et al. Structural insights into the lipid and ligand regulation of serotonin receptors. Nature, 2021, 592(7854): 469-473.
21. Jakab RL, Goldman-Rakic PS. 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci U S A, 1998, 95(2): 735-740.
22. Bortolozzi A, Masana M, Díaz-Mataix L, et al. Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT_1A receptors but not 5-HT_2A receptors. Int J Neuropsychopharmacol, 2010, 13(10): 1299-1314.
23. Thomas K, Malcolm B, Lastra D. Psilocybin-assisted therapy: a review of a novel treatment for psychiatric disorders. J Psychoactive Drugs, 2017, 49(5): 446-455.
24. Willins DL, Deutch AY, Roth BL. Serotonin 5-HT_2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse, 1997, 27(1): 79-82.
25. Stahl S. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. 5th ed. London: Cambridge University Press, 2021: 79-216.
26. McKenna DJ, Repke DB, Lo L, et al. Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes. Neuropharmacology, 1990, 29(3): 193-198.
27. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport, 1998, 9(17): 3897-3902.
28. Madsen MK, Fisher PM, Burmester D, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology, 2019, 44(7): 1328-1334.
29. Muthukumaraswamy SD, Carhart-Harris RL, Moran RJ, et al. Broadband cortical desynchronization underlies the human psychedelic state. J Neurosci, 2013, 33(38): 15171-15183.
30. Roth BL, Nakaki T, Chuang DM, et al. Aortic recognition sites for serotonin (5HT) are coupled to phospholipase C and modulate phosphatidylinositol turnover. Neuropharmacology, 1984, 23(10): 1223-1225.
31. Conn PJ, Sanders-Bush E. Selective 5HT-2 antagonists inhibit serotonin stimulated phosphatidylinositol metabolism in cerebral cortex. Neuropharmacology, 1984, 23(8): 993-996.
32. Yasuda R, Hayashi Y, Hell JW. CaMKII: a central molecular organizer of synaptic plasticity, learning and memory. Nat Rev Neurosci, 2022, 23(11): 666-682.
33. Guo X, Zhou J, Starr C, et al. Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. Cell, 2021, 184(16): 4299-4314. e12.
34. Rehman SU, Ikram M, Ullah N, et al. Neurological enhancement effects of melatonin against brain injury-induced oxidative stress, neuroinflammation, and neurodegeneration via AMPK/CREB signaling. Cells, 2019, 8(7): 760.
35. Liu J, Feng X, Wang Y, et al. Astrocytes: GABAceptive and GABAergic cells in the brain. Front Cell Neurosci, 2022, 16: 892497.
36. Xie Y, Kuan AT, Wang W, et al. Astrocyte-neuron crosstalk through hedgehog signaling mediates cortical synapse development. Cell Rep, 2022, 38(8): 110416.
37. McClure-Begley TD, Roth BL. The promises and perils of psychedelic pharmacology for psychiatry. Nat Rev Drug Discov, 2022, 21(6): 463-473.
38. Wallach J, Cao AB, Calkins MM, et al. Identification of 5-HT_2A receptor signaling pathways responsible for psychedelic potential. bioRxiv, 2023, 31: 2023.
39. Cao D, Yu J, Wang H, et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science, 2022, 375(6579): 403-411.
40. Bombardi C, Di Giovanni G. Functional anatomy of 5-HT_2A receptors in the amygdala and hippocampal complex: relevance to memory functions. Exp Brain Res, 2013, 230(4): 427-439.
41. Ling S, Ceban F, Lui LMW, et al. Molecular mechanisms of psilocybin and implications for the treatment of depression. CNS Drugs, 2022, 36(1): 17-30.
42. Vollenweider FX, Vontobel P, Hell D, et al. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [¹¹C]raclopride. Neuropsychopharmacology, 1999, 20(5): 424-433.
43. Tye KM, Mirzabekov JJ, Warden MR, et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature, 2013, 493(7433): 537-541.
44. Peciña M, Sikora M, Avery ET, et al. Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: implications for anhedonia, anxiety and treatment response. Eur Neuropsychopharmacol, 2017, 27(10): 977-986.
45. Allen HN, Bobnar HJ, Kolber BJ. Left and right hemispheric lateralization of the amygdala in pain. Prog Neurobiol, 2021, 196: 101891.
46. Izadi MS, Radahmadi M. Overview of the central amygdala role in feeding behaviour. Br J Nutr, 2022, 127(6): 953-960.
47. Tovote P, Esposito MS, Botta P, et al. Midbrain circuits for defensive behaviour. Nature, 2016, 534(7606): 206-212.
48. Kraehenmann R, Preller KH, Scheidegger M, et al. Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol Psychiatry, 2015, 78(8): 572-581.
49. Stroud JB, Freeman TP, Leech R, et al. Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression. Psychopharmacology (Berl), 2018, 235(2): 459-466.
50. Mertens LJ, Wall MB, Roseman L, et al. Therapeutic mechanisms of psilocybin: changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. J Psychopharmacol, 2020, 34(2): 167-180.
51. Molendijk ML, Bus BA, Spinhoven P, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry, 2011, 16(11): 1088-1095.
52. Castrén E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses. Mol Psychiatry, 2017, 22(8): 1085-1095.
53. Casarotto PC, Girych M, Fred SM, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell, 2021, 184(5): 1299-1313. e19.
54. Moliner R, Girych M, Brunello CA, et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat Neurosci, 2023, 26(6): 1032-1041.
55. Numakawa T, Yokomaku D, Richards M, et al. Functional interactions between steroid hormones and neurotrophin BDNF. World J Biol Chem, 2010, 1(5): 133-143.
56. Yeo BT, Krienen FM, Sepulcre J, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol, 2011, 106(3): 1125-1165.
57. Kerestes R, Davey CG, Stephanou K, et al. Functional brain imaging studies of youth depression: a systematic review. Neuroimage Clin, 2013, 4: 209-231.
58. Chi S, Song M, Lee JH, et al. Prospective study on resting state functional connectivity in adolescents with major depressive disorder after antidepressant treatment. J Psychiatr Res, 2021, 142: 369-375.
59. Zhang S, Chen JM, Kuang L, et al. Association between abnormal default mode network activity and suicidality in depressed adolescents. BMC Psychiatry, 2016, 16(1): 337.
60. Wu B, Li X, Zhou J, et al. Altered whole-brain functional networks in drug-naïve, first-episode adolescents with major depression disorder. J Magn Reson Imaging, 2020, 52(6): 1790-1798.
61. Siegel JS, Subramanian S, Perry D, et al. Psilocybin desynchronizes the human brain. Nature, 2024, 632(8023): 131-138.
62. Deco G, Sanz Perl Y, Johnson S, et al. Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression. Nat Mental Health, 2024, 2(9): 1-15.
63. Matsushima Y, Eguchi F, Kikukawa T, et al. Historical overview of psychoactive mushrooms. Inflamm Regen, 2010, 29(1): 47-58.
64. Brandrup E, Vanggaard T. LSD treatment in a severe case of compulsive neurosis. Acta Psychiatr Scand, 1977, 55(2): 127-141.
65. Leonard HL, Rapoport JL. Relief of obsessive-compulsive symptoms by LSD and psilocin. Am J Psychiatry, 1987, 144(9): 1239-1240.
66. Nichols DE. Psilocybin: from ancient magic to modern medicine. J Antibiot (Tokyo), 2020, 73(10): 679-686.
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