Our Discovery Center in Philadelphia is nearly a year old. We talk to Dr Jason Wallach, Assistant Professor of Pharmaceutical Sciences at USciences, who is leading the work with the COMPASS team. He tells us about the progress that has been made so far.
What is the Discovery Center and what are you hoping to achieve there?
The Discovery Center is a collective of leading scientists interested in developing innovative psychedelic therapeutics. More specifically, the focus of the Center is on the discovery and development of life-changing therapeutics for neuropsychiatric indications.
Central Nervous System (CNS) drug discovery has largely stalled, leading to many abandoning drug development in this area completely. This has left a vacuum in the pipeline and an unacceptable absence of efficacious interventions for patients in many psychiatric indications. This is especially notable in the case of mood disorders like major depressive disorder (MDD). However, there has been some progress, including the recent approval of esketamine for MDD. This illustrates that there are novel ways forward.
I am confident that psychedelics can create radical shifts in perspective and outlook, which will have profound implications for psychiatric care. Everyone is touched by mental health issues, either personally or through loved ones. We want to use our expertise and finite time on this planet to help address these issues.
What inspired you to pursue a career researching psychedelic compounds?
I’ve had a long-standing fascination with psychoactive compounds from an early age. To be honest, I am not even sure where it originated, but I recall reading feverishly about the topic after checking out books from the school library.
I have always been intrigued by the fact that a small amount of a chemical could induce such powerful and strange experiences that are socially taboo. This led to an interest in consciousness and the treatment of psychiatric diseases and disorders, which I followed up on in my undergraduate studies, pursuing a bachelor’s degree in cell and molecular biology from Indiana University of Pennsylvania, and then a PhD in pharmacology and toxicology at USciences.
Reading the work of Dr Alexander Shulgin, specifically PiHKAL and TiHKAL, was the final push I needed to focus efforts around psychedelics. Dr Shulgin made a resounding case for the scientific and clinical potential of psychedelic drugs. His deep-seated love for science and discovering the secrets of nature is infectious. Through his work, I began to see drug design as an art as much as a science. I come from a family of artists so this aspect appealed to me. Dr Shulgin’s work led me to discover the work of other pioneers like Albert Hofmann and David Nichols, who also inspired me and continue to do so.
How big is the Discovery Center now?
The Discovery Center is a network of labs. This enables us to work with the best people, wherever they are based.
We were joined earlier this year by experts from labs at Medical College of Wisconsin (MCW) and UC San Diego. Dr John McCorvy (MCW), a leading G protein-coupled receptor (GPCR) pharmacologist, is running detailed pharmacological characterisations of the top compounds identified. And Dr Adam Halberstadt (UCSD), a behavioural pharmacologist with expertise in psychedelic drugs, is helping us to evaluate compounds in vivo.
Are there new psychedelic compounds to be discovered or are you modifying existing compounds?
Our discovery efforts are a combination of exploring modifications of existing compounds and pursuing new psychedelic structures, which medicinal chemists refer to as scaffolds. For the former, there is room for improvement with existing compounds, many of which were not developed with clinical use as a specific goal. At the same time, identifying novel scaffolds can provide unique and innovative polypharmacology, functional signaling properties, and pharmacokinetic profiles. This unique pharmacology could translate into compounds with new and unique clinical profiles. It is thus important to pursue both approaches.
What is the most difficult thing about your work?
Translatability between preclinical results and clinical outcomes remains one of the major challenges in CNS discovery. The human CNS is an incredibly complex system; in fact, it is the most complex system we are aware of. As such, many pitfalls can derail a CNS discovery project. You have to be mindful to acknowledge these pitfalls and not let prior expectations and bias disrupt your work. It is incredibly easy to mislead yourself, if you are not being constantly critical.
While I won’t give up our “secret sauce”, I will say it is my belief that if you are not doing something different in this space, you’re doing it wrong. It is true that in the case of psychedelics, we have clinical trials, historical usage, and a wealth of anecdotal evidence to support their efficacy in many areas. This is a benefit as it allows us to focus immediate efforts on addressing issues like maximising this efficacy, enhancing tolerability, and improving access. However, translatability between the models available and patients remains the greatest challenge to our work.
What is the most exciting thing about your work?
Psychedelic drugs have potential in mood disorders, post-traumatic stress disorder, substance use disorders, anxiety disorders, and more. If this broad potential is demonstrated with controlled clinical trials, as I believe will happen, it will be amazing and revolutionary.
What I believe underlies the broad applicability, is that psychedelics can induce profoundly positive changes in outlook, mood, and thought patterns. This gives them a unique potential to work across psychiatric boundaries (which may be philosophical constructs rather than biologically imposed) by improving core symptomology – this could reshape how we understand and treat psychiatric disorders. Such a perspective change is drastically needed, in my opinion, as the current classification around psychiatric disorders is, in many cases, limited and uncomfortably devoid of a strong biological foundation to justify its continued acceptance. Psychedelics could help us develop more targeted and effective psychiatric care.
I also believe psychedelics may find use as catalysts, being incorporated as a core component of wider holistic treatment paradigms for improving mental health. Such an approach could benefit millions of people. In summary, psychedelic therapies hold tremendous promise and it’s very exciting to be part of this.