Ancient and indigenous cultures have been utilizing nature’s pharmacy through the therapeutic use of plant medicines since time immemorial. With modern society on the cusp of the psychedelic renaissance, many of these novel compounds are poised to make a dramatic entrance into the clinical arena. Indeed, mother nature displays a seemingly infinite capability for drug discovery and development. However, the integration of traditional plant-based psychedelic compounds into modern pharmacopeia is projected to follow the traditional “single-molecule” pathway leading to novel IP’s and more robust treatments compared to natural compounds. This evidence-based review will explore the “plant to pill” pathway in the medicalization and clinical utility of prescriptible psychedelic compounds based on psychedelic plant medicines.

Plant-Based Compounds Are Models That Improved Drugs Are Built Upon

The use of bioactive natural products as herbal drug formulations dates back thousands of years. However, the isolation, characterization and clinical application of these compounds through the drug discovery process is a relatively recent development with its beginnings in the 19th century. Plants have long been the source of novel pharmacologically active compounds, with many blockbuster drugs having been inspired by natural plant compounds. The current state of drug research and development in the psychedelic space calls for unique, patentable agents that will likely be molecular derivatives of traditional, plant-based psychedelic compounds, such as psilocybin and DMT. While these powerfully psychoactive and therapeutically promising plant-based molecules have value in their natural state, they function even better as chemical models or templates for the synthesis of new drug candidates. The process of modulating a natural compound into a patentable and prescriptible drug is a major area of interest in the emerging psychedelic space.

Tools Revolutionizing Drug Development: Combinatorial Chemistry & Computer-Based Molecular Modeling

New approaches to drug discovery exploiting advanced principles of combinatorial chemistry and computer-based modeling are poised to bring radical innovation to the emerging psychedelic space. Such advanced synthesis and modeling techniques have led to many modern synthetic drugs with core structures and scaffolds based upon natural compounds.1 Crafting novel modulations to classic psychedelic compounds in order to create novel derivatives offers two major benefits: the potential for a more efficacious, less toxic drug and the opportunity for intellectual property protection and patents. New synthetic biology tools are also emerging, providing scientists with new drug creation tools, allowing them to ask the question “how does nature solve this problem?” With the addition of synthetic biology techniques to the existing chemistry and computer modeling paradigms, researchers have new found capabilities to rapidly create novel molecules never previously possible, with improved pharmacological activity. While the application of synthetic biology helps maximize diversity, the application of medicinal chemistry enables achievement of maximum yield of these extraordinary and unique compounds. The need to harness the synergistic capabilities of computer modeling, synthetic biology and medicinal chemistry to restructure natural compounds into novel pharmaceutical drugs is greater now than ever—especially in the emerging psychedelic space.

Utilizing an Advanced Combinatorial Approach to Effectively Maneuver Regulatory Framework of Drug Development

The pathway to market for prescription drugs entails a rigorous and expensive screening process that some 90% of drugs fail to see through to the end. With the average drug costing approximately $1 billion dollars to complete clinical trials, the need for a clearly defined go-to-market strategy is imperative in this vertical market. As such, utilizing the latest innovations and synthesis tools during drug development, such as combinatorial chemistry and computer-based molecular modeling, is crucial for success in the psychedelic medicine space. Further advances in technology are sure to expand the range of therapeutic applications psychedelic medicine will be used for. Exploring this process in the context of converting a plant-based psychedelic, such as psilocybin, into a prescription medication will help further elucidate this important pathway to drug development.

A Case Study Examining the Formulation of a Unique Psychedelic Derivative from Psilocybin

The combinatorial approach described above is a novel path towards psychedelic derivative creation that leverages shorter, more cost-effective processes and maximizes diversity and yield. The functional impact these tools have on the potential for creating patentable and prescriptible psychedelic compounds can best be illustrated by an example. Psilocybin, the active ingredient in magic mushrooms, has shown incredible clinical efficacy for a wide variety of difficult to treat neuropsychiatric conditions.2 Below is an example of this the general process of this drug development pathway as it relates to our example with psilocybin.

Steps in Plant-to-Pill Pathway for Potential Psilocybin Derivative:

  1. Isolation: As a starting point, first obtain a feedstock such as psilocybin from psilocybe cubensis (“magic mushrooms”) or else use another similar molecule, which could be obtained from a variety of sources.
  2. Bioconversion: Apply synthetic biology tool (e.g. an enzyme) to the feedstock and modify it to create a novel intermediate molecule.
    1. The new intermediate produced will look similar to the feedstock (e.g. psilocybin) but will have different pharmacological properties and effects.
    2. The modification to the molecular structure, creates a new access point for the chemistry which follows.
  3. Chemical synthesis: The real power emerges when taking the intermediate produced in Step 2 and applying a combinatorial chemistry approach at the new access point to convert the intermediate into hundreds or thousands of new patentable compounds
    1. Many new compounds that were not even previously synthesizable are now rapidly created.
    2. Utilization of a combined bioconversion / chemical synthesis process with few steps makes maximum yield in future commercial production an easily achievable goal.

Looking Ahead to the Impact of Prescriptible Psychedelic Derivatives on Modern Medicine

Drug synthesis based on complex combinatorial chemistry and synthetic biology is certainly no easy task. As research in this space evolves, advances in drug development are poised to radically reduce production costs and, ultimately, the price of the drug for patients everywhere. As Chemists strive to discover synthesis protocols with fewer steps, the field of plant-derived psychedelic medicine is sure to make significant strides. The future of psychedelic medicine is poised to impact a wide variety of conditions. The production of these unique synthetic derivatives based on psychedelic compounds is projected to be the main path towards the medicalization of these compounds. As research in the field progresses, new isolation and screening techniques are bound to help usher in this novel new generation of medicine!

Works Cited

  1. Combinatorial Chemistry in Drug Discovery.
  2. Daniel, J. & Haberman, M. Clinical potential of psilocybin as a treatment for mental health conditions. Ment. Health Clin. 7, 24–28 (2018).