Is Hemp CBD a Legitimate Ingredient of Dietary Supplements?
Is it time for the hemp CBD dietary supplements industry to
panic? Not at All, Say Insiders. This post from Nutritional
Outlook highlights the questions raised by FDA’s CBD warning
letters to some players of the dietary supplements industry.
When FDA sends a group of warning letters calling out a
particular dietary supplement ingredient, people tend to sit up
and take notice. But when that ingredient is as new, as trending,
and as controversial as hemp CBD, attention goes sky high.
On February 4, FDA issued warning letters to eight makers of
products being illegally sold as dietary supplements while making
disease-benefit claims. Some worry the agency is seeking to
exclude cannabidiol (CBD) from the definition of a legitimate
dietary supplement ingredient.
In a letter[1] to one of the companies, CBDy, FDA stated:
You should be aware that, based on available evidence, FDA has
concluded that CBD products are excluded from the dietary
supplement definition under section 201(ff)(3)(B)(ii) of the Act
[21 U.S.C. § 321(ff)(3)(B)(ii)]. Under that provision, if a
substance (such as CBD) has been authorized for investigation as
a new drug for which substantial clinical investigations have
been instituted and for which the existence of such
investigations has been made public, then products containing
that substance are outside the definition of a dietary
supplement. There is an exception if the substance was “marketed
as” a dietary supplement or a conventional food before the new
drug investigations were authorized; however, based on available
evidence, FDA has concluded that this is not the case for CBD.
This is the same language FDA used in a Q&A publication[2] the
agency first published on its website back in May 2015, titled
“FDA and Marijuana: Questions and Answers.” Buried within the
document’s information on marijuana was a short nod to questions
about CBD’s allowance as a dietary supplement ingredient.
FDA’s Issues with CBD Supplements
A recent spate of FDA warning letters does not mean the emerging
CBD dietary supplements market is in trouble, say insiders. But
it does raise some important questions about what’s fair in terms
of drugs versus supplements.
By stating it “has concluded that CBD products are excluded from
the dietary supplement definition,” FDA appears to clearly spell
out that, at this time, the agency does not consider CBD a
legitimate supplement ingredient. CBD holds neither Generally
Recognized as Safe (GRAS) status for use in food and beverages,
nor has anyone filed a notification with FDA for CBD as a new
dietary ingredient (NDI) for supplements.
For now, the crux of the agency’s CBD issue, based on FDA’s
statements, centers on two Investigational New Drug (IND)
applications that were filed by drug firm GW Pharmaceuticals for
its Sativex and Epidiolex CBD drug products. Per the Federal Food
Drug & Cosmetic Act (Section 201(ff)(3)(B)(ii)), if a drug
company, via an IND application, has said it is investigating an
ingredient as a drug, and if supplement marketers cannot prove
that the ingredient was sold as a dietary supplement prior to the
IND filing, then the ingredient is prohibited from being a
dietary supplement ingredient. FDA has said “the law is intended
to maintain incentives for companies to establish the clinical
safety and efficacy of drug products.” (The agency made this
statement following the 1997 case involving a red yeast rice
supplement, Cholestin, and a Merck drug, Mevicor, containing the
same active ingredient—a case that ultimately saw the Cholestin
supplement removed from the market.)
Supplement Ingredient Prior to IND?
The easy question to ask off the bat is whether there was ever a
CBD dietary supplement on the market before GW Pharmaceuticals
filed—and FDA accepted—its IND applications for Sativex and
Epidiolex. (The company was founded in 1998.) If proof exists, it
would seem simple enough for the supplement company selling the
product to step forward with the evidence. In its warning letter
to CBDy, FDA invited the company to “present the agency with any
evidence that has bearing on this issue” to show that CBD
supplements were on the market prior to the IND filing.
In a February 19 statement responding to FDA’s recent CBD warning
letters, the Hemp Industries Association (HIA) said, “It is the
position of the HIA that legal hemp products containing CBD were
marketed as foods and dietary supplements long before cannabidiol
formulations were submitted to FDA for testing as a ‘new drug.’”
Speaking to Nutritional Outlook, HIA’s executive director, Eric
Steenstra, says, “The FDA has not yet presented any evidence
regarding their claim [that CBD was not sold as a dietary
supplement or conventional food prior to GW Pharmaceuticals’ IND
applications]. We do believe that products containing CBD were
marketed and sold prior to any IND, and we intend to work with
industry members at the appropriate time to share the evidence.”
But finding the evidence is not as simple as it seems. For one
thing, FDA does not post publicly the date on which an IND
application was accepted. (A January 4, 2006, press release on GW
Pharmaceuticals’ own website announced that FDA had accepted the
IND application for Sativex.)[3] This makes determining an
official cut-off date to answer the “Which came first?” question
difficult.
Another controversy is whether GW Pharmaceuticals’ Sativex drug
can be considered comparable to any of the pure CBD oils sold by
the supplements industry because Sativex is a blend of both CBD
and another hemp cannabinoid, delta-9-tetrahydrocannabinol (THC).
CBD supplement companies selling purely CBD oils argue that these
products cannot be compared “apples to apples” with Sativex
because Sativex also contains THC. (GW Pharmaceuticals’ other
drug, Epidiolex, however, contains only CBD.)
“There are legitimate questions that can be raised,” says Michael
McGuffin, president of the American Herbal Products Association
(AHPA).
McGuffin acknowledges that GW Pharmaceuticals met the three
criteria it needed for an IND “that are described in the specific
provisions of the law: they had an IND, they had initiated
substantial clinical research, and they had said so publicly.”
But, he adds, “‘What was the article?’ has to be one question.”
(The Federal Food Drug & Cosmetic Act refers to an ingredient as
an “article.”)
“The provision of the law says that when [a drug company meets
all three criteria for the IND], then the drug industry, the drug
marketer, has exclusivity for that article,” McGuffin says. But
“what was Sativex? Sativex is a cannabis derivative that contains
a certain amount of THC and a certain amount of CBD.”
So, while supplement companies would not be able to sell this
combination of THC and CBD if the GW Pharmaceuticals IND holds
true, that doesn’t necessarily mean that supplement companies
wouldn’t be able to sell other cannabinoid products.
“What was the article that was protected by that provision?
What’s clear is supplement companies can’t sell that [Sativex]
article,” McGuffin says. But, he questions, “Is it also just as
clear that supplement companies can’t sell any of the
constituents contained in that article? If that is the case, or
if that’s FDA’s interpretation, then how well substantiated is
that interpretation?”
“I don’t think we can ignore it,” he says, continuing, “I don’t
have a contrary opinion as much as I think it’s a legitimate
question to ask whether FDA is correct in saying that because
Sativex and Epidiolex met the three IND criteria, that means that
[the dietary supplements industry] can’t market any of the
constituents in any of those drug products.”
One company raising these types of questions publicly is CBD oil
company CV Sciences Inc. (San Diego, CA), formerly known as
CannaVest Corp. The company has written a position paper
responding to the statements FDA made in the agency’s May 2015
marijuana Q&A posting. CV Sciences has been disseminating its
position response to its own contacts within the dietary
supplements industry. (The company says it has not, and does not
plan to, however, send the document directly to FDA.)
According to CV Sciences’ paper, “all requirements to consider
CBD under the IND preclusion regulations have not been adequately
conducted, thus furthering our opinion that CBD is not precluded
from the definition of a ‘dietary supplement.’” It continues, “it
is our opinion, which is broadly shared by the marketplace, that
CBD has been marketed as a dietary supplement prior to
commencement and public notice of any substantial clinical
investigations instituted on CBD, as the investigations that were
publicized were not substantial, due to being limited in number
and preliminary in nature, thereby rendering the IND preclusion
inapplicable.”
Speaking to Nutritional Outlook, Stuart Tomc, vice president,
human nutrition, for CV Sciences, says, “We’re going to argue the
idea of what is a substantial clinical investigation and when is
making it public. We’re going to take on the IND issue. If
someone’s going to have to lead this debate, it’s going to be us.”
At this point, it’s still worth noting that, to date, no CBD
supplement company has come forth with evidence showing that its
CBD supplement product was on the market prior to a CBD IND filed
by the drug industry. McGuffin says, “I’m not aware of anyone
having concluded that there either was or was not a CBD product
on the market prior to the GW date.”
Regardless, the fairness question raised by the IND provision
excluding supplements from the market troubles many.
“What the [FD&C Act] provision says, in summary, is that for any
article, if the drug industry gets there first, they get an
exclusivity,” McGuffin says. “And what they need to do to get
there is to say that they’re really interested in getting there.
They have to satisfy those three provisions. They don’t actually
have to be in the marketplace [selling product]. And if they
satisfy those three provisions, they get an exclusivity.”
He continues, “If the supplement industry gets to the marketplace
first, we can share the marketplace with the drug industry. So, a
basic fairness question arises: ‘Is that fair that the drug
industry gets exclusivity and we get a shared marketplace?’”
Consider, also, the long time it takes for a drug firm to get its
drug product to market. Merck, McGuffin says, took years,
possibly longer than a decade, to get to the marketplace with
Mevicor after the scientific publications on lovastatin, the
active ingredient in red yeast rice, appeared as far back as
1979. In the case of CBD, McGuffin points to a 1973 university-
researched article[4] on CBD for health benefits, titled “The
anticonvulsant activity of cannabidiol and cannabinol.”
Fast-forwarding to today, McGuffin says, “That’s 34 years of
publicly available information. Can one drug company now own
that? Is that okay?”
Instead, he says, “What if there was some kind of time
restriction? What if, for example, an additional criteria was
established that the drug industry has to establish those three
[IND] criteria within X years from the first publication of the
scientific research on that substance” in order to maintain its
market exclusivity?
“Let’s assume that we want rules that protect the research
interests of the drug industry,” he says. “But we also want rules
that protect consumer access to long-used ingredients. Do we want
to think about a revision to this provision in the law?”
Responsible Industry
Short of a revision to the law any time soon, CBD firms are
taking steps on their own to protect their industry—namely, by
ensuring they and their colleagues are marketing these products
lawfully and responsibly.
CV Sciences’ Tomc says he was “thrilled” to see FDA issue warning
letters to companies making illegal drug claims. “We were
thrilled that the warning letters went out, because these people
don’t understand the dietary supplement space [and] come from the
cannabis space or are entrepreneurs,” he says. “We actually think
these warning letters are great for the CBD market.”
“We implore, we beseech, all the other CBD companies to follow
the regulations of the FDA. We need to make sure that people
aren’t making medical claims because we’re not selling medicine,”
adds Sarah Syed, director of marketing, CV Sciences. “It’s a
challenge because the market is growing, but many people don’t
know what they’re doing wrong. They don’t know what they don’t
know, and they don’t know the regulations behind dietary
supplements and the health claims that you cannot make.” Syed and
Tomc point out the “variance” of companies in the market, which
includes larger, established firms like CV Sciences as well as
small start-ups and individuals growing their own cannabis.
Efforts are being made to bring the larger CBD market in line
with the regulations, including efforts by AHPA’s own Cannabis
Committee. The committee was formed five years ago when, McGuffin
says, “we saw this emerging marketplace and need of a forum and
community for the best companies to get together and discuss how
they could establish businesses with long-term marketplace
opportunity and not a short-term marketplace opportunity.”
Just last week, on February 19, the committee held a call with a
wide representation of CBD companies in the market. Tomc says,
“Here was the tone: Don’t make disease claims. If you are making
disease claims, hang up right now, fix it, and come back.” Tomc
says these types of calls “show the industry is being proactive.”
Industry Concern
Does the CBD industry at large worry that the recent FDA warning
letters threaten the future of the CBD supplements industry? Tomc
says no. He says that while FDA has “insinuated” that CBD may not
be a dietary supplement ingredient, he also points out that
warning letters only went to many of what he calls the “smaller
players” in the CBD market. “All the letters went to very small
players in the CBD space,” he says. “The larger players in this
space really have not received any warning letters.”
Does this mean only smaller companies have made disease claims?
Or does it mean that FDA, as a whole, has chosen not to actively
pursue the category unless companies are breaking the law? Has
the agency decided to leave the responsible CBD supplement market
alone until the case is settled as to whether or not CBD is a
legitimate supplement ingredient?
In the agency’s own words in its May 2015 Q&A piece, FDA did not
state that it is banning CBD. Instead, it said, “When a product
is in violation of the FD&C Act, FDA considers many factors in
deciding whether or not to initiate an enforcement action. Those
factors include, among other things, agency resources and the
threat to the public health. FDA also may consult with its
federal and state partners in making decisions about whether to
initiate a federal enforcement action.”
In terms of FDA pulling CBD supplements off shelves, Tomc says,
“We’re not there yet.” He adds, “There would have to be a trend
toward public harm. There is no trend toward public harm. The
amount of effort, the case that would have to be built—FDA is not
going into health food stores and telling people you cannot carry
these products. That’s not going to happen.”
He adds, “FDA did not say you can no longer sell this. There has
been no enforcement action. It’s all been Q&A posturing. Nothing
has happened yet. I think that’s important to remind everybody
about, because we still have the process of making the argument
to society in general and to regulators as to where this
ingredient is going to end up.”
In the meantime, Tomc says, CV Sciences’ goal is to continue
strengthening the science behind its ingredient. He says the
company has completed its own toxicological study that would be
the foundation of a GRAS self-affirmation. The data is now under
review.
Notably, Tomc says, it would be the first toxicological study
done “in the history of cannabis.” He says, “No one’s ever done
it for hemp, hemp protein, hemp meal, hemp seeds, hemp
oil—nothing cannabis-related has ever been tested to be safe.”
John Endres, ND, chief science officer for AIBMR Life Sciences
Inc. (Puyallup, WA), which specializes in GRAS services, says,
“As far as I know, there has been no GRAS self-determination
completed for any CBD-rich hemp oil.”
This would make CV Sciences’ data a landmark in the CBD
industry—and, indeed, the larger cannabis industry. Whether Tomc
thinks such data could cause FDA to see CBD in a new, positive
light, he says instead, “It could set a precedent that FDA may
adopt in deciding which suppliers they’ll allow on the market.”
“What we’re doing now is demonstrating that the ingredient we’re
bringing to market is safe and effective. And that’s our primary
responsibility,” he continues. “The indefensible position is the
lack of formal toxicological evidence of safety. I don’t blame
anybody for having questions about safety until you see the data.
That’s good, skeptical thinking.”
“Ingredients that are sold either for the addition to foods or as
dietary supplements need to demonstrate that they are safe for
consumption,” Endres says. “The CBD products that are on the
market are different in that some are much higher in CBD than
what is naturally occurring and therefore should be the subject
of rigorous toxicological assessments to determine what the safe
cumulative daily exposure is. The conclusions of such
toxicological studies are then used to support regulatory status
for the intended use of these products—GRAS for food ingredients
and NDI notifications for dietary ingredients/dietary
supplements.”
He concludes, “The completion and publication of safety studies
on a CBD-rich hemp oil product in a peer-reviewed academic
journal specializing in toxicology will be, to the best of my
knowledge, the first in recent times and a monumental step
forward in putting real science behind a product. I would have to
conclude that the public and the FDA should applaud this effort
as well as the time and expense it requires.”
CBD: Just the Beginning
In many ways, the challenges CBD faces are the growing pains that
any ingredient relatively new to the supplements market would
face, including carving out a place in the regulatory domain. The
demand for this ingredient is very high, according to CV
Sciences, with Tomc adding that many of the more than 500 stores
carring CV Sciences’ CBD oil products complain they can’t keep up
with the demand. As marijuana is increasingly legalized across
the country, the CBD industry is additionally challenged by
individuals and small companies wanting to participate in the
supplements market but not familiar with the regulations.
But, say individuals we spoke to, the bottom line is that there
are CBD companies looking to market products responsibly.
“Yes, I do believe there is a responsible center of the
cannabis/CBD/medical marijuana industry developing, and we’re
certainly working to keep them organized and informed,” AHPA’s
McGuffin says.
HIA’s Steenstra says, “HIA member companies are marketing CBD
responsibly, and none were sent letters. We believe that the vast
majority are in compliance with [the Dietary Supplement Health
and Education Act].”
As for CV Sciences, the company believes that one day, CBD
supplements and drugs will be able to live in harmony. In its
position letter, the company states, “Based on global demand for
hemp-derived CBD, a compromise will eventually be reached, with
artisanal hemp extracts sold in coexistence with pharmaceuticals,
as is the case with prescription omega-3 fish oils and
commercially available omega-3 offerings.”
“This isn’t the end of the CBD market,” Tomc says. “It’s just
getting started.”
