Can CBN Replace Melatonin? Results from a Double-Blind Placebo-Controlled Study ft. Alleh Lindquist

Can CBN Replace Melatonin? Results from a Double-Blind Placebo-Controlled Study ft. Alleh Lindquist

Alleh Lindquist: We're really trying to break that down, because we do believe fundamentally that cannabinoids will have a massive impact on the health of people. But you've got to hit these things so you can build consumer trust and confidence, and get these products into the channels that the average person has access to — not just dispensaries, because that's a limited channel for sure. Bryan Fields: What's up guys, welcome back to another episode of The Dime. I'm Bryan Fields, and with me as always is Kellan Finney. This week we've got a very special guest, Alleh Lindquist, CEO of FlorWorks. Alleh, thanks for taking the time. How are you doing today? Alleh Lindquist: I'm doing great, thanks for having me on the show. Excited to dive in. Kellan, how are you doing? Kellan Finney: I'm doing really good, really excited to talk to Alleh and dive into a really hot topic in terms of making cannabinoids medically beneficial and the steps FlorWorks has been taking. I'm even more excited because it's nice to have a West Coaster back on the pod again finally. How are you, Bryan? Bryan Fields: Yeah, I'm doing good, and yeah, that is true — we've got another West Coaster. But I think it's important to talk about CBN today, all the benefits it has, and actually the importance behind the scientific claims here. Being the non-scientist in the room, I'm looking forward to having this simplified for me so everyone listening can really understand what is true and what is not true. So, before we dive in, can you give a little background about yourself and how you found your way into the cannabis space? Alleh Lindquist: Yeah, I've got a pretty interesting background story. I started as a commercial advertising photographer in my 20s, shooting global ad campaigns in the sports and lifestyle space. I was actually on a shoot — a yoga shoot for a magazine — and I met somebody who was growing cannabis under the medical marijuana system here in Oregon. I'd always been a consumer, and I just thought that was really interesting and decided to dive in. I built some grow operations, then got into extraction very late in the days when there were just the first machines — we were building and designing them. I ended up getting the first recreational extraction license in the state of Oregon, built up a company and a couple of brands — vape pens, dabbable products — and learned a lot about that foundational cannabinoid extraction and distillation work. I ended up exiting that company in 2019, and through that process had come across some scientists and expanded my view of the potential of rare cannabinoids, even novel cannabinoids that haven't been created yet. I started working on a project that became FlorWorks, basically to find a pathway for manufacturing CBN at scale and bring it to market — it wasn't available at the time. We did that within our first year, built a process, and went out to some folks I know in the industry, particularly Grön and Wyld, who are some of the larger, more substantial edible companies out there, and said, hey, there's an old anecdote that old weed causes a more drowsy or sedative effect due to the oxidation of THC into CBN, and we built a process to do this at scale. We think there could be a great product line here. They bought into it, launched those products, and now CBN SKUs are four of the top five selling SKUs across the nation in dispensaries. That was the entry point for FlorWorks to start exploring the therapeutic potential of cannabinoids and where that would go. Kellan Finney: That totally makes sense in terms of how you got to this point, but there must have been a conversation internally — do we want to take this path, or should we just continue on? What happened internally to decide to explore cannabinoid clinical trials, and to think that this was the path you should take? Alleh Lindquist: Being at the forefront of where regulation is going, thinking about what a mature industry would look like down the road — it's a messy space. You've got federal and state differences, hemp versus cannabis, and a lot of complexity around where the FDA and DEA sit on these things. When we saw this was working, people were buying the product, they wanted CBN — that gave us the confidence to say this could be a true sleep aid product, and what's the pathway to get there? What regulatory framework would you need to get dietary ingredient standing and take this from dispensaries — or the hemp markets, as I'll refer to them — to something like a Kirkland Signature? What are the FDA requirements to be able to make a claim? We just dug in and started down that process. Kellan Finney: So by taking that initiative, you guys are essentially paving the road — if you're successful, anyone else who wants to use CBN as an ingredient will be leaning on a lot of the work you're doing right now to make those claims. What was the internal conversation like — "hey, we're going to have to spend money to carry this task up the hill, and a lot of other people won't have to climb that same hill"? Alleh Lindquist: Actually, it isn't that way — this work and these claims are for FlorWorks only. It's a natural compound, but we use a proprietary process to make it — we even have a patent on the manufacturing process — and we've trademarked the ingredient as True CBN, similar to what traditional supplement ingredient suppliers do. The sleep studies are done on True CBN, and even though it's an identical compound to CBN, there's an impurity profile that's been cleaned up, so we know exactly what it looks like. The toxicology work and the dietary ingredient filing are all done on FlorWorks CBN, or True CBN, and we're now looking at licensing that as an active ingredient to make claims and meet safety standards. So it's not for everyone. Bryan Fields: That's an important business decision — I think that's why this hasn't been done before, or it just hadn't been approached this way. Alleh Lindquist: Right, and fortunately we had good insight from traditional nutraceutical and supplement companies. A great example is KSM-66, an ashwagandha ingredient out of India — they're the dominant global supplier, and it actually says "KSM-66," not "ashwagandha," as the active ingredient. All the claims around ashwagandha are really tied to their proprietary ingredient. We've taken a similar approach at FlorWorks. Otherwise, it would be really difficult, particularly to convince investors to invest in this work if we couldn't own it and would just be doing the work for everybody. Bryan Fields: I think that's an important distinction, because people see CBN on products and there might be claims where people bend the rules in a gray area. I think what your team has done really signifies a difference — your product has claims validated by science, which is separate from claims validated by make-believe. Alleh Lindquist: Yeah, for sure, and I think that's fine in a sense. The FDA is more interested in egregious claims than something like sleep, but the real question is: what would it take for a Nature's Made, a Life Extension, a Kirkland Signature, a GNC, a Vitamin Shoppe, or a retailer like Target to actually accept this as an ingredient, or feel comfortable having it on their shelves? They're not going to have products that say "sleep" on the front unless there's a legitimate study backing that claim, because there's liability involved. The bigger issue is that no cannabinoid has been approved for human consumption today. The Farm Bill legalized hemp, which essentially legalized cannabinoids, but it didn't approve them for consumption in a product, as a food ingredient, or as a supplement. CBD has a wildly interesting nexus, because it was approved as Epidiolex, an epilepsy drug — the whole Charlotte's Web story — before the 2018 Farm Bill. There's an FDA rule that something approved as a drug cannot go backwards and become a supplement. So essentially all CBD being sold across the market is being sold off-label as an epilepsy drug, without the regulations of the drug industry — there's no legitimate legal framework for the sale of CBD in the U.S. today. That caps adoption; you can't get into mainstream channels, and mainstream consumers don't accept this stuff yet. We're really trying to break that down, because cannabinoids can have a massive impact on health, but you've got to hit these things to build consumer trust and get into channels beyond dispensaries. Bryan Fields: We just talked about a lot of different cannabinoids — why did FlorWorks choose to pursue CBN specifically? Alleh Lindquist: I think it was a little bit of luck — our chemist had a vision for CBN before the company even started, based on that anecdote about old cannabis having oxidized THC turning into CBN. We could have chosen CBC or THCB or something else, but CBN felt right, and it turned out to be the best-performing rare or minor cannabinoid to date. With our study confirming, in a double-blind, placebo-controlled trial, that it's effective as a pure compound for sleep, it turns out we made the right choice — a little luck, and a little foresight from our chemist, Chas, who knew exactly where he was targeting. Kellan Finney: Yeah, definitely. So let's talk about that double-blind placebo-controlled study. What needs to happen prior to starting that, and what's the first step for those unfamiliar with the concept? Alleh Lindquist: There are companies that do this — we used a company called Radicle Science, which wants to democratize research for supplements to build valid claims. We came to them and said we think CBN could be effective for sleep, based on anecdotal data from customers using different dosages, some who'd been keeping sleep journals for a year. We tested three dosages: 25, 50, and 100 milligrams. The difference here is that most products out there combine CBN primarily with THC, but we aren't a THC company — we wanted this to eventually be in mainstream channels outside of dispensaries, so no THC. We found 25 and 50 milligrams were in the range people reported as effective, with a few people with more aggressive sleep issues taking up to 100 milligrams. The study is double-blinded, so nobody knows what they're taking, there's a placebo arm with no CBN, and the study is written to correct scientific standards and IRB-registered, which allows it to be published and validated. It's survey-based, so it also needs a large enough cohort for statistical significance — all of that was met. We even included melatonin as an arm, since it's our real competitor in the sleep aid market — it's a hormone, and taking hormones changes brain chemistry, with different reported side effects. We actually ran the largest study on melatonin in history in the process, and 50 milligrams of CBN outperformed melatonin, which was great to see. Also, 100 milligrams showed no improvement over 50 — there seems to be a saturation point. That's important for consumer trust — we're not just trying to give people as much as possible; we found an optimal dose. We filed a patent on those dose ranges for CBN for the treatment of sleep disorders as well. Bryan Fields: How do you break down male versus female, weight, age, all those variables — and how do you ensure the self-reported data is clean? How do you know someone who said they slept well didn't have ten drinks that night, or weren't doing certain other activities? Alleh Lindquist: The study itself is an already-accepted sleep study model — it's called PROMIS, and it's been used elsewhere. Radicle Science recruits for a wide diversity of ethnicities, weights, and genders to give you an average, since this is about statistical outcomes. There are also questions in the questionnaire designed to weed through some of those confounding issues. This is a first step in validation — it's an expensive study, but not a full clinical in-lab study hooked up to monitors. Because of that price point, this was a great opportunity to validate the anecdote as a first step. We're now moving toward another study with a lot more monitoring data — blood samples, actual sleep cycle tracking — with Oregon Health & Science University (OHSU). We've just signed an LOI for that, and it will actually focus on dementia patients and their caregivers, since sleep issues are one of the biggest side effects of neurodegenerative disease that compounds those conditions. They don't love using melatonin for hormone reasons, and drugs like Ambien have serious side effects that could be difficult combined with dementia. When we brought this to them, they were excited to have another potential option, and we're preparing that study with OHSU now. Kellan Finney: I have a quick question — what was the dosage for melatonin, and did you test other melatonin dosages during the study, or is that the accepted standard dose? Alleh Lindquist: Five milligrams — that's the standard dose for melatonin. I don't think it's generally recommended to take more than that. Each arm in a study is expensive, so we had the placebo arm, three CBN dosage arms, and the melatonin arm — a five-arm study in total. Bryan Fields: How long does a study like this take? Do you plan for a year and then run it for a month — how does that work? Alleh Lindquist: The study itself is 30 days — participants take the product every day and report daily. But there was probably three months of preparation leading into it — deciding dosage, preparing the ingestible form. We used a gel cap to keep things simple, since our interest was purely in CBN itself, not other compounds or bioavailability boosters — we wanted a fundamental baseline on CBN's effects. We had some delays because UPS lost half the product when we shipped it out, so we had to remake and reship everything. That mistake actually allowed us to add the 100-milligram arm as a last-minute addition, since some customers said they were using that much — and we got the important data point that you don't actually need that much. After the study, there's review of all the data, running statistics, and writing the manuscript — altogether about six or seven months before we had a finished manuscript. Then you search for a journal, and peer review takes more time. We're hoping we're on track for a publication around August 25th. Kellan Finney: Amazing. So, just to make sure I understand — you have a hunch CBN could be beneficial, you test five different arms, and once the data comes back, do you run a secondary double-blind study to further narrow in on the most beneficial range, or is there a point where you say, "okay, this is where we are"? Alleh Lindquist: For this one, we got a good result, so there are legitimate efficacy claims here — clinically validated for improving sleep quality and sleep duration, among others. We actually sent the whole manuscript to a regulatory legal firm and asked them to draft a memo on what valid claims the study supports, because in this industry you have to double-check everything, even your own work. We've tried to legitimize this work especially coming from an industry that carries a lot of stigma. There's still a ton of stigma, but there's also a ton of excitement — the scientific community, practitioners, and doctors have been responding really positively, because it gives them another tool for sleep issues. Bryan Fields: Now that you can successfully make these claims, does that open doors to something like a Costco? What other steps need to be taken? Alleh Lindquist: The biggest step is general toxicology work — proving the product is safe at the dosages in question, and in excess, at significantly higher doses than recommended. There's a list of about seven baseline studies required for dietary ingredient filing, or what's called GRAS — Generally Recognized as Safe — a food designation created sometime around the 80s or early 90s. That rule grandfathered in things already being consumed before that point; anything new has to complete those studies. Cannabinoids were being consumed, but not legally, so they don't meet grandfathered status and have to go through this process. Completing this is what retailers want to see before taking on risk selling something not approved for human consumption. That's why big brands like Kirkland Signature, who had interest in CBD when the hemp bill passed, all circled around the industry and then the music stopped once it became clear CBD had this regulatory issue from Epidiolex already being an approved drug. There's an effort to change that, but it's been ongoing for years. So you need both an approved-for-human-consumption status and valid efficacy claims — otherwise you're just selling something that could be snake oil. Kellan Finney: Did you have any assumptions going into the study — thinking "I believe X" and then Y happened — or was there anything that surprised you when you looked at the data? Alleh Lindquist: I'm always a skeptic, especially having seen the amount of unproven claims made across cannabinoids in general — my mentality was "they don't do anything until we prove it." It was a risk, because CBN was already selling as a sleep aid in dispensaries, and if the study had come back showing no better than placebo, we could have killed that entire story. So there was a feeling in the gut of, "is this the beginning or the end of the CBN story we've just started?" It turned out to be the beginning. I wasn't actually the original CEO of this company — I helped bring it together early on, but was asked to take over about two and a half years ago. At that point the company was just making CBN with a small client cohort, and we were no longer the leader — other companies had started manufacturing CBN too. So when I took over, it wasn't just about building a better reputation and stronger customer relationships — like with Grön and Wyld — but also about how we'd advance this further. I looked at the sleep study as a Hail Mary throw down the field, and we've now caught it at about the 95-yard line with the sleep study and the toxicology work — we'll finish the final toxicology study within a week, everything looks good, and we're on track to get the dietary ingredient filing by the end of this year. So we're going to run to that finish line and start bringing CBN out to compete with traditional sleep aids in traditional retail channels. Bryan Fields: Let's talk about that strategy, because it's interesting — you're going to compete with traditional sleep products, but you can also go back to the cannabis industry and say, "you can keep selling CBN products with made-up claims, or use our validated ingredient as a differentiator." Is that a conversation you're having with brands? Alleh Lindquist: I'll say the THC-plus-CBN product is a different product entirely — 10 milligrams is generally the max amount of CBN in an edible today, but anecdotally, CBN combined with THC creates a really desirable, repeatable high effect — it modulates the way THC feels, making it more of a body high, more relaxing, melty. That's a great product for people who want to get high and also sleep better as a result, because it's so relaxing — you don't need 50 milligrams for that effect. The 50-milligram dose is really for people who don't want any psychoactive effect. I love those combination products, but beyond that, there's a customer who wants lower THC and is really focused on sleep — walking into a dispensary hoping cannabis can help without wanting to get high. Wyld is actually the first company to launch a True CBN active-ingredient product in the dispensary channel — it's 2.5 milligrams of THC with 25 milligrams of CBN, just going to market now. I'm still waiting on feedback, but it has enough CBN to be considered a clinically validated claim for improving sleep quality, with just a touch of THC — potentially the perfect intro cannabis product for dispensary shoppers. Kellan Finney: Is that the gating factor for a brand to be able to include a nutraceutical-approved claim on their packaging — that they have to use the True CBN you manufacture, at the doses used in the studies? Alleh Lindquist: Yes, to make the claims it has to be True CBN — it needs to be called True CBN, because the study was run on that trademarked ingredient, made under specific manufacturing controls. Obviously the cannabis industry itself doesn't need dietary ingredient filing, since the FDA doesn't oversee cannabis at the state level — that's a different market. The hemp CBD market floats in a gray zone, not really approved for human consumption. But to make claims, and especially for marketing, a company can say, "this is a True CBN product, and here's a published study in a legitimate scientific journal getting attention from doctors," which builds consumer trust beyond where the market is today. Bryan Fields: Any considerations around studying the THC-and-CBN pairing directly, and how significant of an accomplishment is all this? Are scientists outside the industry surprised by what you've accomplished? Alleh Lindquist: We can't study THC today, actually, because it's a Schedule I drug — you'd need a DEA license, and it's much more complicated, so we're barred from stepping into that. I'd love to be able to do that, and think there could be great effects there, even with light doses. If it moves to Schedule III, I think that's going to be complicated to analyze — we're adding new regulations on top of existing ones that don't reconcile with each other, plus conflicting state-level rules. There's not a lot of precedent for studying a complex mixture like whole-plant cannabis extract — the FDA doesn't have a framework for that, and you'd need rigorous manufacturing controls to guarantee identical formulation every time, which isn't really possible even growing the same strain. Rescheduling has a big impact on the industry as a whole — removing Schedule I status certainly reduces stigma over time, but I think it's still complicated. Outside of Delta-9 THC specifically, you could argue hemp-derived Delta-9 is a hemp derivative, handled outside Schedule I or III entirely. Beyond that, all other cannabinoids besides CBD can follow standard FDA protocols — either an Investigational New Drug filing to create a drug like Epidiolex, or a food additive or dietary ingredient filing. No one has ever said you can't do this with a cannabinoid — it's just that THC and CBD, the first two big cannabinoid stories, have their own unique regulatory issues, and we're just now getting to the emergence of minor and rare cannabinoids. Cannabinoids don't all do the same thing — they bind differently to CB1 and CB2 receptors and interact differently with other receptors in the body. We've got two other research programs running right now — one screening cannabinoids for a neuroprotective effect with the Salk Institute, and one for the ability to kill cancer cells with the National Cancer Institute. We've screened about 40 different compounds, ranging from CBD, CBG, and CBC to more obscure things and CBN derivatives — some do these things really well, some don't do it at all. There's a lot to dig in and screen, and then once you understand individual compounds, you can start exploring how they interact — moving toward the concept of the entourage effect, which I generally view as just an excuse for not knowing what's important in a mixture. Kellan Finney: Is there a risk of conducting a study with THC as a Schedule III drug and creating a similar situation to what happened with Epidiolex, where a drug approval ends up blocking other regulatory pathways? Alleh Lindquist: I hadn't quite thought about that as another layer of complexity, but yeah — THC as an intoxicant would never be approved as a dietary ingredient or food ingredient. We had to run studies on CBN specifically showing it doesn't have psychoactive effects, because that's disqualifying for dietary or food ingredient status — even something like a grass ingredient needs to be safe enough to put in cereal that kids eat. THC is never going to meet that standard. From a recreational standpoint, we just need a framework like alcohol — taxed in a reasonable way so it's not prohibitive for the industry to function, which isn't always the case today, especially if the feds add more taxes on top of state taxes. That's heavily cumbersome and will continue to let the black market thrive. On the hemp side, you've now got Delta-8 and other THC derivatives pulled out of hemp and sold as hemp products — people don't necessarily want Delta-8, they want weed, and they're using what's available at a reasonable price point. We've created a gray area that isn't good for consumers, safety, or following any particular rules. I'm not a prohibitionist — I think every bit of increased access is better — but there's a massive failure at the political level, mostly pandering with no real action or thoughtfulness about how complex and bad the situation has gotten. I remember 12 years ago thinking this industry would go one direction, and I was wrong about the trajectory — it's honestly more chaotic now than it was, because there's no straight line. We need a good recreational framework for cannabis, and Schedule III potentially helps for THC specifically as a prescribed therapeutic that can be researched. All other intoxicating cannabinoids could go that route, while the rest could either become drugs like CBD, or ideally have more available access like nutraceuticals and supplements, since that framework already exists — people just need to get out of the way of the rules. Bryan Fields: What does the scientific community outside the cannabis industry think? Are they surprised to hear there's a validated double-blind, placebo-controlled study behind a cannabinoid therapy? Alleh Lindquist: In some cases, yeah. The doctors at OHSU were blown away, especially at the size of the study. I go to a lot of biotech and healthcare conferences — I just came from one called Sleep, which is the conference for sleep doctors, practitioners, and researchers presenting science around sleep and treatment. I'd say there's generally a curious, excited approach, though you do run into people who just say "cannabis is a drug, get out of here with that" — that's just stigma and lack of understanding. But there's more and more acceptance. I was on a panel at South by Southwest earlier this year with our chief science officer — a PhD biochemist, an MIT biochemist who did cannabinoid receptor work at Scripps up to 2010 — some really foundational work in understanding cannabinoid receptors. Epidiolex was really the first big milestone, approved as a drug. It's pretty uncommon to get funding for a compound you can't patent, which I've run into a lot with some of the derivatives we've screened — one compound we found was even better than CBN for neuroprotection, but both are known compounds you can't patent directly, though we've filed patents around the usage of those compounds for treating specific diseases. It's hard to find biotech funding for that kind of work, partly because there's less capital flowing into biotech and early-stage work generally right now. What we're really trying to do is understand why CBN is better at neuroprotection than other cannabinoids, what mechanisms are at play, and then use those mechanisms to design and predict new structured compounds inspired by cannabinoids — compounds we could patent. That's where I think pharma really gets disrupted. Cannabinoids are also generally very safe and can pass the blood-brain barrier without causing damage, which most compounds can't do, so they could have a big impact in both the nutraceutical and pharmaceutical spaces. Bryan Fields: Are there any other cannabinoids on your radar that you think could be as disruptive as CBN going forward? Alleh Lindquist: We're not actively working on this right now, since we're focused on the neuroprotective work, but I've thought about what could be the next CBN from a dietary supplement standpoint. THCV is interesting — if it turned out to be an appetite suppressant, since the CB1 receptor system modulates appetite, it could be an incredible dietary ingredient for weight loss. There are already drugs targeting CB1 receptors as an inverse antagonist to block appetite for obesity and diabetes, versus the very popular GLP-1 drugs, which are a different receptor system entirely. The earlier generation of CB1-blocking drugs actually caused suicidal thoughts, because blocking that receptor affects mood and behavior too. Our thinking is: instead of blocking the receptor, can you stimulate it the way cannabinoids do to get a specific desired outcome, like appetite suppression, without the broader damage? We're still trying to understand the mechanism for CBN's sleep effect too — it might not even be CB1 or CB2 receptors; CBD alone hits something like 20 different receptors in the body, cannabinoids are generally pretty "promiscuous" molecules. There was research out of Israel on children with serious behavioral issues who were treated with a 20-to-1 CBD-to-THC ratio broad-spectrum extract — life-changing results — but when they lost that strain and replaced it with a different 20-to-1 strain, it didn't work. So what was actually responsible? Some minor cannabinoid, some other interaction? It's complicated with entourage compounds, but we now have AI and machine learning platforms that can speed this up — there's enough existing cannabinoid data to help predict interactions, even for compounds we don't fully understand yet. It's an exciting time to potentially fully map the cannabinoid receptor system and validate some of the function-based claims people put on strains today — energetic, creative, and so on — which right now is mostly unproven. Bryan Fields: That's the perfect way to end it, because this really opens up endless rabbit holes, and what your team is doing is genuinely significant. Alleh, for those listening who want to get in touch and learn more about the studies you're doing, where can they find you? Alleh Lindquist: Our website is florworks.com — you can find us there. We also have the gel caps from the sleep study available at cbnforsale.com for anyone who wants to try them. Reach out through the website with any questions, and if you're a researcher who wants to work with us, we're always actively looking for academics and researchers — we'll provide the cannabinoids to help advance this work. Bryan Fields: I love it. We'll get this up with the show — thanks for taking the time, this was a lot of fun.