The buzz around cannabis and psychedelics continues to dominate headlines as we find ourselves two years into the COVID-19 pandemic. Due to widespread uncertainty and general well-being at the forefront of everyone’s minds, the psychedelics industry has flourished during this time, and is likely here to stay. An eclectic group of companies have popped up, many of which were started by general psychedelics enthusiasts, and cannabis and tech tycoons. Now that multiple psychedelics have made their way into clinical trials around the world, basic scientific and pharmaceutical questions still need answering. Which compounds are best for which specific indications and at what dosage? Will second and third generation psychedelic drugs be beneficial or detrimental? How can we better predict clinical outcomes in patients? These questions have largely been asked by academics to date, but more commercial businesses are tackling these hard questions. I co-founded one such company, Psilera Inc., and our goal is to find the best options for patients from both psychedelics themselves as well as psychedelic-inspired synthetic derivatives.
Psilera was founded by two PhD drug discovery chemists with a passion for helping patients struggling with mental health, addiction, and neurodegenerative disorders. Dr. Chris Witowski and myself have collectively worked with natural compounds for almost 30 years. A major catalyst for the formation of Psilera was working directly with patients in the cannabis industry. We designed the product line for AltMed Enterprises (now a subsidiary of Verano Holdings) with a focus on pharmaceutically rigorous delivery methods like patches, inhalers, and oral solutions. The vertical integration of the cannabis industry in various states gave us the opportunity to personally speak with patients and create surveys for patient feedback on our products and their experiences. We realized very quickly that personalized medicine was going to be the key to the future of mental health treatments because, unfortunately, one size does not fit all. There were many beneficial aspects of the cannabis industry, but there were also various drawbacks, and if we wanted to bring pharmaceuticals to the market that could truly change patients’ lives, we needed to find other routes and diverse options. This is why we decided to form Psilera.
There are natural compounds beyond cannabis that can help neurological and psychiatric conditions, and many of these can be classified as “psychedelics”.1  Our research at Psilera is specifically focused on the plant and fungal compounds known as N,N-dimethyltryptamine (DMT) and psilocybin. These compounds are largely known from ayahuasca ceremonies and magic mushrooms. Humans have been using these compounds for centuries, possibly millennia, but it wasn’t until the mid- to late-1900’s that chemists started to experiment with making even better versions of these compounds.2 
DMT and psilocybin are both tryptamines with similar properties in the brain and body and have excellent safety profiles compared to many pharmaceuticals.3  One of the major limitations of DMT is its limited oral bioavailability. Psilocybin can be difficult to manufacture on large scale and patients can form a tolerance over time. That is why our first research focus at Psilera was finding better delivery methods for DMT such as transdermal patches and creating more stable derivatives of both compounds with more efficient syntheses.
One of the other significant hurdles in the psychedelics industry is understanding how these compounds actually work in the body; the mechanism of action or MOA. Psilera has also started a computational chemistry program designed to help us understand how these compounds are affecting serotonin receptors in the brain and throughout the body. Why is there such a large difference in duration of action between psilocybin (6-8 hours) and DMT (~30 minutes)? Is it more than just the enzymes and metabolism in our bodies? A greater understanding of the MOA can help us more adequately design new compounds with lower hallucinations while still maintaining the neuroprotective and mood benefits of psychedelics. This is important because the current psychedelic models require patients to be with a psychiatrist for extended periods of time to monitor their hallucinations.  This will be extremely difficult to scale to millions or even billions of people worldwide. The cost is also a concern for accessibility. Insurance will not cover these current treatments and the out-of-pocket costs are thousands of dollars per treatment in the United States.
To date, Psilera has successfully tested two new derivatives of DMT in mouse models to show that hallucinations may not be necessary to treat depression, anxiety, learning disorders, and memory. We are also testing our DMT transdermal patch in various rat models for anxiety disorders and hope to have this in the clinic very soon. Many psychedelics initially induce anxiety-like effects and elevated heartrates in patients when taken in large doses, so a smaller dose (microdose) released transdermally over time could help remove some of these side effects.
The COVID-19 pandemic and social media have only exacerbated an already growing population of patients with mental health and addiction disorders. Psychedelics offer an excellent starting point for novel drug discovery in neurological conditions that have been neglected for decades, but they must be mindfully approached. The opioid epidemic has taught many researchers that we cannot blindly try new compounds without serious assessment of their side effects and abuse potential. As long as companies and academics remain vigilant through the discovery process when working with such powerful compounds, we have a uniquely rare opportunity to find the safe, naturally-derived medications for millions of patients worldwide.
References: Kelmendi B, Kaye AP, Pittenger C, Kwan AC. Psychedelics. Curr Biol. 2022;32(2):R63-R67. [journal impact factor = 10.83; times cited = 0]
 Shulgin AT, Shulgin A. TIHKAL: The Continuation (Vol. 546). Berkeley, CA: Transform Press, 1997.
 Nichols DE, Nichols CD. The Pharmacology of Psychedelics. Handbook of Medical Hallucinogens, eds Grob C, Grigsby J, New York: Guilford Press, 2021.
 Schenberg EE. Psychedelic-assisted psychotherapy: A paradigm shift in psychiatric research and development. Front Pharmacol. 2018;9:733. [journal impact factor = 4.40; times cited =55]