HORMONAL MODULATION OF PSILOCYBIN RESPONSIVITY ACROSS THE FEMALE REPRODUCTIVE LIFESPAN

Katarzyna Pawłucka; Aleksandra Pawłucka; Joanna Kadłuczka; Makary Hejduk; Magdalena Grzymek; Justyna Bury; Katarzyna Kraska; Jan Potoniec; Weronika Kępa; Aneta Sobek; Martyna Więcławek

doi:10.31435/ijitss.3(51).2026.6195

Authors

Katarzyna Pawłucka Jagiellonian University Medical College, Krakow, Poland https://orcid.org/0009-0001-4273-6599
Aleksandra Pawłucka St. John Grande Hospital of the Brothers Hospitallers of Saint John of God, Kraków, Poland https://orcid.org/0009-0005-6765-9314
Joanna Kadłuczka Ludwik Rydygier Specialist Hospital in Cracow, Kraków, Poland https://orcid.org/0009-0002-9347-0767
Makary Hejduk Independent Public Health Care Facility in Myślenice, Poland https://orcid.org/0009-0004-7579-4471
Magdalena Grzymek The University Hospital in Krakow, Kraków, Poland https://orcid.org/0009-0000-4337-0261
Justyna Bury Medical University of Silesia in Katowice, Poland https://orcid.org/0009-0001-4778-2375
Katarzyna Kraska Medical Center in Łańcut Sp. z o.o., Łańcut, Poland https://orcid.org/0009-0004-0464-6826
Jan Potoniec Gabriel Narutowicz Municipal Specialist Hospital in Krakow, Krakow, Poland https://orcid.org/0009-0000-5282-7833
Weronika Kępa Independent Researcher, Poland https://orcid.org/0009-0000-8378-9681
Aneta Sobek Medical Center in Łańcut Sp. z o.o., Łańcut, Poland https://orcid.org/0009-0002-6759-5419
Martyna Więcławek The University Hospital in Krakow, Kraków, Poland https://orcid.org/0009-0006-7956-9962

DOI:

https://doi.org/10.31435/ijitss.3(51).2026.6195

Keywords:

Psilocybin, Estrogen, Testosterone, Menstrual Cycle, Menopause, PMDD

Abstract

Objectives: This narrative review synthesizes current evidence regarding the modulation of psilocybin responsivity by female sex hormones (estrogen, progesterone, testosterone) across the lifespan, aiming to identify molecular mechanisms, clinical implications, and critical knowledge gaps for personalized psychedelic medicine.

Methods: Databases including PubMed, ClinicalTrials.gov, and ANZCTR were searched for literature published between 2000 and 2026. Search strategies utilized combinations of terms related to psilocybin, sex hormones, the menstrual cycle, pregnancy, menopause, and premenstrual dysphoric disorder (PMDD). Peer-reviewed studies, clinical protocols, and preclinical models were evaluated.

Main Findings: Molecular data from human PET and preclinical studies suggest that estradiol may upregulate cortical 5-HT2A receptor availability, while testosterone appears to modulate serotonin transporter (SERT) expression. These pathways potentially overlap with psilocin's pharmacodynamics. Preclinical evidence from a 2025 postpartum mouse model signals a critical warning, suggesting that postpartum psilocybin administration may paradoxically amplify anxiety-like behaviors and induce long-term anhedonia in offspring. Clinically, preliminary qualitative data suggest potential microdosing efficacy in PMDD, though rigorous randomized controlled trials are needed to confirm these findings. Major data gaps persist regarding the impact of menopause and combination oral contraceptives on psychedelic experiences.

Conclusions: Mechanistic and preclinical evidence suggests that the female hormonal landscape may influence psilocybin responsivity. However, the current lack of stratified human clinical data precludes definitive dosing or timing recommendations. Integrating hormonal tracking into future psychedelic trial designs is imperative for establishing safe, personalized therapeutic frameworks.

References

Kessler, R. C., & Bromet, E. J. (2013). The epidemiology of depression across cultures. Annual Review of Public Health, 34, 119–136. https://doi.org/10.1146/annurev-publhealth-031912-114409

Cohen, Z. Z., & Blest-Hopley, G. (2025). Females in psychedelic research: A perspective for advancing research and practice. ACS Pharmacology & Translational Science, 8(8), 1837–1846. https://doi.org/10.1021/acsptsci.5c00255

GBD 2019 Diseases and Injuries Collaborators. (2020). Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. The Lancet, 396(10258), 1204–1222. https://doi.org/10.1016/S0140-6736(20)30925-9

Albert, P. R. (2015). Why is depression more prevalent in women? Journal of Psychiatry & Neuroscience, 40(4), 219–221. https://doi.org/10.1503/jpn.150205

Lim, G. Y., Tam, W. W., Lu, Y., Ho, C. S., Zhang, M. W., & Ho, R. C. (2018). Prevalence of depression in the community from 30 countries between 1994 and 2014. Scientific Reports, 8, 2861. https://doi.org/10.1038/s41598-018-21243-x

Barth, C., Villringer, A., & Sacher, J. (2015). Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Frontiers in Neuroscience, 9, 37. https://doi.org/10.3389/fnins.2015.00037

Becker, J. B., McClellan, M. L., & Reed, B. G. (2017). Sex differences, gender and addiction. Journal of Neuroscience Research, 95(1–2), 136–147. https://doi.org/10.1002/jnr.23963

Anker, J. J., & Carroll, M. E. (2010). Sex differences in the effects of allopregnanolone on yohimbine-induced reinstatement of cocaine seeking in rats. Psychopharmacology, 210(1), 63–72. https://doi.org/10.1016/j.drugalcdep.2009.11.002

Calipari, E. S., Juarez, B., Morel, C., Walker, D. M., Cahill, M. E., Ribeiro, E., & Nestler, E. J. (2017). Dopaminergic dynamics underlying sex-specific cocaine reward. Nature Communications, 8, 13877. https://doi.org/10.1038/ncomms13877

Passie, T., Seifert, J., Schneider, U., & Emrich, H. M. (2006). The pharmacology of psilocybin. Addiction Biology, 7(4), 357–364. https://doi.org/10.1080/1355621021000005937

Carhart-Harris, R. L., & Goodwin, G. M. (2017). The therapeutic potential of psychedelic substances. Neuropsychopharmacology, 42(1), 2105–2114. https://doi.org/10.1038/npp.2017.84

Carhart-Harris, R. L., Giribaldi, B., Erritzoe, D., Forsythe, G., Wall, M. B., Beliveau, V., & Nutt, D. J. (2016). Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. The Lancet Psychiatry, 3(7), 619–627. https://doi.org/10.1016/S2215-0366(16)30065-7

Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021). Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry, 78(5), 481–489. https://doi.org/10.1001/jamapsychiatry.2020.3285

Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barriga, E. V., Wilson, L. I., & Olson, D. E. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170–3182. https://doi.org/10.1016/j.celrep.2018.05.022

Kugaya, A., Epperson, C. N., Zoghbi, S., van Dyck, C. H., Hou, Y., Fujita, M., & Innis, R. B. (2003). Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women. American Journal of Psychiatry, 160(8), 1522–1524. https://doi.org/10.1176/appi.ajp.160.8.1522

Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264–355. https://doi.org/10.1124/pr.115.011478

Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., & Nutt, D. J. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences, 109(6), 2138–2143. https://doi.org/10.1073/pnas.1119598109

Shao, L. X., Liao, C., Dietz, I., Gooden, K. C., Khan, I., Greb, A. C., & Olson, D. E. (2021). Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron, 109(16), 2535–2544. https://doi.org/10.1016/j.neuron.2021.06.008

Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 71(3), 316–344. https://doi.org/10.1124/pr.118.017160

Vollenweider, F. X., & Kometer, M. (2010). The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11(9), 642–651. https://doi.org/10.1038/nrn2884

Kranz, G. S., Wadsak, W., Kaufmann, U., Savli, M., Baldinger, P., Gryglewski, G., & Lanzenberger, R. (2015). High-dose testosterone treatment increases serotonin transporter binding in transgender individuals: A longitudinal PET study. Biological Psychiatry, 78(8), 525–533. https://doi.org/10.1016/j.biopsych.2014.09.010

Fink, G., Sumner, B. E., Rosie, R., Grace, O., & Quinn, J. P. (1996). Estrogen control of central neurotransmission: Effect on mood, mental state, and memory. Cellular and Molecular Neurobiology, 16(3), 325–344. https://doi.org/10.1007/BF02088099

Schmidt, P. J., Nieman, L. K., Danaceau, M. A., Adams, L. F., & Rubinow, D. R. (1998). Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. New England Journal of Medicine, 338(4), 209–216. https://doi.org/10.1056/NEJM199801223380401

Taylor, C. M., Pritschet, L., Yu, S., & Jacobs, E. G. (2020). Progesterone shapes medial temporal lobe volume and functional connectivity across the human menstrual cycle. NeuroImage, 220, 117125. https://doi.org/10.1016/j.neuroimage.2020.117125

Sumner, B. E., & Fink, G. (1995). Estrogen increases the density of 5-HT2A receptors in cerebral cortex and nucleus accumbens in the female rat. Journal of Steroid Biochemistry and Molecular Biology, 54(1–2), 15–20. https://doi.org/10.1016/0960-0760(95)00075-B

Biegon, A., Reches, A., Snyder, L., & McEwen, B. S. (1983). Serotonin and estrogen interaction in the rat brain. Life Sciences, 33(8), 789–795. https://doi.org/10.1016/0024-3205(83)90053-X

Cyr, M., Landry, M., & Di Paolo, T. (2000). Modulation by estrogen-receptor agonists of 5-HT2A receptors in rat brain. Neuropsychopharmacology, 22(5), 513–520. https://doi.org/10.1016/S0893-133X(00)00085-3

Rybaczyk, L. A., Bashaw, M. J., Pathak, D. R., Moody, S. M., Gilders, R. M., & Holzschu, D. L. (2005). An overlooked connection: Serotonergic mediation of estrogen-related physiology and pathology. BMC Women’s Health, 5, 12. https://doi.org/10.1186/1472-6874-5-12

Prossnitz, E. R., Arterburn, J. B., Smith, H. O., Oprea, T. I., Sklar, L. A., & Hathaway, H. J. (2008). Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annual Review of Physiology, 70, 165–190. https://doi.org/10.1146/annurev.physiol.70.113006.100518

Ettrup, A., da Cunha-Bang, S., McMahon, B., Lehel, S., Dyssegaard, A., Skibsted, A. W., Jørgensen, L. M., Hansen, M., Baandrup, A. O., Bache, S., Svarer, C., Kristensen, J. L., Gillings, N., Madsen, J., & Knudsen, G. M. (2014). Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. Journal of Cerebral Blood Flow & Metabolism, 34(7), 1188–1196. https://doi.org/10.1038/jcbfm.2014.68

Halbreich, U., Borenstein, J., Pearlstein, T., & Kahn, L. S. (2003). The prevalence, impairment, impact, and burden of premenstrual dysphoric disorder (PMS/PMDD). Psychoneuroendocrinology, 28(Suppl. 3), 1–23. https://doi.org/10.1016/S0306-4530(03)00098-2

Sacher, J., Neumann, J., Okon-Singer, H., Gotowiec, S., & Villringer, A. (2013). Sexual dimorphism in the human brain: Evidence from neuroimaging. Magnetic Resonance Imaging, 31(3), 366–375. https://doi.org/10.1016/j.mri.2012.06.007

Hatzipantelis, C. J., Liu, M., Love, A., Leventhal, S. J., Maera, H., Viswanathan, S., Avetisyan, E., Belinsky, L., Rangel, M. M., Jain, N. J., Kelly, M., Copeland, C., Khatib, Y. A., Fiehn, O., Olson, D. E., & Stolzenberg, D. S. (2025). Psilocybin during the postpartum period induces long-lasting adverse effects in both mothers and offspring. Nature Communications, 16(1), 8630. https://doi.org/10.1038/s41467-025-64371-5

Halberstadt, A. L., & Geyer, M. A. (2011). Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology, 61(3), 364–381. https://doi.org/10.1016/j.neuropharm.2011.01.017

Dubey, N., Hoffman, J. F., Schuebel, K., Yuan, Q., Martinez, P. E., Nieman, L. K., Rubinow, D. R., Schmidt, P. J., & Goldman, D. (2017). The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Molecular Psychiatry, 22(8), 1172–1184. https://doi.org/10.1038/mp.2016.229

Hantsoo, L., & Epperson, C. N. (2020). Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle. Neurobiology of Stress, 12, 100213. https://doi.org/10.1016/j.ynstr.2020.100213

Straumann, I., Holze, F., Becker, A. M., Ley, L., Halter, N., & Liechti, M. E. (2024). Safety pharmacology of acute psilocybin administration in healthy participants. Neuroscience Applied, 3, 104060. https://doi.org/10.1016/j.nsa.2024.104060