Cannabis Was Medicine. Now the Proof Is Catching Up, ft. Joel Stanley and Dr. Marcel Bonn-Miller

Listen Now

Joel Stanley and Dr. Marcel Bonn-Miller: There's no difference between what we're doing and what Pfizer, Eli Lilly, whoever is doing when they're developing a drug. Same exact groups at the FDA that we have to go through that they have to go through. Same exact rigor and approval process. It's identical. We are developing drugs. It's actually harder for us in some ways. Bryan Fields: It feels like cannabis already won cultural acceptance. Joel, why is medical validation still such a different and harder problem? Joel Stanley and Dr. Marcel Bonn-Miller: Fantastic question. I would say that medical validation is difficult for anything that is plant-based and outside the conventional pharmaceutical realm, because what we truly see as 'real medicine' is pharmaceutical, approved by the FDA. Cannabis is a very multifaceted plant with so many active cannabinoids creating a pharmacological response in our bodies. The system for approving a medicine, and for physicians to be able to legally prescribe it, is the FDA drug approval process, and until very recently you couldn't take a complex plant through that process. Now you can. That's one reason, at the highest academic and institutional level, why it's been difficult to prove out cannabis as medicine. Then there's the social reason. This started as a medicine — it was legalized as a medicine. California's constitution changed first for medical cannabis, with no real rules. Then Colorado allowed medical cannabis, again with no real rules, and regulated medical programs followed. Many people were helped. Back then, 2010 through 2015, there were multiple documentaries, including ones on us and on Charlotte Figi and the children with epilepsy who moved to Colorado. It was, and is, a powerful medicine. But what happened is that money and markets took the main stage for years. Things became commoditized — quality went down, consistency went down. People weren't making medicine anymore; they were making money. That gave the true medicine a bit of a black eye in the social and market view. So cannabis has been shown to work as medicine — the data is there and more is coming — but there's been a veil placed over cannabinoid therapies, largely from markets that allowed the stigmatization of a commoditized product to rule the past several years. Bryan Fields: Marcel, taking that one step further — how do we remove that veil? Joel Stanley and Dr. Marcel Bonn-Miller: As Joel said, we've seen the evidence, but there was a period where cannabinoid therapeutics seemed to do so many different things, and I think that's part of the confusion — it can help with this, it can help with that — and the messaging got a little convoluted. What we're doing is one example of the fix, but really it's about getting the science done and separating things out. The reality is we're in a natural experiment: people are using all sorts of different molecules from the plant, and the challenge — which is in some ways a good problem to have — is that these cannabinoids, some more than others, have multiple different mechanisms of action in the body. We're so trained to think about a single molecule with one mechanism doing one thing, but here we're talking about a plant with all this different stuff in it. Even CBD alone hits multiple mechanisms in the body, which is why it can help with epilepsy, anxiety, and inflammation — it's promiscuous in how it interacts with the body. So it's a massive task. We do have real-world evidence — people using cannabinoids, filling out measures, collecting data the right way — but the FDA doesn't really look at that. It's not necessarily the FDA's fault; it's just how drug development has always worked: clinical trial after clinical trial, very cut and dried. There hasn't been a precedent for real-world evidence to factor in the way it could, though I think we're heading there under the current administration — there does seem to be more receptiveness. We need more of the actual science out there, need to cut through the hype and get to the reality of what these compounds are, because it is fascinating. It's not a panacea — CBD doesn't work for everything, CBN doesn't work for everything, THC doesn't work for everything. They each have their place, and there's a lot of nuance. That's part of why I'm working with Joel and on multiple other drugs in the botanical space — these compounds have been sitting in the hopper for so long because there wasn't a pathway with the FDA, and now there is. Bryan Fields: In some ways patients were ahead of the science. How should the industry interpret that without overclaiming, while still pushing the ball forward? Joel Stanley and Dr. Marcel Bonn-Miller: Living through the Charlotte's Web phenomenon, with thousands of families on a waiting list — these were people out of all medical options, usually with a child with a severe seizure disorder, autism, or a related central nervous system condition. The results were, and are, impressive, but as Marcel said, it's not a panacea; it doesn't work for everyone. We've seen people with the exact same genetic mutation and diagnosis respond completely differently — the Charlotte's Web product was a knockout for one and not for the other. But because of the diverse mechanisms of action, sometimes someone didn't get a seizure reduction but saw such substantial behavioral improvement that they're still on the product today, some since 2013. So there's a lot of good, alongside a real seizure-reduction benefit for many, and I don't want to discount that. At the same time, when something gets hyped that big — and I'm grateful to Sanjay Gupta for telling Charlotte's story, because I think it changed the world's perception of cannabis and whole-plant medicine — it's double-edged. Many parents who were out of options kept pushing it even when it didn't work for their child. The story felt like a panacea to some, and in a lot of ways it is almost too fantastic to be true. We've been done a bit of a disservice by the hype, and every new health product goes through that. The danger is the pendulum swinging so far back that people say it doesn't work at all. The truth is in the middle: it doesn't work for everyone, but it works for many, many millions of people who currently can't get it prescribed in a standardized, consistent way. It became a fad almost, and now we're seeing the contraction — the market blew up and is now coming back. It's such a powerful story, and I understand why it got overhyped, because people hear it and grab onto that hope. Bryan Fields: Do you think that overhyping contributed to the scientific community's hesitance? What do we need to do to help them open up their curiosity, and are you seeing change in the scientific community, Joel? Joel Stanley and Dr. Marcel Bonn-Miller: I'd love to hear Marcel's answer to this, but I'll give a quick one. Thank God for Marcel — and our good friend Ryan Vandrey at Johns Hopkins — they built the world's largest cannabis research registry. When I first met them, and when they met Heather Jackson, whose son Zakai was a super-responder to Charlotte's Web, they were some of the first to really look at it. Marcel, Ryan, and I spoke with many academics and physicians — some of them practically laughed me out of the room. Marcel and Ryan were among the first to say, 'No, we know there's a there there, and we love what you're doing — let us help you crunch the numbers and find out what's real and what's not.' They've been with us ever since. In many ways the ball is rolling downhill for us now because it's been legitimized — their track record in academia helped this gain steam, and the partnership Marcel helped create with Johns Hopkins through the Realm of Caring Foundation did a lot to legitimize it. It's changed a ton since I first met Marcel and Ryan. It has changed a ton. I've been doing cannabinoid research for about 23 years, and in the beginning there were far fewer people in the field. Almost everyone at that time — with some exceptions, like Raphael Mechoulam and a few others — was studying the harms of cannabis, because that's where the funding was; nobody was funding therapeutic research, and nobody really knew what CBD even was. Now we're in a completely different place: there are multiple academic journals dedicated to cannabis research, several conferences beyond just the International Cannabinoid Research Society, which used to be the only one, and universities with accredited cannabis programs — I helped build the curriculum for Thomas Jefferson University's program, and University of Maryland was among the first. You can get certificates and degrees now. Researchers who used to study alcohol are shifting to study cannabis. There's a lot more funding from organizations beyond the National Institute on Drug Abuse, which historically only funded studies on cannabis-related harms. Now complementary and alternative medicine divisions are funding research into cannabinoid therapeutics, including a growing focus on the 65-plus population — University of Colorado Boulder just published some great studies there. It's exciting, but there's still a mountain to climb, and we need more people doing this work, because each cannabinoid represents years of research on its own. Bryan Fields: With all this momentum, is it hard to stay focused instead of chasing every promising new area? Joel Stanley and Dr. Marcel Bonn-Miller: It's a balance. Part of me is always looking — some of the work I love is figuring out what CBL does, what CBE does, and so on; each one is basically a career, taking decades to go from ground zero all the way through. But you need to stay focused and dedicated to get from point A to point B, so it's both a creative outlet and a discipline. Drug development is a different animal. Building Charlotte's Web was different — we had demand from day one, in part because our first 'chief marketing officer' was really Sanjay Gupta telling the story of a little girl named Charlotte. Drug development, by contrast, is long and arduous. Getting to the point where the FDA reviews your data and says the risk-reward is good enough to approve takes many years. For a company like ours, a new biotech with our lead drug in Phase 2, we have to stay focused — even though we already know anecdotally, and now with real clinical data, that this formulation works substantially well for certain seizure disorders. Staying focused on one indication is vital, not just for us but for any drug development company. You choose your indication and formulation for a reason, and you have to stick with it. That's not boring, though, because autism only has two FDA-approved drugs, both with substantial side effects that essentially work by shutting off the brain and are used as a last resort. Our research registry shows thousands of people already using products like Charlotte's Web to great effect, avoiding those more dangerous drugs. So staying targeted is simple when I think about how many people we can help — we'll likely see millions of people using this drug for autism, and beyond that, off-label prescribing as physicians learn more about what cannabinoids can help with. Bryan Fields: I imagine before settling on autism there were other indications you considered. Does your mind still wander to those? Joel Stanley and Dr. Marcel Bonn-Miller: Of course — there's only so much funding and only 24 hours in a day. We could open multiple pipeline indications for this first drug, but raising funds has been difficult; I started Ozna Biosciences in spring 2021, right as the markets fell apart in fall 2021 — it's been one of the worst times in memory to raise for startups and biotech, though that's changing now. We've been fortunate to raise what we have and get our pipeline drugs to where they are. One day we'll have the funds for more scientists at the mass spec, more botanists exploring nature, and more clinicians and academics deciding which indications each pipeline drug deserves. That's big pharma money, and we'll get there. Bryan Fields: Let's talk about AJA-001 — is that how it's pronounced? Can you set up what it is and where it stands today? Joel Stanley and Dr. Marcel Bonn-Miller: AJA-001, as we say it quickly, is how our first pipeline drug is coded within the FDA. It targets autism spectrum disorder, specifically irritability and aggression. We have years of data, including some solid clinical data, on similar CBD/THC-ratio products. It's a high-CBD, lower-THC, full-spectrum formulation — meaning the molecules aren't isolated — and the THC still likely plays a large role in why this and similar products work. What's special is that it comes from Charlotte's Web genetics and my new company, Ozna Biosciences. I left the Charlotte's Web board — I was its founding CEO — after we built it into a vertically integrated operation unlike anything else in hemp or cannabis: same genetics, attention to region and soil, feeding, harvesting, drying, storing, and extracting. We spent about ten years building a machine that could standardize nature to the highest level possible, which is exactly what's lacking in dietary supplements. So I left the Charlotte's Web board to start a botanical drug company, and quickly partnered with Charlotte's Web, since it's the only company that can manufacture this highly standardized botanical drug. At Ozna, we take on the heavy task of characterizing the drug — we've identified over 6,000 compounds in it. The FDA previously didn't allow botanical drug development because we didn't even have the technology to say what was in these plants. Now we do. We've standardized nature, learned to characterize it, and are moving it through the FDA as potentially the first systemically absorbed botanical drug. Commercially, it's a partnership between Ozna Biosciences, Charlotte's Web, and British American Tobacco, called Deloria — BAT has invested $15 million to date to bring it to Phase 2 readiness for autism spectrum disorder, and we're about to enter the clinic. BAT has been a fantastic financial partner. People ask why we'd take money from big tobacco — for me it's simple: they've created a fund for health and wellness, and if we can take money that might otherwise go into addiction and instead use it to help create what could be the third drug available for autism patients, and a far safer one, that's a good use of it. Bryan Fields: What's the hardest problem in taking a multi-compound botanical and making it behave like a drug? Joel Stanley and Dr. Marcel Bonn-Miller: It depends on the plant. With cannabis, the hardest part is controlling your raw material and agricultural process. You can control extraction with tight SOPs and control storage, but really dialing in the genetics, then stabilizing them so every plant is essentially a clone of itself, with a consistent phytochemical fingerprint at harvest — that's the hard part. Credit goes to my brother Jared, who built Charlotte's Web's seed-to-shelf agricultural process. That standardized raw material set us up for the next heavy lift: characterizing those molecules, which most pharma companies aren't built to do because they deal with one molecule at a time. When I joined, and they told me, 'this genetic, at harvest, will show this ratio,' I thought, how do you know this? Then the certificate of analysis came back spot on. That level of reproducibility, batch after batch, is incredibly difficult to achieve, and it's easy to take for granted once you're inside the machine. The other piece is that we haven't had the technology to characterize botanicals until recently — the updated FDA botanical drug guidance we work under is from 2016, so we've had this pathway for about ten years, and most people, including investors, don't know it exists. When we talk to investors, most assume 'pharma' means single molecule and anything plant-based is a supplement, or that it's just not possible, because they don't know this FDA pathway is new. But there's no difference between what we're doing and what Pfizer or Eli Lilly does — same FDA groups, same rigor, same approval process. It's actually harder for us because of the characterization piece; they have one molecule and one receptor. It's also easier in some ways, because unlike a brand-new chemical entity, we already have safety data — cannabinoids and psilocybin, for example, have been advanced directly to Phase 2 by the FDA because so much is already known about them. That's highly de-risked drug development, even though the front-end chemistry, manufacturing, and controls work is much harder. Bryan Fields: Once people understand you can measure variability, is there an expectation that you can also control it? Joel Stanley and Dr. Marcel Bonn-Miller: Yes — we do have to control the variability. Nature comes with variability, and when we set botanical drug specifications, batches have to fall within those targets to be approved for a clinical trial and eventually the market, so we tightly control it. There's a small amount of wiggle room, but it's still very tight — the FDA's guidance says that once you show you've standardized to the maximum level possible, they'll let you into the clinic to determine efficacy and safety. So yes, we promise to control that variability. In this one drug alone we've identified over 6,000 compounds — many related, many already known, like carbohydrates, lipids, plant waxes, chlorophyll and its degradation products. But we've also found cannabinoids with no common names, just chemical structures, that we can't simply order as reference standards from a supplier like Cayman Chemical or Sigma-Aldrich. Our chemists have had to isolate or synthesize them, validate the method, cross-check it with another lab, and then test for it in every batch — that's chemistry manufacturing controls, and it's far harder for a complex plant than for a single molecule, but it's doable, and we're doing it. Bryan Fields: Six thousand compounds sounds like a lot — is that unusual? Joel Stanley and Dr. Marcel Bonn-Miller: Our mushroom drugs in the pipeline have fewer than a thousand compounds; we're currently characterizing our second pipeline drug and expect around 450 compounds there. But cannabis and some plants are just extremely complex — that level of phytochemical diversity is normal for a plant. That complexity is exactly why botanical drug development wasn't accepted in the past — we only understood one molecule at one receptor at a time. Now that we've accepted this more complex science, even if we can't fully understand what all these molecules are doing together, if it can be standardized, shown safe, and observed to be effective, there's no reason not to develop it as medicine. Bryan Fields: It feels like a side quest — your chemists stumble on something new, isolate it, and have to characterize it before moving on. Joel Stanley and Dr. Marcel Bonn-Miller: Sometimes we get very valuable IP out of it. For example, in one of our mushroom drugs, we found a novel strain with what we believe is a previously unknown tryptamine that appears highly active at serotonin receptors and highly safe. While characterizing that drug in our normal process, we end up discovering compounds that could be valuable for single-compound medication too — we're not against that; we love single-molecule and synthetic science as much as botanical science. Sometimes nature isn't the most efficient path, similar to how synthetic acetylsalicylic acid became more practical than sourcing salicylic acid from white willow bark, even though it's a great drug either way. So our process can surface compounds valuable to conventional drug development, even while we stay focused on our lead full-spectrum mushroom drug. Bryan Fields: Does AI help in this area? Joel Stanley and Dr. Marcel Bonn-Miller: Yes, it already is — really it's supercomputing and large language models helping us crunch data, like the pages and pages a mass spectrometer prints out for a single molecule. AI helps with drug discovery and development and lets us distill data far faster, flagging, for instance, that an unknown molecule looks like a cannabinoid or a tryptamine. Bryan Fields: Do you feel urgency to accelerate into these blue-ocean discoveries, or do you have to take it one step at a time? Joel Stanley and Dr. Marcel Bonn-Miller: It's a lot. I believe I'll spend my career at Ozna Biosciences and eventually get to spend more time in drug discovery, because I love looking at plants and talking with scientists, herbalists, and traditional healers around the world — there's a lifetime of low-hanging fruit in nature, often backed by thousands of years of writings, that's worthy of becoming pharmaceutical. I won't get to all of it, and that's exciting and humbling. The mission, simply put, is bringing ancient medicine through standardization to people covered by insurance, and we won't get there without staying single-minded and disciplined about drug development, taking our best shots on goal. Bryan Fields: Last question — what would you want the world to understand now that it may not appreciate for years? Joel Stanley and Dr. Marcel Bonn-Miller: Staying in cannabinoid medicine specifically — the world has gone through a roller coaster in popularity, both socially and among investors. The green rush, or 'green flush,' created a bubble; companies didn't perform the way investors expected, and it left cannabinoids with a bit of a black eye. On the social side, stories like Charlotte Figi's, cancer patients surviving chemotherapy because they could eat again, and veterans with PTSD getting off opioids, were powerful, but the recreational and financial rush stole the thunder from the medicinal side, and people are confused about where things stand. What I believe people will know in less than ten years is that these are real medicines — profound, life-saving for many, though not for everyone — because they interact with our largest cell receptor system, the endocannabinoid system. It's going to blow people's minds how many people are helped by cannabinoid therapies, and I wish people understood that right now. I think in ten, fifteen, maybe twenty years, people are going to realize how much better botanical medicine can be than single-molecule medicine in many cases — not that single-molecule medicine doesn't have its place. With cannabis, full-spectrum CBD requires a much lower dose than CBD isolate to achieve the same effect, as we see in the Epidiolex data; the entourage effect, terpenes, and the interplay of cannabinoids all matter. Eastern medicine has understood this for a long time, and Western science is catching up. If you're standing in a pharmacy choosing between two FDA-approved drugs — one an organic botanical with strong efficacy, one a single synthetic molecule with efficacy — which one are you buying? That's the shift we're working toward, and I'm excited to be riding the beginning of that wave, even though our current job is largely just educating people that this exists, because a lot of people are still scratching their heads. Bryan Fields: Thank you both — it's really enlightening to hear this and to remember where we started and how far we've come. Thanks for taking the time, Joel and Marcel. This was a lot of fun. Joel Stanley and Dr. Marcel Bonn-Miller: Absolutely. Thank you. Our pleasure. Thanks for having us.