Psilocybin’s Therapeutic Pathway

Targeting 5-HT2A Receptor: A Case Study

Pam Conboy and Leah Linder, ND

Background

Psilocybin has been used as a ceremonial sacrament for thousands of years. It may offer, along with holistic and community support, a safe, nonpharmaceutical approach to optimizing mental functions. A case study detailing psilocybin as a novel mental health intervention under the protection of the Religious Freedom Restoration Act is the focus of this article.

Psilocybin is a 5H-HT_2A serotonin receptor agonist that also influences both dopamine and glutamate levels. 5H-HT_2A receptors are primarily located in the brain¹ but are also present in the central and peripheral nervous systems.² They are responsible for mediating emotion, mood, and other neuropsychiatric processes.³ Psilocybin has been shown to disintegrate associative brain networks and their integration with sensory functions, as well as to enhance cortical activation, thereby producing a high-entropy state.⁴ Hypothalamic-pituitary-adrenal axis signaling modulation, endocrine function regulation,⁵ and anti-neuroinflammatory activity (eg, microglial and astrocyte modulation)⁶ can also be counted among its functional attributes.

One of the more compelling actions of psilocybin, however, is its ability to enhance neuropsychological plasticity.⁷ Although healthy individuals experience variable synaptic plasticity throughout the lifecycle, dysfunctional plasticity is associated with a variety of neuropsychiatric disorders.⁸ It is hypothesized that the plasticity-associated perceptual shifts and novel emotional processing produced by psilocybin and its active metabolite, psilocin, are the basis for therapeutic efficacy in cases including anxiety, traumatic stress, depression, and addiction.^9,10

Despite its compelling therapeutic promise and strong safety profile,¹¹ a negative stigma developed around psilocybin due to its association with 1960’s counterculture. This led to the US government’s 1970 designation of psilocybin as a Schedule 1 drug, effectively refuting both its clinical benefit and erroneously suggesting a propensity for addiction.¹² The United Nations’ Convention on Psychotropic Substances soon followed with its own international ban on psychedelics (1971).¹³ These actions effectively stymied psychedelic research and significantly delayed a deeper understanding of psilocybin’s therapeutic value.¹⁴

The therapeutic promise of psilocybin, however, could not be ignored indefinitely. In 2004, UCLA researchers initiated clinical trials utilizing psilocybin in the treatment of existential anxiety and depression among advanced-stage cancer patients.¹⁵ In 2006, Johns Hopkins and a team led by Roland Griffiths published a paper that concluded “when administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences.”¹⁶ The ensuing interest led to the formation of the Center for Psychedelic and Conscious Research, which has since published over 200 related papers making psilocybin the most extensively studied psychedelic.¹⁷ Although an analysis of specific mental health findings with psilocybin is beyond the scope of this article, the body of work available is significant enough to drive an upswell in interest from researchers, practitioners, and lay persons alike. To date, only Oregon and Colorado have decriminalized psilocybin use, with many other states and municipalities considering similar legislation.¹⁸ Use exemptions do exist, however, for both medical research and the sincere use of entheogenic substances as a sacrament under the Religious Freedom Restoration Act (RFRA) of 1993.¹⁹ A case study using psilocybin as a mental health intervention, under RFRA protection, follows.

The Case*

*The patient provided informed consent for the publication of her intervention report, acknowledging that all identifying information would be kept confidential and that the report would be used solely for educational and research purposes.

SF is a 50-year-old woman, counseled about the therapeutic use of psilocybin by her neurologist, who has participated in related research. Her very complex medical history included avascular necrosis of the hips, dyshidrotic eczema, L4-L5 disc rupture and collapse with sciatica, exocrine pancreatic insufficiency, eosinophilic esophagitis, mast cell activation syndrome, epilepsy, and more, most accompanied by medications. However, her primary reason for exploring the use of this psychedelic was to address her PTSD, bipolar II, and persistent depressive disorder diagnoses in a more holistic manner.

Prior History: Psychoactive Interventions

SF had been on multiple medications for depression, PTSD, and bipolar disorder since she was 13 years old. She describes this period as a deep darkness in thought and emotion. Although her recollection of specific psychoactive medications is vague, her experience with conventional psychiatric care is outlined here for reference.

In 2004, at the age of 30, SF began seeing a new psychiatrist, who prescribed several medications to stabilize her mood. Despite initial interventions, her symptoms persisted, and the psychiatrist responded by increasing the dose and adding new psychoactive agents. By 2006, she was on 14 psychiatric medications, which led to an overdose and hospitalization for medical detox. This experience left her mentally and emotionally shaken, making her extremely hesitant to continue on a pharmaceutical pathway to help manage her symptoms. Following hospitalization for the overdose, SF discontinued all mood-stabilizing medications, until 2008 when she resumed bupropion 100 mg BID, fluoxetine 20 mg BID, and clonazepam 1 mg PRN following breast implant surgery. She remained on that regimen for 2.5 years before again tapering off under medical supervision. In 2016, in response to unmanageable symptoms, she returned to medications, taking bupropion 100 mg BID, fluoxetine 20 mg BID, and alprazolam 0.5 mg PRN for another 2.5 years. At that time, her breast implants were removed following a diagnosis of breast implant illness. Since her most recent psychoactive medication tapering (2019), she has attempted to manage her psychiatric diagnoses with natural therapies such as sunlight, grounding, breath work, music, and diet with the addition of CBD, as needed. Although these modalities were beneficial, the depression persisted, leading her once again to bupropion 100 mg BID, fluoxetine 20 mg BID, and alprazolam 0.5 mg PRN. However, before filling these prescriptions, SF opted to pursue the psilocybin option.

The Psilocybin Option

After a detailed medical intake and consultation with an RFRA-protected, nonprofit religious organization,²⁰ SF chose to explore a macrodose psilocybin experience in a spiritual, ceremonial retreat. Her experience included meditative and movement practices along with a 5 gram dose of organically grown, third-party tested, psilocybin-containing mushrooms served in powder form dissolved within a lemon tea.

The psychedelic experience lasted approximately 4 hours, after which SF reported deep spiritual insights and self-reflective revelations about her relationship with herself and others. Although the ceremonial journey left a deeply positive impression, the more compelling feature of her experience has been the enduring changes in behavior and attitude, which she continues to integrate into her daily life.

Prior to the macrodose ceremony and 2 months afterward, SF completed the Hamilton Depression Rating Scale (HAM-D) and the Generalized Anxiety Disorder Scale (GAD-7). Despite the scores noted on Table 1, SF verbally reported that her depressive symptoms had completely resolved.

Table 1. SF’s HAM-D and GAD-7 Scores Pre- and Post-Psilocybin

Scale	Pre-Psilocybin Score and Classification	2-Months’ Post-Psilocybin Score and Classification
HAM-D	42 Very Severe Depression (≥23)	10 Mild Depression (8-13)
GAD-7	21 Severe Anxiety (15-21)	2 Minimal Anxiety (0-4)

A month after her macrodose ceremony, SF was able to safely and successfully wean off most of her prescribed medications under medical supervision. She continues to utilize proprietary supplements sourced from the same religious organization including 200 mg of whole mushroom psilocybin on a pulsing schedule (Table 2). [The pulsing protocol was developed by Setas Seminary cofounder, and coauthor of this article, Dr. Linder, based on her patients’ experience with other existing schedules and protocols.²⁰] She also takes a daily blend of organic Ganoderma lucidum (150 mg), organic Hericium erinaceus (175 mg), organic Tilia europaea (100 mg), organic Withania somnifera (100 mg), and L-theanine (75 mg). Moreover, SF has increased her physical activity and adopted several lifestyle practices, including meditation, breath work, and sound healing, to support and maintain her mental health goals.

Day 1   Psilocybin & Supplement	Day 2   Supplement Only	Day 3   Psilocybin & Supplement	Day 4   Psilocybin & Supplement	Day 5   Supplement Only	Day 6   Supplement Only	Day 7   Psilocybin & Supplement
Day 8   Psilocybin & Supplement	Day 9   Psilocybin & Supplement	Day 10   Supplement Only	Day 11   Supplement Only	Day 12   Supplement Only	Day 13   Supplement Only	Day 14  Supplement Only
Day 15   Supplement Only	Day 16   Supplement Only	Day 17   Supplement Only	Day 18   Supplement Only	Day 19   Supplement Only	Day 20   Psilocybin & Supplement	Day 21   Supplement Only
Day 22   Psilocybin & Supplement	Day 23   Psilocybin & Supplement	Day 24   Supplement Only	Day 25   Supplement Only	Day 26   Psilocybin & Supplement	Day 27   Psilocybin & Supplement	Day 28   Psilocybin& Supplement

Conclusion

Psilocybin, along with supportive holistic lifestyle practices and community support has the potential to offer a nonpharmaceutical approach to optimize mental function, mood, and effective relationship management. Until psilocybin becomes more broadly available through the traditional medical model, RFRA guided use under the care of medically and psychedelic-trained individuals within a holistic framework may offer a safe and effective modality with profound beneficial shifts for individuals seeking naturopathic and holistic approaches to mental health challenges.

References

1. Beliveau V, Ganz M, Feng L, et al. A high-resolution in vivo atlas of the human brain’s serotonin system. J Neurosci. 2017;37:120-128. doi: 10.1523/JNEUROSCI.2830-16.2016
2. Hoyer D, Clarke DE, Fozard JR, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev. 1994;46:157-203.
3. Nichols DE, Nichols CD. Serotonin receptors. Chem Rev. 2008;108:1614-1641. doi: 10.1021/cr078224o
4. Nichols DE Psilocybin: from ancient magic to modern medicine. J Antibiot. 2020;73:679-686. doi: 10.1038/s41429-020-0311-8
5. Johnson JD, Barnard DF, Kulp AC, et al. Neuroendocrine regulation of brain cytokines after psychological stress. J Endocr Soc. 2019;3:1302-1320. doi:10.1210/js.2019-00053
6. Flanagan TW, Nichols CD. Psychedelics as anti-inflammatory agents. Int Rev Psychiatry. 2018;30:363-375. doi:10.1080/09540261.2018.1481827
7. Carhart-Harris RL, Leech R, Hellyer PJ, et al. The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci. 2014;8:20-22. doi:10.3389/fnhum.2014.00020
8. Appelbaum LG, Shenasa MA, Stolz L, et al. Synaptic plasticity and mental health: methods, challenges,challenges and opportunities. Neuropsychopharmacology. 2023;48:113-120. https://doi.org/10.1038/s41386-022-01370-w
9. Dinis-Oliveira RJ. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Drug Metab Rev. 2017;49:84-91.
10. López-Giménez JF, González-Maeso J. Hallucinogens and serotonin 5-HT_2A receptor-mediated signaling pathways. Curr Topics Behav Neurosci. 2018;36:45-73.
11. Hendricks PS, Johnson MW, Griffiths RR. Psilocybin, psychological distress, and suicidality. J Psychopharmacol. 2015;29:1041-1043. doi: 10.1177/0269881115598338
12. United States Drug Enforcement Administration. Drug scheduling. https://www.dea.gov/drug-information/drug-scheduling. Accessed September 12, 2024.
13. George DR, Hanson R, Wilkinson D, et al. Ancient roots of today’s emerging renaissance in psychedelic medicine. Cult Med Psychiatry. 2022;46(4):890-903. doi: 10.1007/s11013-021-09749-y
14. Lowe H, Toyang N, Steele B, et al. The therapeutic potential of psilocybin. Molecules. 2021;26(10):2948. doi: 10.3390/molecules26102948

15. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71-78. doi: 10.1001/archgenpsychiatry.2010.116
16. Griffiths RR, Richards WA, McCann U, et al. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006;187:268-283. doi: 10.1007/s00213-006-0457-5
17. Johns Hopkins Center for Psychedelic & Consciousness Research. Academic publications. https://hopkinspsychedelic.org/publications. Accessed September 12, 2024.
18. Psychedelic Alpha. Psychedelic legalization & decriminalization tracker. Mapping psychedelic drug policy reform in the United States. https://psychedelicalpha.com/data/psychedelic-laws. Accessed September 12, 2024.
19. Congress.Gov. H.R. 1308—Religious Freedom Restoration Act of 1993. https://www.congress.gov/bill/103rd-congress/house-bill/1308. Accessed September 12, 2024.
20. Setas Seminary Church of Spiritual Integration. Reno, Nevada. setasseminary.org