Structure Activity Relationship between the Emerging Psychedelic Industry and Unmet Medical Needs
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Structure Activity Relationship between the Emerging Psychedelic Industry and Unmet Medical Needs
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Psilocybin mushrooms are at the center of a new psychedelic industry. Once formerly banned or heavily regulated, which limited clinical research into the active compounds' psilocybin and psilocin. However recent research has thrust this botanical and its active compounds are into the limelight and is building the foundation for promising medical therapies, particularly in the mental health space. This resurgence comes at a time being hailed as the “psychedelic renaissance” as an explosion of exemptions are being granted for psychedelic research, and promising studies are being published.1 One study showed psilocybin helped 40 out of 51 patients with life-threatening cancer reduce their depressive and anxiety levels by over 50%, for up to 6 months with just a single dose.2 Another study found similar to LSD, psilocin is a 5-HT2A agonist, which causes epigenetic modifications that promotes the formation of cell growth proteins in mice. This might explain the increased neuronal growth that has been associated with psychedelic drugs.3,4 In order to validate these studies, the precise quantification of the compounds and methods used under the study is required. And the literature has not yet found an agreement on the best method to use. We present an overview of the current literature, and discuss methods we developed to produce robust and reliable results. Furthermore, it is important to track the IP space around psychedelics. Compass Pathways, one of the first public for-profit psychedelic companies, was recently granted a patent for a crystalline form of psilocybin they named Polymorph A.5 A patent grants the right to exclude others from the use of that crystalline form.6,7 Now this patent is being challenged. But what does that mean? And why should people care? Lastly we discuss how companies are attempting to monopolize the use of psilocybin through the patenting process.
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Structure Activity Relationship between the Emerging Psychedelic Industry and Unmet Medical Needs
- 1. Structure Activity Relationship: Emerging Psychedelic Industry and Unmet Medical Needs Dr. Markus Roggen
- 2. Introduction DELIC Labs is a research venture that seeks to add fundamental scientific insight to the field of cannabis and mushroom production. We seek to support the cannabis and mushroom industries by establishing a centralized hub in Vancouver, BC, for collaborative research focused on: • Process Design • Process Optimization • Process Analytics • Formulation Research
- 3. Collaborative Research DELIC Labs collaborates with academic, industry and private groups around the globe. Some highlights of those collaborations are: • University of British Columbia, Vancouver • Loyalist College, Belleville • Via Innovations by Dr. Monica Vialpando • Verdient Science by Dr. Linda Klumpers Fundamental Collaboration
- 4. Outline • Psilocybin Mushrooms and Psychedelic Compounds • Your Brain on Psychedelics • Psychedelic Treatments, Trials and Traps • Psilocybin Testing and a Universe of Molecules • Psilocybin Patents and Crystal Engineering 4
- 5. Magic Mushrooms • A polyphyletic group of >200 psilocybin-containing fungi 5 Psilocybe Mexicana
- 6. Magic Mushrooms and Friends • Tryptamines • 1, 2, 3, 5, 6, 7 • Phenethylamines • 4, 8, 9 • Lysergamides • 10 6
- 7. Magic Mushrooms • A polyphyletic group of >200 psilocybin-containing fungi • Potential therapeutic • Alternative antidepressant • Psychedelic therapy • Undiscovered natural products 7 Neural interconnectivity for a brain functioning normally (a), and following psilocybin treatment (b) (R. L. Carhart-Harris, et. al., Proc. Natl. Acad. Sci., 2012)
- 8. Magic Mushrooms • A polyphyletic group of >200 psilocybin-containing fungi • Potential therapeutic • Alternative antidepressant • Psychedelic therapy • Undiscovered natural products 8 Neural interconnectivity for a brain functioning normally (a), and following psilocybin treatment (b) (R. L. Carhart-Harris, et. al., Proc. Natl. Acad. Sci., 2012)
- 9. Interest in Psychedelics • Everyone is interested in psychedelics • Health Canada is granting a record number of exemptions for psychedelics research • Have you seen the Netflix Show ”How To Change Your Mind”? • “Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.” Shao LX, et al. Neuron. 2021 9 0 20 40 60 80 100 2017 2018 2019 2020 2021 Relative Interest Internet Search Term Trends (Global) Psilocybin Therapy Psilocybin Microdosing https://terpenesandtesting.com/the-dark-side-of-psychedelic- research-and-how-we-can-improve/
- 10. Interest in Psychedelics • “the dose of psilocybin significantly reduced anxiety and depression scores “ - 2011 Grob et. Al; UCLA • “psilocybin, compared to placebo, greatly improved anxiety and depression scores” - Ross et al, 2016; NYU School of Medicine • “significant decreases in anxiety and depression scores” - Griffiths et al, 2016; Johns Hopkins • “the treatment significantly reduced depression scores” - Carhart-Harris et al, 2016 10 0 20 40 60 80 100 2017 2018 2019 2020 2021 Relative Interest Internet Search Term Trends (Global) Psilocybin Therapy Psilocybin Microdosing
- 11. The Dark Side of Psychedelic Research With Attention comes Scrutiny • MDMA clinical trial by MAPS: patient inappropriately touched, blindfolded, and pinned down • Additionally, accusations of sexually assault by one therapist outside of the clinic • Health Canada halted all approved MDMA trials for review! 11 https://www.cbc.ca/news/canada/british-columbia/bc-mdma-therapy- videos-1.6400256 Courtesy of New York Magazine's Cover Story: Power Trip
- 12. The Dark Side of Psychedelic Research Problems with MAPS clinical trials: • Negative experiences were not included as adverse effects • Mishandlings of data representation in publications • Pooling disjointed results from different experiments • Increasing suicidal thoughts developed, but were never listed as adverse events • Effectively no qualification requirements to be a counselor in the MAPS trials 12 https://www.cbc.ca/news/canada/british-columbia/health-canada- mdma-trial-complaints-flaws-safety-issues-1.6409849
- 13. The Dark Side of Psychedelic Research What to improve? • Introduction of trial practices and boundary standards of other medical fields • Including trial preregistration • Rejection the use of “nurturing touch” and approach of “equal footing” • Stop encouraging therapists to experiment with the drug to gain insight • Pick a lane: “natural,” “spiritual,” and “traditional” is not medical research but ‘60 free love 13 Brennan W, Jackson MA, MacLean K, Ponterotto JG. A qualitative exploration of relational ethical challenges and practices in psychedelic healing. Journal of Humanistic Psychology. September 2021.
- 14. The Foundations of Psychedelic Research • Psychedelics won’t burn holes in our brain • They can cause hallucinogen persisting perception disorder • They can increase suicidal thoughts • They are known to change the regulation of brain pathways • For botanical therapies, we have no idea what and how much the patient is taking 14 Trends Pharmacol Sci. 2021;42(11):929-942 Nature. 2015. doi:10.1038/nature.2015.16968
- 15. Analytics To treat a patient, we need to know what we are giving them! • Delic Labs’ approach to metabolomics 15
- 16. 16 • Openly available analytical data not usually verified • Low statistical power and comparison Little Historical Data GCMS of 5-HT, Huestis, 1991 Psilocybin FTIR, SWGDR G 2007 HPLC-UV of 5-MeO-DMT, Jenks, 2014 Malaca S, et.al.. Toxicology and Analysis of Psychoactive Tryptamines. Int J Mol Sci. 2020
- 17. 17 Psilocybin Mushroom Extract RP-HPLC Psilocybin Psilocin Psilocybin y = 126.96x + 296.94 R² = 0.9974 Psilocin y = 87.997x + 241.8 R² = 0.9965 0 20 40 60 80 100 120 Concentration (ppm) Psilocybin Psilocin Psilocybin mushroom extract RP-HPLC (C18, H2O/MeOH) 0.93% RSD 3.1% Acc.
- 19. 19 Molecular Networking Jeramie Watrous, Pieter C. Dorrestein, et al. PNAS 2012
- 20. Psilocybin Mushroom Network 20 Intelligent interfering ion filtration and Database match
- 21. Psilocybin Mushroom Speciation m/z Area Metabolite name 205.13472 1263791 Psilocin 118.08699 1103497 Valine 105.07035 527298 Styrene 122.09708 364078 Phenylethylamine 116.07133 192491 Proline 144.08167 189373 Tryptophanol 175.1194 183314 Arginine 104.1076 164397 Choline 121.06538 155866 Phenylacetaldehyde 133.09773 122698 Ornithine . . .
- 22. Crystal Structure To treat a patient, we need to have the legal right to giving it! • A little primer on patent law and crystal structure 22
- 23. Psilocybin as Medicine and Patent • Psilocybin cannot be patented as a molecule • Therefore, patent on Composition of Matter • Compass Pathways was granted a patent for a crystalline form of psilocybin, Polymorph A. • This patent grants exclusive rights • But does it hold up? Do we care? 23 https://terpenesandtesting.com/crystallizing-the-relationship-between-patents-polymorphs-and-psilocybin/
- 24. Crystal Engineering • Three States of Matter: gas, liquid, or solid. • Solid: molecules scrambled or highly ordered structures (crystals) • Crystals: infinitely repeating patterns • Nature of the repeat pattern matters, “polymorphs” • Over half of all organic molecule crystals have at least two polymorphs • Each polymorph has unique properties 24
- 25. Unique Crystalline Forms of Psilocybin • Psilocybin is hydroscopic, (in this case, a trihydrate) • Hydrate A (below) contains water molecules • Depending on storage conditions psilocybin can gain or lose water molecules • Polymorph A’ unit cell is in the shape of rectangular prisms with 90° • Polymorph B is rhomboid-shaped prisms with roughly a 95° 25 Baertschi SW, Alsante KM, Reed RA. Pharmaceutical Stress Testing; CRC Press: Boca Raton, 2011.
- 26. What about the Compass Pathway Patent • Compass claims discovery of new crystalline form of psilocybin (Polymorph A) • X-ray crystallography shows distinct diffraction peak at 17.5˚ • New, undiscovered structure or • Mixture of 81% Polymorph A’, 19% Polymorph B, and small amounts of Hydrate A. 26 Acta Crystallogr C Struct Chem. 2022;78(Pt 1):36-55
- 27. Summary • Many psychedelic compounds, botanical and synthetic • Many medical applications • But current clinical trials are flawed • We don’t even know what is in psilocybin mushrooms • Delic Labs works on closing that knowledge gap with metabolomics • Crystal structure or psilocybin can affect medical properties • Crystal structures can be patented, but should they? Thank you! Any Questions? 27 Dr. Markus Roggen markus@deliclabs.com
- 28. Thank you! Questions? Dr. Markus Roggen markus@deliclabs.com
Editor's Notes
- These things might make some participants feel more welcome, but they also put them at risk of being touched when they are unable to give consent. The level of individualistic makes it difficult to know how much the reduction of depressive symptoms is due to the drug, and it also makes it difficult to pool the experiences of patients when they are each having such different experiences. In some cases, it has led to patients becoming overly dependent on their therapists and seeing them as a friend, which led to distress when the treatment suddenly ended.
- Toxicology and Analysis of Psychoactive Tryptamines (nih.gov) Malaca S, Lo Faro AF, Tamborra A, Pichini S, Busardò FP, Huestis MA. Toxicology and Analysis of Psychoactive Tryptamines. Int J Mol Sci. 2020 Dec 4;21(23):9279. doi: 10.3390/ijms21239279. PMID: 33291798; PMCID: PMC7730282.
- Ontological Classification Metadata, peak, noise processing Chromatographic deconvolution Precursor demultiplexing
- Classical MN: Consider all fragmentation patterns in a sample as vectors. Compare spectral vectors to each other, The similarity between the two numbers is defined as the cosine angle between vectors.
- It is likely that Polymorph B showed up due to challenges in maintaining uniform heating and preventing microenvironments as a result of their large-scale production, which is easier to control on a smaller, lab scale. Further, since psilocybin is hygroscopic, a dried crystalline sample corresponding to Polymorph A would quickly absorb water, changing it back to Hydrate A. This calls into question the shelf stability of Compass’s crystalline psilocybin, and whether they would truly be selling a pure form of Polymorph A. Many of these concerns would need to be addressed going forward if Compass Pathways is to hold onto and defend the rigor of their patent. If Compass Pathways is unable to address these concerns, they are most likely to lose their patent preventing sole claim on the production of Polymorph A, keeping medical psilocybin in the public domain for research and commercial purposes. However, if their patent is granted, it could lead to monopolistic control over the production of medical psilocybin. How? Only one group can be granted a patent for a polymorph structure, and US Food and Drug Administration (FDA) approval often follows. If Polymorph A is granted approval as the first FDA–approved medical psilocybin, then Compass would be the sole supplier of medical psilocybin until other companies succeed in discovering a new structure, getting a patent, and FDA approval.