Linking it all together

Every year in the United States over 795,000 people have a stroke. Stroke is a leading cause of serious long-term disability and reduces mobility in more than half of stroke survivors age 65 and older.1 Stroke-related deficits typically result from damage to the brain, such as neuronal cell death, loss of connectivity, and neuroinflammation.2

Current stroke treatments, such as administration of tissue plasminogen activator (tPA), to more intensive thrombolysis and mechanical thrombectomy, are focused on restoring blood flow to the affected area of the brain, reducing the damage caused by the stroke, and preventing future strokes.3 Often, patients are provided anti-platelet medications, or aspirin following strokes to reduce likelihood of another stroke.4 Outside of pharmacological remedies, functional recovery due to post-stroke plasticity is currently most effectively recruited through intensive physical/cognitive therapy.5 For example, stroke patients typically will be offered speech, occupational, and physical therapy for their recovery. 

However, these treatments do not address the underlying causes of stroke or promote brain repair – therefore there is a need for additional treatment modalities that can promote recovery and improve outcomes.

There may be new therapeutic potential to meet a dire need for enhanced post-recovery options for stroke patients. Microdosing psilocybin mushrooms has been shown to have potential in enhancing neuroplasticity, neurogenesis, and reducing neuroinflammation, which may aid in the recovery from stroke. 6, 7, 8  Furthermore, the addition of hericenones (lion’s mane), and niacin (Vitamin B3), can provide increased efficacy in neuroplasticity properties.9

The stroke recovery landscape consists of several distinct and important stages ranging from acute phase, early recovery, subacute recovery, late recovery, and chronic phase (see Appendix 4). Late recovery and chronic phase are of special interest to develop a new intervention that can reignite the “critical period” of recovery and better actualize the highest possible outcome.17 The focus on these stages allows the dust to settle from the stroke trauma, stabilization to take root. There may be reasonable arguments for intervention to take place as early as possible, yet it will be prudent to first identify if any benefit can be attained whatsoever from these substances. 

Neuroplasticity and neurogenesis are important processes for brain repair and recovery after stroke. Neuroplasticity refers to the ability of the brain to reorganize new neural connections (think “neurons that fire together, wire together”), while neurogenesis refers to the generation of new neurons. These processes are crucial for the recovery of neurological function after stroke, as they can help compensate for the loss of neurons and neural connections in the affected area of the brain.21

Recent studies have shown that microdosing psilocybin mushrooms can enhance neuroplasticity and neurogenesis. 11,20 Microdosing psilocybin can increase creative thinking, empathy, and subjective well-being.12 These findings suggest that psilocybin may enhance neuroplasticity by promoting the growth of new neural connections and facilitating the reorganization of existing ones. Furthermore, a studies have found that psilocybin can increase the expression of brain-derived neurotrophic factor (BDNF), a protein that plays a crucial role in promoting neuroplasticity and neurogenesis. 13, 23

Neuroinflammation is a common feature of stroke and is associated with neuronal damage and death.2 Inflammation occurs as a response to injury, and it can lead to the release of reactive oxygen species and pro-inflammatory cytokines, which can cause further damage to the brain. Therefore, reducing neuroinflammation is an important therapeutic target for stroke.10

Recent studies have shown that psilocybin mushrooms have anti-inflammatory properties.14 Recent studies found that psilocybin can reduce the production of pro-inflammatory cytokines in vitro. 15 Furthermore, a study by Galvão-Coelho found that psilocybin induced neuroinflammation reduction led to enhanced recovery in mood disorders. 16  These findings suggest that psilocybin may have therapeutic potential in reducing neuroinflammation after stroke.

Microdosing (the process of taking a sub-perceptive quantity of a psychedelic) psilocybin, a psychoactive compound found in certain mushrooms (psilocybe cubensis), has been suggested to have therapeutic potential for a variety of medical conditions, including depression, anxiety, and addiction.18, 24, 25 Furthermore, there is indication that lower doses lead to increased neurogenesis.22 There is limited but growing research on the effects of microdosing psilocybin on stroke recovery. 

While psilocybin alone has demonstrated these potential neurological benefits, there’s an additional opportunity to further enhance these properties and deliver a superior therapeutic effect. Paul Edward Stamets’ 2018 patent outlines an innovative delivery combination that could build closer to the investigative effects.

A composition including psilocybin containing mushrooms combined with hericenones, and niacin (vitamin B3 ), colloquially known as the “Stamets Stack,” uniquely aids in repairing and improving neurologic functioning and signaling. (Schartner et al.(2017) reported substantial increased global neural signal diversity in a psilocybin - human clinical study. 11 Additionally, niacin is known to be a neural anti-inflammatory, and, in itself, has been implicated in improving neural functioning. As niacin activates nerve endings, the addition of niacin contributes an added benefit by enhancing the neurogenic effects of psilocybin and hericenones by helping these nootropics cross the blood brain barrier, and migrate throughout the nervous systems, and to its end points.9,19

Moreover, niacin is a vasodilator improving blood flow in the brain by relaxing constricted blood vessels.19 This unique combination not only rebuilds myelin upon the axons, it also activates new astrocyte/astroglial cells and neuronal nodes of crossings such as the synaptic regions, particularly in the hippocampus. 9

References

1. Centers for Disease Control and Prevention. (n.d.). Stroke facts. https://www.cdc.gov/stroke/facts.htm(CDC Stroke Demographics)

2. Sekerdag, E., Solaroglu, I., & Gursoy-Ozdemir, Y. (2018). Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options. Current neuropharmacology, 16(9), 1396–1415. https://doi.org/10.2174/1570159X16666180302115544 

1. Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options - PMC (Outcomes of stroke neural impact)

3. Gravanis, I., & Tsirka, S. E. (2008). Tissue-type plasminogen activator as a therapeutic target in stroke. Expert opinion on therapeutic targets, 12(2), 159–170. https://doi.org/10.1517/14728222.12.2.159

1. tPA as a therapeutic target in stroke - PMC (tPA & thrombolysis)

4. Rothlisberger, J. M., & Ovbiagele, B. (2015). Antiplatelet therapies for secondary stroke prevention: an update on clinical and cost-effectiveness. Journal of comparative effectiveness research, 4(4), 377–384. https://doi.org/10.2217/cer.15.22

1. Antiplatelet therapies for secondary stroke prevention: an update on clinical and cost–effectiveness - PMC (Anti-platelet for stroke recurrence)

5. Szelenberger, R., Kostka, J., Saluk-Bijak, J., & Miller, E. (2020). Pharmacological Interventions and Rehabilitation Approach for Enhancing Brain Self-repair and Stroke Recovery. Current neuropharmacology, 18(1), 51–64. https://doi.org/10.2174/1570159X17666190726104139

1. Pharmacological Interventions and Rehabilitation Approach for Enhancing Brain Self-repair and Stroke Recovery - PMC (Therapies for stroke recovery)

6. Schartner, M., Carhart-Harris, R., Barrett, A. et al. Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Sci Rep 7, 46421 (2017). https://doi.org/10.1038/srep46421

1. Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin | Scientific Reports

7. Nkadimeng, S. M., Steinmann, C. M. L., & Eloff, J. N. (2021). 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. Journal of inflammation research, 14, 3729–3738. https://doi.org/10.2147/JIR.S317182

1. 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 - PMC

8. Petri G., Expert P., Turkheimer F., Carhart-Harris R., Nutt D., Hellyer P. J. and Vaccarino F.. 2014 Homological scaffolds of brain functional networks. J.R. Soc. Interface. 11: 20140873. 20140873. http://doi.org/10/1098/rsif.20140873

1. Homological scaffolds of brain functional networks | Journal of The Royal Society Interface

9. Staments Stack Patent (US20180021326A1). (n.d.). Retrieved from https://patents.google.com/patent/US20180021326A1/en

10. Lowe, H., Toyang, N., Steele, B., Valentine, H., Grant, J., Ali, A., Ngwa, W., & Gordon, L. (2021). The Therapeutic Potential of Psilocybin. Molecules (Basel, Switzerland), 26(10), 2948. https://doi.org/10.3390/molecules26102948

1. The Therapeutic Potential of Psilocybin - PMC ( Therapeutic Potential of psilocybin)

11. Schartner, M., Carhart-Harris, R., Barrett, A. et al. Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Sci Rep 7, 46421 (2017). https://doi.org/10.1038/srep46421

1. Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin | Scientific Reports (neuroplasticity)

12. Calder, A.E., Hasler, G. Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacol. 48, 104–112 (2023). https://doi.org/10.1038/s41386-022-01389-z

1. Towards an understanding of psychedelic-induced neuroplasticity | Neuropsychopharmacology (neuroplasticity)

13. Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., & 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

1. Psychedelics Promote Structural and Functional Neural Plasticity - PMC (neuroplasticity & BNDF)

14. Szabo A. (2015). Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities. Frontiers in immunology, 6, 358. https://doi.org/10.3389/fimmu.2015.00358

1. Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities - PMC (inflammation)

15. Nkadimeng, S. M., Steinmann, C. M. L., & Eloff, J. N. (2021). 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. Journal of inflammation research, 14, 3729–3738. https://doi.org/10.2147/JIR.S317182

1. 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 - PMC (inflammation)

16. Richardson, B., MacPherson, A., & Bambico, F. (2022). Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments. Brain, behavior, & immunity - health, 26, 100554. https://doi.org/10.1016/j.bbih.2022.100554

1. Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments - PMC (inflammation & mood disorder)

17. Lindvall, O., & Kokaia, Z. (2015). Neurogenesis following Stroke Affecting the Adult Brain. Cold Spring Harbor perspectives in biology, 7(11), a019034. https://doi.org/10.1101/cshperspect.a019034

1. Neurogenesis following Stroke Affecting the Adult Brain - PMC (Neurogenis following stroke)

18. Prochazkova, L., Lippelt, D.P., Colzato, L.S. et al. Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting. Psychopharmacology 235, 3401–3413 (2018). https://doi.org/10.1007/s00213-018-5049-7

1. Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting | SpringerLink (microdosing)

19. Gasperi, V., Sibilano, M., Savini, I., & Catani, M. V. (2019). Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications. International journal of molecular sciences, 20(4), 974. https://doi.org/10.3390/ijms20040974

1. Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications (niacin)

20. Shao, L.-X., Liao, C., Gregg, I., Davoudian, P. A., Savalia, N. K., Delagarza, K., & Kwan, A. C. (2021). Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron, 109(16), 2535-2544.e4. https://doi.org/10.1016/j.neuron.2021.06.008

1. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. neuroplasticity

21. Otero-Ortega, L., Gutiérrez-Fernández, M., & Díez-Tejedor, E. (2021). Recovery After Stroke: New Insight to Promote Brain Plasticity. Frontiers in neurology, 12, 768958. https://doi.org/10.3389/fneur.2021.768958

1. Recovery After Stroke: New Insight to Promote Brain Plasticity - PMC (stroke recovery)

22. Khan, S. M., Carter, G. T., Aggarwal, S. K., & Holland, J. (2021). Psychedelics for Brain Injury: A Mini-Review. Frontiers in neurology, 12, 685085. https://doi.org/10.3389/fneur.2021.685085

1. Psychedelics for Brain Injury: A Mini-Review - PMC

23. de Vos Cato M. H., Mason Natasha L., Kuypers Kim P. C. Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Frontiers in Psychiatry Vol. 12, 2021 https://www.frontiersin.org/articles/10.3389/fpsyt.2021.724606

24. Cameron, L. P., Nazarian, A., & Olson, D. E. (2020). Psychedelic Microdosing: Prevalence and Subjective Effects. Journal of psychoactive drugs, 52(2), 113–122. https://doi.org/10.1080/02791072.2020.1718250

1. Psychedelic Microdosing: Prevalence and Subjective Effects - PMC

25. Kuypers K. P. C. (2020). The therapeutic potential of microdosing psychedelics in depression. Therapeutic advances in psychopharmacology, 10, 2045125320950567. https://doi.org/10.1177/2045125320950567

1. The therapeutic potential of microdosing psychedelics in depression - PMC