We are at a pivotal moment in the renaissance of psychedelics, with the industry as a whole seeing a vast number of differentiated drug discovery, clinical trial, regulatory, and intellectual property milestones reached in the first half of 2021.
Today, we’ve brought together the following experts in IP, clinical trials, and drug discovery to discuss the current state of the psychedelic industry:
- Graham Pechenik, editor-at-large of Psilocybin Alpha and founder of Calyx Law, a firm that specializes in IP strategy for cannabis and psychedelics ventures;
- Ben Lightburn of Filament Health, an exclusively-natural psychedelic drug discovery and extraction technology company leveraging its in-house good manufacturing practices and Health Canada Dealer’s License; and
- Dr. Josh Woolley of the Translational Psychedelic Research (“TrPR”) Program at the University of California, San Francisco (“UCSF”), an experienced clinician and researcher
Graham Pechenik: Ben, could you tell us a little bit about your background, Filament’s focus on natural psychedelics vs. synthetically prepared formulations, and what Filament has been up to?
Ben Lightburn: I’ve spent most of my career as an entrepreneur researching, developing, and commercializing novel extraction technologies. Prior to founding Filament, I was the CEO of Mazza Innovation, taking it from pre-pilot stage to a full scale 35,000 sq. ft. GMP facility with IP-protection, and onto a successful exit in 2018. The key scientific and operational team from Mazza have joined together to form Filament Health, as we recognized a dearth of expertise in botanical extraction in general, and an industry-wide focus on synthetically prepared psychedelics.
Natural vs. Synthetic – Naturally-derived psychedelics are produced by extracting and purifying compounds derived from plants and fungi, yielding measurable and standardized end products. Synthetic derivatives are single-compound formulations developed in a laboratory. One critical difference between the two is related to intellectual property protection: natural IP is most often related to a process, while synthetic IP is frequently associated with an individual, polymorphic form. With natural psychedelics, research and development is tied to the compounds occurring within plants or fungi, and with synthetic psychedelics, new formulations are developed that don’t usually occur in nature. Currently, there are vast resources and attention devoted to synthetic variants and a comparatively small number of operators focusing on natural extracts. We are currently unaware of any FDA-approved clinical trials underway to investigate natural psychedelic extracts.
Filament has recently hit major milestones, receiving our Health Canada Dealer’s License and GMP manufacturing status, advancing our IP filings, and announcing our first drug candidates that will undergo FDA clinical trials. On the drug discovery side, we are currently propagating psychoactive mushrooms, conducting genetic research, and manufacturing compounds, giving us the unique ability to distribute IP and drug candidates to drug developers, researchers, and other licensed parties in the future.
Graham Pechenik: Josh, could you tell us about how you became interested – and involved – in psychedelic research? Tell us about some of the work you are doing at the TrPR Program and what excites you about the current state of psychedelic research.
Dr. Josh Woolley: I am a psychiatrist and clinical researcher. My lab has focused on developing and testing novel treatments for serious mental illness. We are particularly interested in understanding and improving the social deficits that are common in multiple psychiatric disorders – schizophrenia, mood disorders, and substance use disorders. Roughly seven years ago, I met George Sarlo, a holocaust survivor and philanthropist. He told me about how his recent ayahuasca experience was transformative, allowing him to process his early life trauma in ways the numerous other more mainstream treatments he had tried over the last 50 years, had not. I was also following the exciting early clinical work from Hopkins and NYU that centered on cancer patients, and felt our group could make a contribution by exploring the potential of psychedelics to help other patient populations.
With Mr. Sarlo’s and several other philanthropists’ help, we were able to design and run our first psilocybin trial, which we published last year: Anderson, Brian T., et al. “Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study.” EClinicalMedicine 27 (2020): 100538. I’ve had great opportunities to get more involved in this area of work through being the UCSF site PI for the MAPS Phase 3 MDMA study, and now the Usona Phase 2b study.
Our group has also been able to raise significant philanthropic support to design and conduct new psychedelic clinical trials. More recently, we have developed collaborations with Filament and other companies to help move the field forward. I am particularly interested in understanding how psychedelics work, both to de-risk and optimize their use, but also, hopefully, to better understand the mechanisms of the psychiatric disorders that we treat.
At TrPR, we have seven psilocybin trials at various stages in the pipeline right now. We plan a phased rollout over the next twelve months. We are working with several patient populations, including: people living with bipolar depression, chronic pain, and depression and anxiety in Parkinson’s Disease. Some of these trials are primarily focused on safety, given that little is known about the effects of psychedelics in these conditions, for example, bipolar depression and Parkinson’s. Others are more focused on clinical efficacy and mechanism, such as the chronic pain study.
I am most excited about determining if and in whom these medicines can be effective and safe treatments. To achieve these goals, we need to harness the expertise of multiple disciplines including psychiatry, neurology, psychology, nursing, and neuroscience to conduct work that translates what we know from animal work into clinical applications. This is the core mission of TrPR. This work is critical to having insurance companies cover these medicines and approaches, which would allow access for people who need them.
Graham Pechenik: Ben, I’ve heard you mention “Psychedelics are more than just mushrooms and mushrooms are more than just psilocybin.” Can you explain? Does this relate to the entourage effect?
Ben Lightburn: There are over one hundred known psychedelic plants and over one hundred known species of fungi with psychoactive properties. This represents a huge number of yet-to-be studied, potentially complementary, psychedelic compounds. When speaking about magic mushrooms specifically, most people think of psilocybin alone as the active compound. While it is certainly found in abundance in most species, there are a number of other active components contained within fungal matter.
Filament will be entering a psychoactive, non-psilocybin mushroom formulation into a clinical trial later this year. We can’t wait to see what we uncover and to share our findings with the world.
The entourage effect describes the complementary effects of multiple compounds outside of the primary API. Because human receptor sites are not universally standardized and identical, it’s possible that a combination of natural compounds could have greater efficacy, fewer side effects, and potentially, a shorter onset period compared to a synthetic isolate preparation.
Across the range of plant and fungi species, we have barely scratched the surface of understanding the potential, perhaps necessary potential, of these secondary compounds. I wholeheartedly believe they must be studied further rather than disregarded out of hand.
Graham Pechenik: Josh, what conditions, compounds, or applications that are not currently receiving much attention, most intrigue you?
Dr. Josh Woolley: There is so much to do! There are numerous conditions that are associated with significant negative outcomes but are notoriously difficult to treat, for which psychedelic therapy might be helpful. In addition to the three we are already studying, there are many more that we are interested in investigating, including PTSD, borderline personality disorder, and methamphetamine use disorder, to name a few. Also, there has been almost no work comparing the clinical effects of different dosages of psilocybin or comparing clinical effects of different psychedelics.
Another exciting area involves 5HT2AR agonists that don’t have psychedelic effects. Will they be antidepressants as well? Will they be as effective as psychedelic 5HT2AR agonists? It is too early to tell but we are excited to find out. To effectively answer these questions, we again need a translational approach that leverages the advantages of different levels of analysis, for example, in vitro receptor physiology, animal models, studies in healthy humans, and clinical trials in specific patient groups.
Graham Pechenik: Ben, how do you go about studying these compounds and why do you think more parties are not focused on botanicals?
Ben Lightburn: Licensing and access are certainly barriers. In Canada, where we operate, one needs a Health Canada Dealer’s License to propagate, study, extract, produce, and distribute psychoactive plant and fungi species. Another route to pursue within our jurisdiction is a Section 56 Exemption, which allows for patients to access psychedelic-assisted psychotherapy on a case by case basis, but that is hardly a solution that can be activated at any sort of meaningful scale.
As one of our peers, Pure Extracts, recently noted, “We are not alone in finding it hard to obtain psychedelic biomass as it is highly regulated by Health Canada with many people reporting that there is little or no product available for R&D purposes.”
There is also a dearth of natural or botanical extraction expertise, not only in the psychedelic sector, but more broadly. To develop extractions from psychedelic plant and fungi species requires analytical standards and the capacity to quantify active compounds, primarily psilocybin, as well as any minor alkaloids.
Lastly, there is a misconception that botanical extracts are not used in pharmaceuticals, which could not be further from the truth. 40% of pharmacy products in the western world are derived from plants, and 42% of all new drugs developed between 1981 and 2019 come from natural origins. In fact, Taxol, the best-selling cancer drug of all time, is an extract from the yew tree. As far as psychedelics go, we have thousands of years of evidence of safe consumption by humans. With these factors considered, it stands to reason that safe, standardized, naturally-derived psychedelic compounds can be a great option in pharmaceutical markets.
Graham Pechenik: Josh, are there significant differences between natural and synthetic psychedelics from a clinical trial perspective?
Dr. Josh Woolley: We just don’t know. Our group and other academic teams have used synthetics so far because they have been the only standardized compounds the FDA has approved. I don’t know of any studies that have compared synthetic and natural compounds, though clearly Indigenous peoples with a rich history of psychedelic use have been using natural compounds for thousands of years. There are theoretical reasons to think that the natural compound could have benefits for patients, but I think we need formal studies to understand more. We are open to working with any formulations as long as they are consistent, measurable, and safe for our patients.
Graham Pechenik: Ben, one perceived advantage of synthetically-produced APIs is the consistency and reliability. How confident are you that these compounds can be extracted and stabilized in a way that is safe and measurable for patients?
Ben Lightburn: Very confident. Without giving away too many secrets, we’ve discovered a means of creating a stable, free-flowing, standardized psilocybin compound that is precise to 2 decimal places, and can’t wait to enter the compounds into our first FDA Phase I Trial to demonstrate this.
Due to the controlled substances act and prohibition, there has been a lack of quality-controlled research and analysis on these substances, and many parties are just learning about their existence.
These are extremely powerful substances and precautions must be taken to ensure the formulations are precise. If produced improperly, there could be severe implications for patient wellbeing. We have patent-pending technologies on extraction, purification, standardization, and composition to ensure best practices in the manufacture of our products, now and in the future.
Graham Pechenik: Josh, Are there current trends or deficiencies in clinical trials that you would like to address?
Dr. Josh Woolley: Yes, while work so far has been exciting, the trials have mostly been open-label. Even in randomized trials, it seems pretty clear that the participants could tell if they received the active or placebo drugs. This lack of adequate masking means that we have to be concerned about placebo effects. . Combining this with the substantial media hype and excitement around psychedelics, there’s a high risk of inflated effect sizes.
Graham Pechenik: Why are novel trial designs or active control conditions important?
Dr. Josh Woolley: Psychedelic therapy, because it combines a drug that has clear perceptual effects with psychotherapy, has all the challenges of both classic pharmaceutical trials and psychotherapy trials, plus unique challenges to psychedelics. That means there are lots of unanswered questions. For instance, it’s not clear yet what role exactly psychotherapy plays in psychedelic treatment. Is it mostly to keep the treatment safe and the patient calm, or is it required to synergize with the drug effect to cause transformative change? Other questions include: Is a single high dose or chronic dosing optimal? Do different patient populations need different approaches? All of this has to be better understood. Given the unique challenges of studying psychedelic therapy, novel trial designs are critical. Furthermore, concurrent basic work is also needed to help untangle mechanisms which will inform design.
Graham Pechenik: As we’ve seen recently in Oregon and California, there is progress in state-sponsored, regulated therapist distribution models, decriminalization, and potentially, recreational models – as well as, of course, the FDA-approved pharmaceutical model. What do you think is the best way to get psychedelic medicines into the hands of patients as the industry progresses? And perhaps, what do you see as your role within these markets?
Ben Lightburn: I think this is an important topic worthy of much greater public, transparent discussion. First and foremost, in any distribution model, the medicine or product must be a standardized, measurable form of the psychedelic. I don’t see something like dry mushrooms being reliably administered by a qualified clinician due to variability in the amount of psychoactive compounds within un-processed batches and cultivars. And, synthetic formulations might simply be too expensive to access for some.
I believe the best way to prove the safety of these compounds – for any market – is through the FDA trial process; however, the quickest and most efficient way to administer these compounds may be through state-sponsored therapeutic programs. As we’ve seen in the cannabis industry, individual states are able to approve regulatory changes much faster than the US Federal Government and also have incentives to do so. We’ve seen this be the case whether addressing the current mental health crisis or the current fiscal crisis.
Dr. Josh Woolley: First, I want to say that I fully support decriminalization of drugs. The War on Drugs has failed and is racist in its implementation. That being said, there is a difference between decriminalization and state-sponsored distribution as a treatment. For the latter, I worry that we don’t yet know for whom and in what delivery model these medicines are safe and effective. Improving our understanding of how psychedelics impact the body, and how they impact specific disease processes, is absolutely critical. These compounds may be risky or just not as helpful for certain people, and we need to know why. Clinical trials are a classic, “gold-standard” way to determine the safety and efficacy of new drugs. Our team at TrPR is focused on leveraging what we can learn from basic science about how psychedelics might work to design the highest-yield, most informative trials possible. I hope that our work will ultimately help regulatory agencies like Federal and State Governments and the FDA drive out the best distribution models.
Ben Lightburn: Great point Josh. One last thing to mention is that in a therapist driven or decriminalized market, I believe any therapist or consumer will choose naturally-derived compounds. I believe the situation is analogous to consumers choosing coffee over synthetic caffeine, or fresh tea leaves over synthetic tea flavour drops.