The standoff between the dietary supplement industry and U.S. FDA on the question of cannabidiol (CBD) continues. Frustration abounds after FDA rejected two new dietary ingredient (NDI) notifications for full-spectrum hemp extracts from Charlotte’s Web (Denver, CO) and Irwin Naturals (Los Angeles), citing the drug preclusion clause of the Federal Food, Drug, and Cosmetic Act (FD&C Act). It is a development that is simultaneously a major blow to the CBD category yet does not meaningfully change anything about the current marketplace. So, the category remains in legal limbo while CBD products continue to proliferate, and now, with FDA seemingly shutting the door, it falls to Congress to devise a regulatory pathway for CBD.
“I think the objections to the NDI notifications are the clearest signal that we have to date that Congress is going to have to solve this problem,” says Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN; Washington, DC). “It is abundantly clear from the objection letters that FDA is going to kick this can down the road and wait for Congress.”
While the outcome of the NDI notifications was not necessarily a surprise considering that FDA has frequently cited the drug preclusion clause as the reason why it does not consider CBD to be a dietary ingredient, more baffling to some is that FDA participated in the NDI notification process in the first place.
John Endres, ND, chief scientific officer of AIBMR Life Sciences (Seattle, WA), for example, wonders why FDA didn’t discourage Charlotte’s Web and Irwin Naturals from submitting NDI notifications in the first place if the agency’s position was that CBD could not be a dietary ingredient, full stop, because of the drug preclusion clause. After all, both companies had extensive communication with the agency during the process. While Irwin Naturals could not comment on the content of its communications with FDA, when asked by Nutritional Outlook, Klee Irwin, CEO of Irwin Naturals, states, “We can say that we answered the agency’s questions about our notification with great specificity and detail over what ended up being a process that took close to a year when including pre-submission meetings, not counting the time it took to put the notification together.”
A great deal of effort was put into these NDI notifications, with both companies investing their time and resources, so the disappointment for the brands—and the industry at large—is understandable. “I think that’s where the frustration comes from: FDA just continues to be a black box on not just CBD but NDIs in general, and NDI enforcement, and that’s not going to work for anybody long term,” says Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA; Washington, DC).
“I think it’s just bad faith on the part of the agency to put the companies through this, and it sends a terrible message to other companies that will disincentivize them to follow that route,” says Mister. “So, what you’re looking at then is a continuation of the current market where companies don’t file NDIs, the market is full of ingestible CBD products, and none of them have been evaluated by the agency.”
The first CBD NDI notifications are in the books. Now what? Waiting mostly. Since Congress seems to be industry’s best hope for a regulatory pathway for CBD, industry must lobby Congress to act, which is no small feat. Political gridlock has been immense, and it’s not clear whether CBD regulation is a high priority for the legislative branches. What we do have are some potential options for legislation that would create an exception for CBD in the FD&C Act. There is a bill in the House of Representatives, a bill in the Senate, and a recently introduced discussion draft of a broader cannabis bill has been introduced in the Senate.
The House bill (H.R. 841), also known as the “Hemp and Hemp-Derived CBD Consumer Protection and Market Stabilization Act of 2021,” would make hemp, CBD derived from hemp, and other ingredients derived from hemp lawful dietary ingredients in dietary supplements under the FD&C Act as long as manufacturers comply with NDI requirements and other FD&C Act policies. The bipartisan bill was originally introduced by U.S. Representatives Kurt Schrader (D–OR) and Morgan Griffith (R–VA) in September 2020, then reintroduced in February 2021. It currently has 30 cosponsors and has largely been endorsed by industry.
The Senate bill (S. 1698), also known as the “Hemp Access and Consumer Safety Act,” is a bit broader, allowing hemp-derived cannabidiol in dietary supplements and food. This bipartisan bill, introduced by Senator Ron Wyden (D–OR) and cosponsored by Senators Rand Paul (R–KY) and Jeff Merkley (D–OR), amends the drug exclusion clauses of Section 201(ff)(3)(B) of the FD&C Act to exempt “hemp, hemp-derived cannabidiol, or a substance containing any other ingredient derived from hemp.” S. 1698, too, has industry support, though some wonder if perhaps the Senate bill offers too much too fast.
“[CRN doesn’t] oppose [S. 1698], but we think it takes on more than we need to take on right now,” explains Mister. “We’d like to see supplements move through quickly and then revisit this issue with food. As much as FDA doesn’t like the idea of having CBD in supplements, they seem to be very opposed to putting it in food. So, we say, why take that on? Let’s get supplements done and demonstrate that they can be sold safely; then we’ll come back and work on food.”
Some in the industry argue that these bills don’t do enough to ensure consumer safety and confidence in CBD. NPA has been advocating for FDA to conduct a health hazard evaluation to set a safe use level for CBD, a proposal that recently received pushback from industry trade associations such as CRN and the American Herbal Products Association (AHPA; Silver Spring, MD). The debate around this issue has become particularly relevant since Senate Majority Leader Chuck Schumer (D–NY), along with Senate Finance Committee Chair Senator Wyden and Senator Cory Booker (D–NJ), introduced the discussion draft of the “Cannabis Administration and Opportunity Act.” That is because, while the bill more broadly legalizes cannabis federally, it also sets forth provisions for the regulation of CBD, one of which requires FDA to set a “recommended daily serving.”
Mister and Michael McGuffin, president of AHPA, contend that the Dietary Supplement Health and Education Act of 1994 (DSHEA) does not give FDA the authority to set a dosage level for dietary supplements—and that allowing them to do so would set a bad precedent for dietary supplements going forward. They argue that the current regulatory framework such as the NDI notification process obviates the need for FDA to have specific limit-setting authority since the agency already needs to review the dosage and safety documentation of individual notifications.
Additionally, through the NDI notification process, should FDA object to the notification’s conclusions and send an “inadequate safety/identity” (IAL) letter, the company submitting the notification could still choose to go to market. The burden then falls on FDA to prove the product is unsafe and therefore should be taken off the market. The fear is that the language of the “Cannabis Administration and Opportunity Act” does not provide enough flexibility for companies to market products at higher doses or, for that matter, increase FDA’s limit through subsequent NDI notifications.
“If FDA gets to set the level up front, companies don’t get any wiggle room,” says Mister. “If you sell any more than that amount, you will be per se illegal with no ability to confront the agency on their data. And, finally, if that were to happen, it would be unlikely for FDA to go back and revisit that number in a year or two. And we’re very optimistic that the safety data on CBD is going to continue to evolve. If they artificially set it too low…that may be the level that we’re going to have to live with for the foreseeable future, and that is not the way DSHEA was set up. DSHEA was set up so that individual companies go to the agency, and then the burden falls back on FDA to say that the product is unsafe.”
Fabricant argues that the setting of a safe use level for CBD is important for consumer safety and the industry’s credibility. “We certainly think there is a safe level of CBD; it’s that it still needs to be determined,” says Fabricant. “We have a product that was a drug. The basis of food and drug law is that foods and drugs differ by two fundamental things: they differ by claims, which isn’t really the issue here, or they differ by dosage/concentration. With drugs, we’re okay with side effects; with foods, we’re not. That’s the basis of food drug law in its simplest, most reductive form. For our purposes, for the industry’s purposes, for our credibility, [it’s important to determine] the dosage at which CBD behaves not in a pharmacological manner, because we’re not selling drugs, but in a physiological manner, and that’s really the issue. This isn’t political science; this is actual science.”
Nor does Fabricant believe that FDA will be unreasonable in the dosage it would set. And even if the dosage were set low, the FD&C Act would still allow companies to raise levels over time through NDI notifications and Generally Recognized as Safe (GRAS) submissions, he says.
“The science evolves faster than the labeling, and I think there is a degree of comfort with that as long as companies are being responsible and taking steps with toxicology studies,” says Fabricant. “It’s always the worry they’re going to set too low of a dose, but there are other avenues to remedy that. The first pathway is to at least have a way to get a foot in the door, at least crack the door open a little bit, and then see how much further it can be pushed open. Also, given the fact that FDA has effectively exercised enforcement discretion, has let all these products out there in the past four years, the wine is already spilled on the table. It’s tough to get back in the bottle.”
What Fabricant would like to see, however, is the “Cannabis Administration and Opportunity Act” be applied to CBD-containing foods as well. He recalls his time as Director of the Division of Dietary Supplement Programs at FDA when energy drink manufacturers were going back and forth between labeling their products as dietary supplements and food. “That’s the situation you want to avoid, because you’re going to see cans of CBD water labeled as supplements,” he says.
More to Learn
The overarching concern from FDA continues to be the lack of safety data for CBD. The most extensive research available for CBD is in a pharmaceutical context, which is not a realistic way to assess the safety of CBD’s long-term consumption in the form of food or dietary supplements. What is clear is that the concentration of CBD in dietary supplements and foods is, generally speaking, significantly lower than the approved CBD drug Epidiolex. It is up to manufacturers to demonstrate that these concentrations are safe for consumers. Unfortunately, as the recent NDI notifications have demonstrated, this may not be enough for FDA.
Another avenue for companies that want to market their CBD products has been independent conclusions of GRAS status. This is done when a manufacturer wants to introduce a new ingredient into the food supply. Usually conducted through an expert panel, the ingredient’s safety is evaluated through a toxicology study. If the results of the study are positive, the manufacturer could then conclude independently that it is generally recognized as safe and may be used in foods. “The information that’s pivotal to the conclusion that the intended uses of an ingredient are reasonably certain to be safe for GRAS is required to be published and widely available in a place where people who can evaluate that kind information can read it, such as journals specializing in toxicology,” explains AIBMR’s Endres.
When it comes to CBD, CV Sciences (San Diego, CA), through safety work done by AIBMR Life Sciences, made the first independent conclusion of GRAS in the category for its PlusCBD Gold formula, conducting the first toxicology study on a hemp extract since 1981. That study determined that the uppermost intake level for the ingredient that was safe for human consumption was 70 mg per day. Not only does the study demonstrate the ingredient’s safety but it also adds to the body of evidence FDA will eventually refer to. This is important to the future of the CBD category. For example, adding to the body of research for CBD was a major reason Irwin Naturals submitted an NDI notification, Irwin says. “We submitted the NDI as a helpful gesture to FDA to provide the safety and historical use data they have been requesting from the public for the last couple of years, in order to help the industry progress,” Irwin tells Nutritional Outlook.
While FDA might dismiss peer-reviewed toxicology studies on a case-by-case basis, such as it did with the recent NDI notifications, broader efforts are underway to demonstrate the safety of CBD.
For example, research technology and information firm ValidCare (Denver, CO) undertook a CBD safety study evaluating the effects of CBD usage on the liver. Thirteen companies (of which Charlotte’s Web was one) volunteered to have their products in the study, and 839 consumers volunteered as test subjects, each taking a CBD product daily for 60 days while journaling their experiences, then submitting themselves to a blood draw. Preliminary findings showed there was no evidence of liver toxicity. These findings were shared with FDA and will be peer-reviewed, says ValidCare. Subsequently, ValidCare has added a second cohort to the study, with additional brands participating and additional financial support.
Besides safety, there is also a lack of research on the effects of CBD. Much is said in blogs and through word of mouth about the ingredient’s many benefits, but how much do we actually know?
“While hemp-derived CBD extract is believed to have neuroprotective, anti-inflammatory, and anxiety-reducing benefits, the ‘how’ by which CBD works is still unclear,” says Pelin Thorogood, Radicle Science (San Diego, CA) cofounder and executive chairwoman. “Most evidence points towards a calming effect in the central nervous system or a reduction in the levels of pro-inflammatory cytokines in our immune system. Consumers and CBD brands alike are hungry for more rigorous scientific data to shed light on how these products can be used to help people live healthier, fuller lives.”
A healthcare B Corp that validates natural products, Radicle Science recently launched its Radicle ACES (Advancing CBD Education and Science) Study, which will utilize its proprietary data analytics platform and a virtual, direct-to-consumer model to deliver objective health outcome data across diverse populations and conditions. The four-week study will evaluate the effectiveness of 13 CBD products on wellbeing, quality of life, pain, sleep disturbance, and anxiety across nearly 3000 participants throughout the U.S.
“Given the growing number of commercially available CBD formulations, there is a lot of confusion about how these products work, what they do for different people, not to mention the basics: when, what, and how much to take for any given condition,” explains Thorogood. “With that in mind, it is not surprising that the top two barriers preventing consumers from trying CBD are still a lack of research on its health benefits and an inability to gauge the effectiveness of specific products.”
All these efforts are crucial when securing the future of hemp-derived CBD. Even failed NDI notifications don’t need to be viewed negatively per se.
“Although we disagree with FDA’s response, in reflecting on the process we do continue to be of the mindset that interaction with FDA and other regulatory agencies is a net positive activity, as the future of the industry, including the sale of hemp-derived products, will need regulatory agencies and the committed members of the industry to work together to make sure consumers are getting safe and effective products,” says Irwin. “We are hoping that FDA’s responses to ours and Charlotte’s Web’s NDI notifications serve as an extra incentive for industry to come together and push Congress to pass a bill clearing the pathway for these ingredients, as well as for the actual Congresspeople who want to provide the positive impact that unshackling this ingredient would have on their jurisdictions.”
Research can be difficult and expensive, with few short-term benefits, but it can be an essential way to set your business up for the future. When regulatory approval is eventually achieved, it’s the brands that have conducted toxicology studies or effectiveness studies that will come out on top. They will not only be better prepared to work with regulators but also be a more attractive brand partner for other companies.
What About Other Cannabinoids?
The fact is that CBD is just the tip of the iceberg when it comes to cannabinoids. So, the future for hemp-derived cannabinoids is sure to be a rich one, but will it also open up the same can of worms CBD is grappling with?
One of the more controversial developments in the hemp-derived cannabinoid space is the commercialization of delta-8 THC products. Marketers of delta-8 THC claim to be legal based on a reading of the 2018 Farm Bill which placed a threshold of 0.3% by dry weight of delta-9 tetrahydrocannabinol (THC) levels for hemp derivatives and extracts. With no mention of delta-8 THC or other tetrahydrocannabinols in the legislation, as well as lack of clarity from the U.S. Drug Enforcement Administration on whether synthetically derived tetrahydrocannabinols from hemp are controlled substances, these products are developing a firm foothold.
Complicating matters is that while there is no guidance on delta-8 THC federally, some states have taken measures to ban the compound. It’s worth noting that delta-8 THC does have intoxicating effects, though not to the same extent as delta-9 THC, making it potentially dangerous. The spike in delta-8 THC products is the result of an oversupply of hemp, which drove down CBD prices. Farmers and extractors began synthesizing delta-8 THC as a way to use that surplus and make their money back. It’s clear from this that farmers and extractors need more options, because having CBD as one of the few commodities available to hemp farmers and extractors is simply unsustainable.
There is already great interest in minor cannabinoids such as cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN) in the dietary supplement space, but that also means there will inevitably be great interest in these in the pharmaceutical space, and therefore, we may have a bit of a race on our hands. The big question is whether these minor cannabinoids fall under the drug preclusion clause. For the time being, it looks like they may be fair game.
“If it had no CBD, or trace amounts of CBD, and is low enough in THC, that shouldn’t be a problem,” says Endres. “I mean, as soon as CV Sciences started selling their legally GRAS products and supplements—the PlusCBD oil—that has not very much but small amounts of CBG, CBN, CBC, those aren’t going to be subjected to the drug exclusionary clause. They’re free game, and it’s probably not a bad path to go down.”
“I do think it leaves the door open for other cannabinoids to pursue an NDI because presumably those have not been studied in clinical trials,” adds Mister. But this approach is not without its own complications.
“So, they’re not subject to drug preclusion, but at the same time we know that the drug industry is watching this very carefully, and as we have seen with other ingredients, some company may come along and say it already had a clinical trial on a cannabinoid,” Mister says. “That is the problem we have with the drug preclusion provision—that 27 years later, we still have very little direction from the agency on how it interprets that provision. We think about what happened over the last year with N-acetyl-L-cysteine (NAC). That’s a case where FDA is going back to 1963 and citing a clinical trial performed then on an inhaled version of the ingredient at a different dosage and saying that clinical trial was enough to trigger the drug preclusion language.”
This avenue may therefore pose its own challenges, but the possibility of legitimacy is absolutely worth exploring. It’s unfortunate that one of the things that dogs the industry is the idea that it’s unregulated. Unfortunately, FDA’s own inaction when it comes to CBD only reinforces this idea, to the detriment of responsible industry and the benefit of fly-by-night brands. What’s clear, however, is that CBD is not going anywhere, and FDA seems to have resigned itself to that by doing the bare minimum, limiting its enforcement to warning letters, and waiting for Congress to create a regulatory pathway.
In the meantime, it’s crucial for industry to secure its future in the CBD space. This means lobbying Congress to pass the necessary legislation, employing good manufacturing practices for CBD products, and, when possible, conducting research that establishes the safety and effectiveness of one’s products. Ultimately, once a regulatory pathway is established, this preparation will allow for an easier transition to legal dietary supplements and food.