Abstract
Introduction: Psilocybin, a tryptamine alkaloid found in mushrooms of the Psilocybe genus, acts by binding to serotonin 2A receptors (5-HT2A), activating metabotropic responses and inducing neuroplasticity processes. Various scientific approaches are integrated, including preclinical and clinical studies, addressing neurophysiological effects and therapeutic potential in neuropsychiatry.
Materials and methods: A narrative review was conducted based on an exhaustive search of scientific literature in the Medline database, using the PubMed search engine, covering the period from 2010 to 2024. The keywords used were: “anxiety,” “depression,” “psilocin,” “psilocybin,” “neurogenesis,” “neuroplasticity,” “neurologic disorders,” “mental disorders,” and “serotonin receptors.” Relevant data were selected regarding the therapeutic potential of psilocybin.
Results: Evidence indicates that psilocybin administration produces both functional and structural brain changes, inducing neurogenesis and modulating dominant brain circuits associated with cognitive rigidity. These effects lead to improvements in depression and anxiety scales. Furthermore, proposals have been made regarding its potential use in neurodegenerative disorders.
Discussion: Psilocybin has emerged as a promising therapeutic tool. Preclinical findings reveal genetic expression of neurotrophins and sustained synaptic remodeling. Functional neuroimaging studies show brain activity changes that correlate with clinical improvements in patients with treatment-resistant affective disorders, suggesting potential benefits in the prevention and treatment of neurodegenerative diseases.
Conclusions: Rigorous research is essential to establish standardized clinical protocols for its safe and effective use.
References
Nichols DE. Psilocybin: from ancient magic to modern medicine. J Antibiot. 2020;73(10):679-86. https://doi.org/10.1038/s41429-020-0311-8
Faccini-Durán G. Apuntes sobre filogénesis del sistema nervioso y la conciencia. Acta Neurol Colomb. 2024;40(1). https://doi.org/10.22379/anc.v40i1.823
Xing L, Kalebic N, Namba T, Vaid S, Wimberger P, Huttner WB. Serotonin receptor 2A activation promotes evolutionarily relevant basal progenitor proliferation in the developing neocortex. Neuron. 2020;108(6):1113-29.e6. https://doi.org/10.1016/j.neuron.2020.09.034
Beliveau V, Ganz M, Feng L, Ozenne B, Højgaard L, Fisher PM, et al. A high-resolution in vivo atlas of the human brain's serotonin system. J Neurosci. 2017;37(1):120-8. https://doi.org/10.1523/jneurosci.2830-16.2016
Casanova AF, Ort A, Smallridge JW, Preller KH, Seifritz E, Vollenweider FX. The influence of psilocybin on subconscious and conscious emotional learning. iScience. 2024;27(6):110034. https://doi.org/10.1016/j.isci.2024.110034
Szafoni S, Gr?blowski P, Grabowska K, Wi?ckiewicz G. Unlocking the healing power of psilocybin: an overview of the role of psilocybin therapy in major depressive disorder, obsessive-compulsive disorder and substance use disorder. Front Psychiatry. 2024;15:1406888. https://doi.org/10.3389/fpsyt.2024.1406888
Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, et al. The therapeutic potential of psilocybin. Molecules. 2021;26(10):2948. https://doi.org/10.3390/molecules26102948
Nutt D, Erritzoe D, Carhart-Harris R. Psychedelic psychiatry's brave new world. Cell. 2020;181(1):24-8. https://doi.org/10.1016/j.cell.2020.03.020
Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-9. https://doi.org/10.1001/jamapsychiatry.2020.3285
Baumeister D, Barnes G, Giaroli G, Tracy D. Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles. Ther Adv Psychopharmacol. 2014;4(4):156-69. https://doi.org/10.1177/2045125314527985
Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637-48. https://doi.org/10.1056/nejmoa2206443
Deco G, Sanz Perl Y, Johnson S, Bourke N, Carhart-Harris RL, Kringelbach ML. Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression. Nat Ment Health. 2024;2(9):1096-110. https://doi.org/10.1038/s44220-024-00298-y
Doss MK, Považan M, Rosenberg MD, Sepeda ND, Davis AK, Finan PH, et al. Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Transl Psychiatry. 2021;11(1):574. https://doi.org/10.1038/s41398-021-01706-y
Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-97. https://doi.org/10.1177/0269881116675513
Gukasyan N, Davis AK, Barrett FS, Cosimano MP, Sepeda ND, Johnson MW, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: prospective 12-month follow-up. J Psychopharmacol. 2022;36(2):151-8. https://doi.org/10.1177/02698811211073759
Sloshower J, Zeifman RJ, Guss J, Krause R, Safi-Aghdam H, Pathania S, et al. Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: results from an exploratory placebo-controlled trial. Sci Rep. 2024;14(1):8833. https://doi.org/10.1038/s41598-024-58318-x
Owe-Larsson M, Kami?ska K, Buchalska B, Mirowska-Guzel D, Cudnoch-J?drzejewska A. Psilocybin in pharmacotherapy of obsessive-compulsive disorder. Pharmacol Rep. 2024;76(5):911-25. https://doi.org/10.1007/s43440-024-00633-1
Kelmendi B, Kichuk SA, DePalmer G, Maloney G, Ching THW, Belser A, et al. Single-dose psilocybin for treatment-resistant obsessive-compulsive disorder: a case report. Heliyon. 2022;8(12):e12135. https://doi.org/10.1016/j.heliyon.2022.e12135
Ching THW, Amoroso L, Bohner C, D'Amico E, Eilbott J, Entezar T, et al. Safety, feasibility, tolerability, and clinical effects of repeated psilocybin dosing combined with non-directive support in the treatment of obsessive-compulsive disorder: protocol for a randomized, waitlist-controlled trial with blinded ratings. Front Psychiatry. 2024;14:1278823. https://doi.org/10.3389/fpsyt.2023.1278823
Singh S, Botvinnik A, Shahar O, Wolf G, Yakobi C, Saban M, et al. Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder. Transl Psychiatry. 2023;13(1):164. https://doi.org/10.1038/s41398-023-02456-9
Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa P, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29(3):289-99. https://doi.org/10.1177/0269881114565144
de Veen BTH, Schellekens AFA, Verheij MMM, Homberg JR. Psilocybin for treating substance use disorders? Expert Rev Neurother. 2017;17(2):203-12. https://doi.org/10.1080/14737175.2016.1220834
Vanderijst L, Hever F, Buot A, Dauré C, Benoit J, Hanak C, et al. Psilocybin-assisted therapy for severe alcohol use disorder: protocol for a double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial. BMC Psychiatry. 2024;24(1):77. https://doi.org/10.1186/s12888-024-05502-y
van der Meer PB, Fuentes JJ, Kaptein AA, Schoones JW, de Waal MM, Goudriaan AE, et al. Therapeutic effect of psilocybin in addiction: a systematic review. Front Psychiatry. 2023;14:1134454. https://doi.org/10.3389/fpsyt.2023.1134454
Brett J, Knock E, Korthuis PT, Liknaitzky P, Murnane KS, Nicholas CR, et al. Exploring psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder. Front Psychiatry. 2023;14:1123424. https://doi.org/10.3389/fpsyt.2023.1123424
Kozlowska U, Nichols C, Wiatr K, Figiel M. From psychiatry to neurology: psychedelics as prospective therapeutics for neurodegenerative disorders. J Neurochem. 2022;162(1):89-108. https://doi.org/10.1111/jnc.15509
Haniff ZR, Bocharova M, Mantingh T, Rucker JJ, Velayudhan L, Taylor DM, et al. Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases. Pharmacol Ther. 2024;258:108641. https://doi.org/10.1016/j.pharmthera.2024.108641
Zheng S, Ma R, Yang Y, Li G. Psilocybin for the treatment of Alzheimer's disease. Front Neurosci. 2024;18:1420601. https://doi.org/10.3389/fnins.2024.1420601
Saeger HN, Olson DE. Psychedelic?inspired approaches for treating neurodegenerative disorders. J Neurochem. 2022;162(1):109-27. https://doi.org/10.1111/jnc.15544
Goel A, Rai Y, Sivadas S, Diep C, Clarke H, Shanthanna H, et al. Use of psychedelics for pain: a scoping review. Anesthesiology. 2023;139(4):523-36. https://doi.org/10.1097/aln.0000000000004673
Nkadimeng SM, Steinmann CM, Eloff JN. Anti-inflammatory effects of four psilocybin-containing magic mushroom water extracts in vitro on 15-lipoxygenase activity and on lipopolysaccharide-induced cyclooxygenase-2 and inflammatory cytokines in human U937 macrophage cells. J Inflamm Res. 2021;14:3729-38. https://doi.org/10.2147/jir.s317182
Nkadimeng SM, Nabatanzi A, Steinmann CML, Eloff JN. Phytochemical, cytotoxicity, antioxidant and anti-inflammatory effects of Psilocybe natalensis magic mushroom. Plants. 2020;9(9):1127. https://doi.org/10.3390/plants9091127
Bornemann J, Close JB, Ahmad K, Barba T, Godfrey K, Macdonald L, et al. Study protocol for “Psilocybin in patients with fibromyalgia: brain biomarkers of action”. Front Psychiatry. 2024;15:1320780. https://doi.org/10.3389/fpsyt.2024.1320780
Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. Addict Biol. 2002;7(4):357-64. https://doi.org/10.1080/1355621021000005937
Wojtas A, Go?embiowska K. Molecular and medical aspects of psychedelics. Int J Mol Sci. 2023;25(1):241. https://doi.org/10.3390/ijms25010241
MacCallum CA, Lo LA, Pistawka CA, Deol JK. Therapeutic use of psilocybin: practical considerations for dosing and administration. Front Psychiatry. 2022;13:1040217. https://doi.org/10.3389/fpsyt.2022.1040217
Tylš F, Pálení?ek T, Horá?ek J. Psilocybin - summary of knowledge and new perspectives. Eur Neuropsychopharmacol. 2014;24(3):342-56. https://doi.org/10.1016/j.euroneuro.2013.12.006
Geiger HA, Wurst MG, Daniels RN. DARK classics in chemical neuroscience: Psilocybin. ACS Chem Neurosci. 2018;9(10):2438-47. https://doi.org/10.1021/acschemneuro.8b00186
Bazzari AH, Bazzari FH. BDNF therapeutic mechanisms in neuropsychiatric disorders. Int J Mol Sci. 2022;23(15):8417. https://doi.org/10.3390/ijms23158417
Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci. 2019;13:363. https://doi.org/10.3389/fncel.2019.00363
Szarowicz CA, Steece-Collier K, Caulfield ME. New frontiers in neurodegeneration and regeneration associated with brain-derived neurotrophic factor and the rs6265 single nucleotide polymorphism. Int J Mol Sci. 2022;23(14):8011. https://doi.org/10.3390/ijms23148011
Jefsen OH, Elfving B, Wegener G, Müller HK. Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. J Psychopharmacol. 2021;35(4):483-93. https://doi.org/10.1177/0269881120959614
Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021;109(16):2535-44.e4. https://doi.org/10.1016/j.neuron.2021.06.008
Sakashita Y, Abe K, Katagiri N, Kambe T, Saitoh T, Utsunomiya I, et al. Effect of psilocin on extracellular dopamine and serotonin levels in the mesoaccumbens and mesocortical pathway in awake rats. Biol Pharm Bull. 2015;38(1):134-8. https://doi.org/10.1248/bpb.b14-00315
Wojtas A, Bysiek A, Wawrzczak-Bargiela A, Szych Z, Majcher-Ma?lanka I, Herian M, et al. Effect of psilocybin and ketamine on brain neurotransmitters, glutamate receptors, DNA and rat behavior. Int J Mol Sci. 2022;23(12):6713. https://doi.org/10.3390/ijms23126713
Du Y, Li Y, Zhao X, Yao Y, Wang B, Zhang L, et al. Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity. Chin Med J. 2023;136(24):2983-92. https://doi.org/10.1097/cm9.0000000000002647
de Vos CMH, Mason NL, Kuypers KPC. Psychedelics and neuroplasticity: a systematic review unraveling the biological underpinnings of psychedelics. Front Psychiatry. 2021;12:724606. https://doi.org/10.3389/fpsyt.2021.724606
Daws RE, Timmermann C, Giribaldi B, Sexton JD, Wall MB, Erritzoe D, et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med. 2022;28(4):844-51. https://doi.org/10.1038/s41591-022-01744-z
Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep. 2017;7(1):13187. https://doi.org/10.1038/s41598-017-13282-7
Gattuso JJ, Perkins D, Ruffell S, Lawrence AJ, Hoyer D, Jacobson LH, et al. Default mode network modulation by psychedelics: a systematic review. Int J Neuropsychopharmacol. 2023;26(3):155-88. https://doi.org/10.1093/ijnp/pyac074
Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA. 2012;109(6):2138-43. https://doi.org/10.1073/pnas.1119598109
Silbersweig DA, Rauch SL. Neuroimaging in psychiatry: a quarter century of progress. Harv Rev Psychiatry. 2017;25(5):195-7. https://doi.org/10.1097/hrp.0000000000000177
England C, Jarrom D, Washington J, Hasler E, Batten L, Edwards A, et al. Methodological approaches to measuring mental health in a cost-of-living crisis: a rapid review. Health Policy. 2024;144:105062. https://doi.org/10.1016/j.healthpol.2024.105062
Nutt D. Illegal drugs laws: clearing a 50-year-old obstacle to research. PLOS Biol. 2015;13(1):e1002047. https://doi.org/10.1371/journal.pbio.1002047
Pepler EF, Barber CG. Mental health and policing: picking up the pieces in a broken system. Healthc Manage Forum. 2021;34(2):93-9. https://doi.org/10.1177/0840470420979635
Peill J, Marguilho M, Erritzoe D, Barba T, Greenway KT, Rosas F, et al. Psychedelics and the 'inner healer': Myth or mechanism? J Psychopharmacol. 2024;38(5):417-24. https://doi.org/10.1177/02698811241239206
Yaden DB, Earp D, Graziosi M, Friedman-Wheeler D, Luoma JB, Johnson MW. Psychedelics and psychotherapy: cognitive-behavioral approaches as default. Front Psychol. 2022;13:873279. https://doi.org/10.3389/fpsyg.2022.873279
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. https://doi.org/10.3389/fphar.2017.00974
Dawood Hristova JJ, Pérez-Jover V. Psychotherapy with psilocybin for depression: systematic review. Behav Sci. 2023;13(4):297. https://doi.org/10.3390/bs13040297
Kessing LV. Depression and the risk for dementia. Curr Opin Psychiatry. 2012;25(6):457-61. https://doi.org/10.1097/yco.0b013e328356c368
Rubin R. Exploring the relationship between depression and dementia. JAMA. 2018;320(10):961-2. https://doi.org/10.1001/jama.2018.11154

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