Why Are Crystal Structures Important in Psychedelic Research?

Crystal structures help researchers understand changes at the molecular level that affect the physical properties of compounds.


X-ray crystallography is a technique that scientists use to figure out the three-dimensional structure of organic, inorganic, or biological material.1 It’s similar to having a microscope that operates at an atomic level. Crystallography is used in several scientific disciplines, including material science, physics, chemistry, molecular biology, and biochemistry. Scientists use crystal structures to study and develop drugs (especially antibiotics and cancer drugs), polymers, and textiles, to name a few.

The process works by first purifying and concentrating the compound. The compound is then crystallized and exposed to a beam of X-rays. The beam is diffracted (bent) by the compound, creating a pattern of spots that are analyzed. The analysis gives information on the size of the repeating unit that forms the crystal and how the crystals are packed together. The data also allows calculating the electron density of the crystals.

Crystal Structures of Psychedelic Compounds

In 2019, researchers solved the crystal structure of fumarate salt forms of the psychedelic compounds:

  • 4-AcO-DMT – 4-acetoxy-N,N-dimethyltryptamine 2,3
  • 4-HO-DPT – 4-hydroxy-N,N-dipropyltryptamine 4
  • MiPTN-Methyl-N-isopropyltryptamine 5
  • 4-HO-MiPT  -4-hydroxy-N-methyl-N-isopropyltryptamine 5

These new crystalline forms could be used to modulate the effects of each compound in a drug formulation (i.e., the entourage effect). Also, determining the crystal structures of psychedelic compounds is essential to understanding their physical properties and for probing their activity at receptors by using modeling studies.

Protein Crystallization is Critical for Understanding Receptors

Scientists also use crystallography to understand the structure and function of larger molecules like proteins (e.g., enzymes, receptors, structural proteins) and nucleic acids (e.g., DNA and RNA).

For example, the 2012 Nobel Prize in chemistry was awarded to two scientists who used X-ray crystallography to see a receptor in action. The scientists captured the moment when a G protein-coupled receptor (GPCR) transferred a signal from the outside of a cell to the inside.6,7 The signal was initiated by a hormone binding to the receptor in the cell membrane. In other words, they caught the receptor in its active state. This is a groundbreaking discovery because it provides critical information that can be used in drug development. Discoveries about GPCRs are particularly important for psychedelic research because the serotonin receptors (except for 5-HT3) belong to the GPCR family.

Another excellent example is a 2017 study that reported the crystal structure of LSD bound to the human serotonin 5-HT2B receptor.8 This work allowed the researchers to propose explanations for the receptor binding, kinetics, stereochemistry, and signaling of LSD at human serotonin receptors. In a 2018 interview with ALIUS, chemist and psychedelics expert Dr. David Nichols described the importance of the crystal structure solved in this study in understanding the long-lasting effects of LSD.9 Dr. Nichols noted how the crystal structure indicated a ‘lid’ or loop in the receptor:

In the x-ray crystal structure of LSD in the 5-HT2B receptor, that loop could be seen laying over LSD within the receptor, and Leucine 209 [an amino acid in the receptor] sort of wedged down between the LSD molecule and the receptor. In essence, EL2 [extracellular loop 2] was able to ‘lock’ LSD into the receptor.

In the same interview, Dr. Nichols also explained the importance of crystal structures of compounds in work he did with NBOMe (N-benzyl methoxy) compounds. He said that the crystal structure,

…gave us an idea of how the side chain of the NBOMe compounds must bind to the receptor.

It is clear that crystal structures are essential for helping researchers ‘see’ what’s going on at a molecular level. This gives them a better understanding of how receptors and compounds look and act in nature.

Crystal Structures and the Entourage Effect

It is important to remember that small changes at the molecular level can translate into significant changes in effect when it comes to drugs. Therefore, working with compounds at the molecular level is essential for unraveling the mysteries of how drugs work and how other compounds affect them.

Crystal structures can never fully explain the interaction of drugs on receptors. However, the information scientists obtain from these studies helps to clarify some aspects of their structure, interaction, and function. These small discoveries add up, resulting in a clearer understanding of complex biochemical processes and pathways.

Barb Bauer Headshot

Barb is the former Editor and one of the founders of Psychedelic Science Review. She is currently a contributing writer. Her goal is making accurate and concise psychedelic science research assessable so that researchers and private citizens can make informed decisions.


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  2. Chadeayne AR, Golen JA, Manke DR. Bis(4-acetoxy-N,N -dimethyltryptammonium) fumarate: a new crystalline form of psilacetin, an alternative to psilocybin as a psilocin prodrug. Acta Crystallographica Section E Crystallographic Communications. 2019;75(6):900-902. doi:10.1107/S2056989019007370
  3. Chadeayne AR, Golen JA, Manke DR. The Crystal Structure of 4-AcO-DMT Fumarate. 2019. https://psychedelicreview.com/wp-content/uploads/2019/03/The-Crystal-Structure-of-4-AcO-DMT-Fumarate.pdf.
  4. Chadeayne AR, Pham DNK, Golen JA, Manke DR. Bis(4-hy­droxy-N,N-di-n-propyl­tryptammonium) fumarate tetra­hydrate. IUCrData. 2019;4(11):x191469. doi:10.1107/S241431461901469X
  5. Chadeayne AR, Pham DNK, Golen JA, Manke DR. The fumarate salts of the N-isopropyl-N-methyl derivatives of DMT and psilocin. Acta Crystallographica Section E Crystallographic Communications. 2019;75(9):1316-1320. doi:10.1107/S2056989019011253
  6. Rasmussen SGF, Choi H-J, Fung JJ, et al. Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature. 2011;469(7329):175-180. doi:10.1038/nature09648
  7. Rasmussen SGF, DeVree BT, Zou Y, et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature. 2011;477(7366):549-555. doi:10.1038/nature10361
  8. Wacker D, Wang S, McCorvy JD, et al. Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell. 2017;168(3):377-389.e12. doi:10.1016/j.cell.2016.12.033
  9. Roseman L, Timmerman C. Psychedelics: From pharmacology to phenomenology. An interview with David Nichols. ALIUS Bulletin. 2018;2:75-85.