Psilocybin is a naturally occurring molecule found in many species of “magic mushrooms” around the world and is (in)famous for its psychoactive properties once converted in the body to the active molecule, psilocin. Scientists were first able to synthesize psilocybin in 1958, but its association with countercultural movements quickly led to it becoming illegal, hampering further scientific research. [1] Recently, clinical trials with psilocybin have shown promise to treat various forms of mental health conditions including depression and anxiety. [2] These results have renewed interest in psilocybin as a potential pharmaceutical tool and in turn, have generated a race between research companies to cash in on the profits. One route to those profits is via patent control. As psilocybin cannot be patented as a molecule, other forms of patent control via crystal engineering are employed. [3]
Figure 1: Crystalline psilocybin and one of its crystal structure.
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. [4] A patent grants the right to exclude others from the use of that crystalline form. Now this patent is being challenged. But what does that mean? And why should people care? To understand the foundation of the Compass Pathways patent and the stakes involved, let’s back up and explain a few things about crystals.
Matter mainly exists as one of three states: gas, liquid, or solid. In the solid state, molecules can be completely scrambled, or they can arrange themselves into highly ordered structures called crystals. Crystals can be thought of as infinitely repeating patterns of molecules in a rigid 3D arrangement through space. Depending on the nature of the repeat pattern, and how molecules align with each other within the crystals, there can be various different crystalline forms called “polymorphs”. Today, it is understood that over half of all organic molecule crystals have at least two polymorphs, each with unique properties. You have likely noticed these unique properties of polymorphs without even realizing. For example, the molecules inside a chocolate bar can arrange themselves into different crystalline polymorphs that influence properties such as taste and that ‘melt in your mouth’ sensation. Chocolatiers go to great lengths to ensure they produce the best tasting polymorph with a melting point close to human body temperature. The reason why your chocolate bar just doesn’t taste quite the same after melting in the car and solidifying in your fridge is that it now exists in a different crystalline form with different properties.
Scientists have discovered that depending on crystallization conditions, psilocybin crystals can be grown into two unique crystalline forms or incorporate small solvent molecules into the structure, such as water molecules. Just like that chocolate bar, these various crystalline forms influence how scientists and drug manufacturers process psilocybin for medical use.
Figure 2: A zoomed in view of Hydrate A. Psilocybin molecules (purple regions) and water molecules (red and grey) form alternating channels inside the crystal.
One of the solvent-containing crystal forms, Hydrate A contains water molecules (see Figure 2). Psilocybin is hygroscopic, meaning it attracts and holds onto water molecules from the atmosphere. In fact, up to three water molecules per psilocybin molecule can be incorporated into the crystal (in this case, we call it a trihydrate). The drying process leaves tiny micropores in the psilocybin crystal which are refilled with new water molecules if the psilocybin crystal is exposed to the atmosphere again. So, it is important to consider the water content during storage and when performing experiments with pure psilocybin crystals. These seemingly insignificant differences between polymorphs and their components can have a significant influence on processing, shelf stability, and bioavailability upon entering the body. [5]
In one of the pure crystalline forms, Polymorph A’, the simplest repeating pattern in the crystal, called the ‘unit cell,’ is in the shape of rectangular prisms with 90° angles while the unit cell of Polymorph B is rhomboid-shaped prisms with roughly a 95° angle (see Figure 3). These unit cells are arranged in a way that, if you played “connect the dots” with each molecule, you would end up drawing a repeating pattern of the most stable arrangements of psilocybin molecules produced during crystallization.
Since the crystalline form can influence a molecule’s pharmaceutical aspects, a new, unique, crystalline form can be patented. Pharmaceutical companies invest large sums of money into drug research and development, and since most drugs are sold as formulations with powdered solids (which are essentially tiny crystallites), polymorph screening is critical to protect their investment as well as intellectual property.
Figure 3: The repeating pattern of molecules inside the crystal of Polymorph A’ and Polymorph B (top) produces different diffractograms (bottom). The diffractogram from Compass Pathway’s patent application with the peak in question at 17.5°, suggests Polymorph A is just a mixture of Polymorph A’ and Polymorph B.
Now back to Compass Pathways and their recently submitted patent. Their claim is that during large-scale crystallization experiments, they discovered a new crystalline form of psilocybin (Polymorph A) which they term the ‘true’ form that is different from the previously discovered crystalline forms. [6] The patent is being challenged in court due to ambiguous scientific jargon and, more critically, because Polymorph A is just a mixture of the two pure crystalline forms, Polymorphs A’ and B combined with small amounts of Hydrate A crystals.
Compass was investigating large-scale production of Polymorph A’ by drying Hydrate A, when they analyzed their results using X-ray crystallography, a technique that involves shooting an X-ray beam at crystals causing them to diffract the X-rays, much like how a glass prism diffracts light, generating a unique diffraction pattern (much like a fingerprint). The diffraction pattern essentially shows the relationship between the angle of incoming X-rays and how strongly those X-rays are diffracted by the crystal. This information can be used to find the structure of the molecule of interest, in this case, one of the psilocybin polymorphs.
Using x-ray crystallography, Compass saw a distinct diffraction peak at 17.5°. This peak is not present in Hydrate A, and was too large to be explained by the minor peak found in Polymorph A’, so they concluded they had discovered their new Polymorph A structure.
However, they failed to note that this distinct peak could indicate the presence of Polymorph B, which has its most prominent peak at 17.4°. Scientists are challenging the patent because, rather than a new, undiscovered structure, the findings are consistent with a crystal with 81% Polymorph A’, 19% Polymorph B, and small amounts of Hydrate A. 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.
References
[1] Hofmann A, Heim R, Brack A, Kobel H, Frey A, et al. Psilocybin und psilocin, zwei psychotrope wirkstoffe aus Mexikanischen rauschpilzen. Helvetica Chimica Acta. 1959;42(5):1557–1572. [journal impact factor = 2.164; times cited = 148][2] Nichols DE. Psilocybin: From ancient magic to modern medicine. The Journal of Antibiotics. 2020;73(10):679–686. [journal impact factor = 2.649; times cited = 15]
[3] Desiraju GR, Nangia A. Use of the term “crystal engineering” in the regulatory and patent literature of pharmaceutical solid forms. Some comments. Crystal Growth and Design. 2016;16(10):5585–5587. [journal impact factor = 4.076; times cited = 11]
[4] Londesbrough DJ, Brown C, Northen JS, Moore G, Patil H, Nichols D. Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use. WO2019073379A1, 2020.
[5] Baertschi SW, Alsante KM, Reed RA. Pharmaceutical Stress Testing; CRC Press: Boca Raton, 2011. [times cited = 14]
[6] Sherwood AM, Kargbo RB, Kaylo KW, Cozzi NV, Meisenheimer P, Kaduk JA. Psilocybin: crystal structure solutions enable phase analysis of prior art and recently patented examples. Acta Crystallogr C Struct Chem. 2022;78(Pt 1):36-55. [journal impact factor = 1.172; times cited = 0]
Author Biographies
In 2018, Dr. Roggen started DelicLabs (formerly CBDV) to conduct fundamental research for the cannabis and hemp industries, providing contract research services with its own laboratory. Dr. Roggen received his PhD in organic chemistry from the Federal Institute of Technology in Zürich. He received further training in physical organic chemistry from The Scripps Research Institute. He entered the cannabis industry in 2014 and held executive positions in cannabis analytic and production companies. Dr. Roggen is a trusted mentor to multiple startups, startup accelerators, and organizations, and held faculty positions at University of British Columbia and Loyalist College.
In 2021, Dr. Duane Hean received his PhD from the University of British Columbia, Vancouver BC, specializing in structural chemistry and crystallography. Dr Hean applies his many years of experience studying chemistry and crystallography to process crystallization by developing scaled-up methods at DELIC labs for the cannabis and psychedelic industry.
Amanda is a microbiology student at the University of Victoria, and an intern scientific writer for DELIC Labs. She writes science-based articles for media outlets, industry, and peer reviewed journals to communicate DELIC Lab’s research insights
