The Need for New Psychedelic Compounds

By Dr. Jason Wallach

The psychedelic research renaissance

It’s an exciting time to be doing psychedelic research. While interest in the field has exploded recently, I have long believed in the therapeutic potential of psychedelic substances and have been confident that psychedelic drug development would once again be taken seriously. However, it is happening much more quickly than scientists like myself had ever anticipated, driven no doubt by both the significant growth in mental illness and the hard work of pioneers in this field.

Natural psychedelic compounds found in fungi, cacti, and other biological life have been used for healing purposes by indigenous cultures across the globe for thousands of years. Scientists have been synthesizing molecules with psychedelic effects for just over a hundred years. Some of these molecules were synthesized versions of natural alkaloids, such as psilocybin (from so called “magic mushrooms”) and mescaline (from the peyote cactus); others were compounds designed by humans, such as MDMA and LSD. By the mid-1960s, more than 40,000 patients in the United States were engaged in psychedelic research studies and being treated in clinical settings[i].

Almost as soon as the studies got going , along with excitement about them, unsanctioned use and fears of a counter-culture in the late-1960s began to take hold. These were some of the main reasons that led regulators to put psychedelic substances under heavy legal restrictions, describing them as without medical value and with potential for abuse and harm. In the U.S. and elsewhere, almost all psychedelic medical research came to an abrupt halt.

Beginning in the early 1990s, clinical research cautiously resumed. These early studies paved the way for additional clinical research with psychedelics, which quickly led to more studies and the current so-called psychedelic renaissance. There are currently more than 50 clinical trials underway worldwide looking at psilocybin alone[ii], and psychedelic therapies including psilocybin, MDMA, LSD, and DMT are being investigated for a range of conditions including depression, substance use disorders, post-traumatic stress disorder (PTSD), and anorexia nervosa.

Next-generation psychedelic compounds

None of the therapies in clinical development has yet been approved. The drug discovery and development process is notoriously long, and science needs to continue to innovate and create the next generation of psychedelic compounds, improving on what exists today.

Today’s psychedelics such as psilocybin and MDMA were not designed by medicinal chemists for specific clinical indications. That is not to say they cannot be used clinically, and indeed they are showing tremendous promise. However, brand new psychedelics can be developed that build upon these molecules to create compounds with improved clinical profiles by optimizing the pharmacodynamics (effect of the drug on the body) and pharmacokinetics (effect of the body on the drug) to improve efficacy and tolerability, or to tailor the drug to a specific patient population.

By starting from scratch, medicinal chemists get to decide what collection of pharmacokinetic and pharmacodynamic properties they want in a psychedelic compound. With existing psychedelics, we do not have this luxury, as their properties are already determined. Identifying the optimal profile is only the start. Once these properties have been identified, lab scientists have to develop that optimal molecule. Typically this is first done in our heads (in cerebro), or on a computer (in silico), then in the lab.

As we learn more about what a class of structurally similar molecules can do (i.e. develop structure-activity relationships), we gain greater understanding and can begin to apply this knowledge to creating the optimal drug candidate. As an example of what new compounds can offer, a briefer duration of action would be useful. Of course, such a development demands understanding more about what the optimal duration is – which may vary by indication. A shorter-acting psychedelic will allow greater patient access, as the time, space, and financial requirements for patients and providers are reduced.

We in the lab can also develop compounds with specific polypharmacology — the activity of a molecule at different receptors. The brain’s 5-HT2A receptor is undoubtedly central to psychedelic activity, but other receptors are known to modulate 5-HT2A activity and contribute to the effects. If we take a musical analogy, the 5-HT2A receptor is the fundamental frequency and other receptors represent the overtones. The resulting sound (the experience and clinical profile) of an individual drug depends on its polypharmacology and the number and type of receptors involved. Understanding of 5-HT2A-related polypharmacology is rapidly expanding and next-generation psychedelics are likely to have polypharmacological profiles to enhance both efficacy and tolerability.

The drug discovery process can require thorough pharmacological evaluation of thousands of molecules to find even a single clinical candidate to move forward to the next stage. Many exciting things are learned during the process and the knowledge gained will aid future scientists and medical chemists. There will be successes and failures along the way, but any exploration, and the discovery what such compounds can and cannot do, is of immense value. One of the things that most excites me is that in learning more about the mechanism of action of psychedelic compounds, we will develop a deeper understanding of the biology of the brain and ultimately of ourselves.

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From early-stage research to clinical outcomes

My team has been working on preclinical drug development of new psychedelics for over a year now. In that time, our team at the University of the Sciences, working with teams at UC San Diego School of Medicine and the Medical College of Wisconsin, has designed, synthesized, and begun to pharmacologically characterize a large number of new compounds, many of which show great promise as potential new drugs.

The goal of our labs and of many others is to create new compounds that can be taken through clinical development and eventually become new therapies for patients, relieving some of the mental health distress in the world.

It is estimated that one in four adults suffers with a mental health disorder. Central nervous system (CNS) drug discovery has stalled in recent years. Many pharmaceutical companies have completely abandoned drug development in this domain, leaving a significant void in the drug development pipeline. As a result, there is a lack of efficacious pharmacologic interventions for those with psychiatric disorders. One notable bright spot is with innovation and development of psychedelic therapy.

One of the major challenges for CNS drug discovery is translatability between early preclinical results and clinical outcomes. The human CNS is the most complex biological system ever discovered. The subjective experience you have now while reading this — your whole reality, in fact — is generated by and contained within your brain. That is an awe-inspiring recognition — but it obviates reductionist approaches to understanding.

Due to the fabulous complexity and physiological interconnectedness of the nervous system, there are many pitfalls that can derail a CNS discovery project. New approaches to CNS drug discovery are needed to surmount the hurdles. At the same time, existing and ongoing clinical trials of psychedelic agents, historical usage, and a wealth of anecdotal evidence provide plenty to learn from. Scientists such as myself now have greater confidence in the basic pharmacology of 5-HT2A underlying efficacy, allowing us to focus efforts on enhancing the efficacy and tolerability, and improving access to psychedelic therapy as well as tackling new indications, for example providing compounds for such stubborn psychiatric conditions as PTSD, substance use disorders, and anorexia nervosa. In the process we will all learn much more about how these fascinating molecules work.

Psychedelics are able to create dramatic, rapid, and lasting shifts in perspective and outlook. I believe strongly that such effects will have profound implications for psychiatric care and clinically relevant outcomes across many diagnostic boundaries. There is potential for psychedelics to radically transform our approach to managing mental health, something which is drastically needed. Research scientists such as myself hope that our work will help make a difference in the world. As the great medicinal chemist, Paul Janssen would say, “the patients are waiting”.

In other words, it is time for me to get back to work!

Jason Wallach

Source: COMPASS Pathways

Dr Jason Wallach is assistant professor of pharmaceutical sciences at University of the Sciences, Philadelphia. He is part of the COMPASS Discovery Center, a collective of leading scientists developing innovative psychedelic therapeutics under a sponsored research agreement between COMPASS Pathways and University of the Sciences.