Over the years, Psychedelic Science Review has kept its readers up to date on important trends emerging in psychedelic research. The importance of psychedelic crystallography, the fundamental work of defining the crystal structures of psychedelic compounds, has emerged as one of the most important areas of new psychedelic research. Importantly, psychedelic crystallography feeds directly into the creation of many of the burgeoning psychedelic industry’s formative patent applications.
PSR Predicted the Importance of Solving Crystal Structures
In December 2019, PSR published an article titled, “Why Are Crystal Structures Important in Psychedelic Research?” The article gave an overview of psychedelic crystallography and some examples of how crystal structures are advancing the understanding of psychedelic compounds. In January of 2020, PSR published “COMPASS Patent Highlights Importance of Crystallography in Psychedelic Drug Development.” That article predicted that “the scope and validity of [COMPASS Pathways’] patent will depend on how x-ray diffraction data is interpreted.”
Psilocybin Structures Provide the Exact Identity of Different Forms
As more psychedelic research companies are coming into the fold, the critical nature of solving the exact structure of crystalline forms of psychedelic compounds has come to a head. In a paper published in Acta Crystallographica Section C, Alexander Sherwood of the Usona Institute and his colleagues describe new crystal structure research they have done on the magic mushroom compound psilocybin. In the paper, the authors highlight errors they discovered in the patent granted to COMPASS Pathways.1 The patent titled, “Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use,” was granted to COMPASS in March 2021.2 Dr. Sherwood explained to BusinessWire in a recent interview that “Crystal structures are the gold standard in chemical characterization.”3
Sherwood et al. describe their study strategy as follows: “Utilizing the three solved structures, an investigation was conducted via Rietveld method (RM) based quantitative phase analysis (QPA) to estimate the contribution of the three different forms in powder X-ray diffraction (PXRD) patterns provided by different sources of bulk psilocybin produced between 1963 and 2021 [they found Hydrate A, Polymorph A, and Polymorph B forms of psilocybin]. Over the last 57 years, each of these samples quantitatively reflect one or more of the hydrate and anhydrate polymorphs.” The research team also evaluated “correlations between the crystal forms present, corresponding process methods, sample age, and storage conditions.”
Their analysis of the COMPASS compound claimed to be pure Polymorph A concluded,
Rietveld refinement demonstrated that the claimed material was composed of approximately 81% Polymorph A and 19% Polymorph B, both of which have been identified in historical samples.
Dr. Sherwood also told BusinessWire that “Crystal structures are the gold standard in chemical characterization, but due to the physical properties of psilocybin, we initially believed that solving the crystal structures would be challenging, if not impossible. Thanks especially to the expert crystallographer, James Kaduk, we can now share this unique view into the atomic structure of a psilocybin crystal. The collaborative spirit and depth of support provided by everyone involved in this research helped to break new ground in psychedelic science.”
Challenge to COMPASS’ Patent Highlights Importance of Precise Chemical Characterization
Sherwood et al.’s paper is highly relevant to an article in Double Blind,4 reporting on a recent challenge Petition to COMPASS Pathways’ patent.5 Staff Writer Shayla Love reported that “[t]he non-profit Freedom to Operate used research from chemists and crystallographers to argue in a legal filing that COMPASS’ form of synthetic psilocybin is not a new invention.”
The central challenge to COMPASS’ patent is that the “Form A” (Figure 1) claimed in the patent wasn’t really a single crystalline form. “Rather, the inventors failed to appreciate that their ‘Polymorph A’ was a mixture of Polymorph A-prime and Polymorph B, which is created by inadequately controlled drying at large scale” (see page 33 of the Petition). Adding expert opinion, the Petition contains statements from James Kaduk, a crystallographer and research professor of Chemistry at the Illinois Institute of Technology, and Sven Lidin, Dean of the Faculty of Science at Lund University and former Chairman of the Nobel Committee for Chemistry.
The Petition claims that COMPASS Pathways never reported the crystal structure for its Form A. Accordingly, they never confirmed (by solving the crystal structure) that they had isolated a single crystalline form of psilocybin. Rather, they relied on PXRD data to define only Form A and that technique did not alert the scientists to the presence of multiple crystalline forms. This oversight ultimately opened the door for the recent patent challenge after studies by Sherwood et al. revealed errors in COMPASS’ use of PXRD data to distinguish its Form A as a novel crystalline form.
COMPASS’ Chief Communication Officer told Shayla Love in an email, “We remain highly confident in the strength of our patents and our polymorph A is the subject of numerous granted patents from several different Patent Offices, confirming that it is novel and inventive.”
When COMPASS filed its original patent application, only one crystalline form for psilocybin (the mono-MeOH solvate, described by pattern J, Figure 1) was known. At that time, COMPASS could have identified, purified, and claimed any single crystalline form of psilocybin except for that one known form. Those purified single crystalline forms would have been new at the time.
The fact that COMPASS did not distinguish one single, specific crystalline form from many other possible forms (and mixtures of the compounds) underscores the unmet need for making single, purified crystalline forms. And, somewhat ironically, COMPASS fell victim to that problem by not distinguishing between different crystalline forms. In other words, COMPASS fell victim to the problem it claimed to solve.
What Does This Mean for Psychedelic Research?
Sherwood et al. concluded, “We show conclusively that all published data can be explained in terms of three well-defined forms of psilocybin and that no additional forms are needed to explain the diffraction patterns.” Studies like these reinforce how understanding nature is vital to psychedelic drug research.
Within the context of biological assays or drug development, correctly identifying the crystalline form is often essential to calculating the compound’s molecular weight. And most downstream biological calculations (like receptor binding affinity, activity, efficacy, potency, toxicity, etc.) depend on the compound’s molecular weight. Errors in assessing the compound’s molecular weight can affect these downstream measurements significantly.
For example, in the case of psilocybin, confusing Form A, anhydrous psilocybin (molecular weight = 284 grams/mole), with its trihydrate form (molecular weight = 338 grams/mole) results in an error of 54 grams per mole, which is approximately 20% error. A person receiving 10 mg of psilocybin Form A mistakenly identified as psilocybin trihydrate would be receiving an equivalent of about 12 mg, based on psilocybin trihydrate. Precisely identifying the specific crystalline form of psilocybin prevents these types of errors.
PSR has noted the importance of rigorous chemical characterization and precise measurements in other areas of psychedelic research. For example, the entourage effect in magic mushrooms highlights the need for precisely identifying the identity of the active components and the exact amount(s) of each. Similarly, solving the crystal structures of individual compounds provides the “gold standard” of analytical precision when scientists consider making formulations containing precise amounts of crystalline compounds for treating specific conditions.
One hallmark of scientific theory is that it is dynamic. It redefines, updates, and rebuilds itself based on new discoveries. The state of the art then propels further research in the direction of deeper understanding. This is one of those times when science gets to reexamine and correct itself.
Thanks to the painstaking work of COMPASS Pathways and Sherwood et al., this aspect of psychedelic research has taken a significant step forward. COMPASS Pathways recently pioneered the area of psilocybin crystalline forms, and now Sherwood et al. have expanded the scope of that important area of research. Future scientists will most likely pay more attention to the precise crystalline forms of psychedelic drug candidates, following Dr. Sherwood’s advice that “Crystal structures are the gold standard in chemical characterization.”