Update on the Regulatory Status of Cannabidiol in Food and Dietary Supplements and Future Prospects


This article covers the regulatory status for using cannabidiol (CBD) as a dietary supplement and presents the US Food and Drug Administration’s (FDA’s) position as well as conflicting viewpoints taken by some in the industry. The impact of the Agricultural Improvement Act of 2018 (2018 Farm Bill) is evaluated along with the future prospects for CBD.
 
Introduction
 
Cannabidiol (CBD) is one of several cannabinoids found in the hemp and marijuana varieties of the Cannabis sativa L. plant. Hemp-derived CBD ingredients have become increasingly popular in foods and dietary supplements due to their purported health benefits and negligible levels of delta-9 tetrahydrocannabinol (THC), the cannabinoid responsible for the psychoactive effects associated with marijuana. This popularity comes despite FDA taking the consistent position that CBD cannot be added to food or dietary supplements due to the investigation and subsequent approval of CBD as a drug. However, despite FDA’s sporadic enforcement, the industry’s disagreement with FDA’s position has led to a proliferation of CBD-containing dietary supplements and food in the market, as well as confusion among the industry as to FDA’s intentions for these product categories. This is especially true with regard to products containing naturally occurring, low CBD levels and easily distinguished from CBD drugs. Recent statements by the agency indicate its willingness to pursue a regulatory framework for CBD to ensure the safe use of this ingredient while preserving consumer access to CBD-containing food and supplements. The timing remains uncertain.
 
FDA’s Position: Overview
 
FDA first turned its attention to CBD in early 2015 with a series of Warning Letters issued to various firms marketing CBD products which they promoted for disease conditions, such as cancer and arthritis, thereby rendering the products unapproved drugs.1 In addition, after testing the chemical content of cannabinoid compounds in some of the products, FDA found that many did not contain the levels of CBD they claimed to contain. In 2016 and 2017, FDA issued numerous additional Warning Letters, again citing disease claims and discrepancies between the labeled CBD content and the actual amounts in the products. However, in several of these letters, FDA also stated that the agency “has concluded based on available evidence that CBD products are excluded from the dietary supplement definition under section 201(ff)(3)(B)(ii) of the Act.”2
 
Under section 201(ff)(3)(B)(ii) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), referred to as the “IND Preclusion,” if an article 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 the substance are precluded from the definition of a dietary supplement—unless the substance was marketed as a dietary supplement or as a conventional food before the new drug investigations were authorized.3 The statute also permits the Secretary of Health and Human Services (through FDA) to issue a regulation allowing the use of an article otherwise prohibited under the IND Preclusion. Of note, the IND Preclusion only applies to dietary supplements and foods and, therefore, cosmetics containing CBD are not impacted by the prohibition.

In the Warning Letters, and in a questions and answers document on cannabis and cannabis-derived ingredients posted on FDA’s website,4 FDA concluded that, based on available evidence, the agency believes that CBD was not marketed in a food or supplement prior to the investigation of CBD as a new drug. Specifically, there is evidence showing as early as 4 January 2006, a CBD ingredient was authorized for investigation as a new drug.5 The agency also notes in the Q&A document that “[i]nterested parties may present the agency with any evidence that they think has bearing on this issue” but that its “continuing review of information that has been submitted thus far has not caused us to change our conclusions.”6

 

These statements leave open the possibility that FDA could reverse its position if industry is able to bring forth credible evidence demonstrating CBD was marketed in food or dietary supplements prior to the authorization for investigation of CBD as a new drug. However, this exercise may not be necessary since FDA announced in December 2018 it is looking at the possibility of utilizing its authority to issue a rulemaking essentially overriding the IND Preclusion as it pertains to CBD, as permitted by the statute.7  

 
A Closer Look at the IND Preclusion Issue and its Applicability to CBD

 

Taking a closer look at the IND Preclusion in 201(ff)(3)(B)(ii), it includes several requirements needing be true for an ingredient to be precluded from the definition of a dietary supplement. First, the article must have been authorized by FDA for investigation as a new drug. Second, substantial clinical investigations must be instituted. Third, the existence of such substantial clinical investigations must be made public. Finally, the forgoing must have occurred prior to the marketing of the article as a dietary supplement or food.8 All of these conditions must be met before the article can be precluded from use in a dietary supplement.

 

As noted above, there is evidence CBD was authorized for investigation as a new drug as early as 4 January 2006.9 However, it is debatable whether FDA has met the additional requirements of the statute and whether the clinical investigations of CBD were, in fact, “substantial” and made public prior to the marketing of CBD as a dietary supplement or food. The studies conducted on CBD prior to its marketing as a food and/or dietary supplement were preliminary Phase I and Phase II studies, rather than full-scale Phase III studies, limited in nature and arguably not “substantial.” To date, however, there is no case law or other precedent for interpreting the meaning of “substantial,” nor is there any legislative history providing insight into what Congress intended when including this language in the statute.

In addition, it could be argued that the use of CBD in a food or dietary supplement predated both the date at which substantial clinical investigations were instituted and the time at which such substantial clinical investigation was made public—raising the possibility that not all requirements for IND Preclusion apply to CBD. The industry has claimed such evidence exists but, to date, FDA has not considered or ruled on this evidence.

 

Industry stakeholders also have put forth arguments the IND Preclusion does not apply to “full spectrum” hemp extracts, which contain all of the naturally occurring compounds in the hemp plant in their natural form, including CBD. The clinical investigations on CBD described above were on an isolated, concentrated form of CBD and, therefore, full spectrum hemp extracts could be considered an entirely different “article” than the CBD “article” studied as an investigational new drug.  Industry is currently in engaged in discussions with FDA on these matters, but recent developments indicate the debate over the applicability of the IND Preclusion may not play out, given the agency’s willingness to explore regulatory pathways to allow the use of CBD in food and supplements, as discussed below.  

 
Impact of the 2018 Farm Bill

 

On 20 December 2018, the president signed into law the Agriculture Improvement Act of 2018 (the 2018 Farm Bill).10 The 2018 Farm Bill categorizes hemp as a legal agricultural commodity and removes hemp and its derivatives—including cannabinoids, such as CBD—from the definition of “marihuana” in Schedule I of the Controlled Substances Act (CSA), provided the concentration of THC is not more than 0.3 percent.11 Prior to the passage of the 2018 Farm Bill, only products derived from exempted parts of the Cannabis sativa L. plant were not considered controlled substances.12 For example, ingredients or products sourced from the mature stalk or sterilized seed of the hemp plant have always fallen outside the definition of “marihuana.” However, CBD is found in only negligible amounts in exempted plant parts, leading both federal and state law enforcement to question the source of CBD products.13 The 2014 Farm Bill also allowed for the growth and cultivation of hemp through state agricultural pilot programs, but only for limited uses.14 Given these limitations and conflicting interpretations about the legal status CBD itself, concerns about enforcement have led many companies to shy away from developing and marketing CBD products. Following the passage of the 2018 Farm Bill; however, many companies viewed the legalization of hemp as an opportunity to freely enter this market.

The 2018 Farm Bill includes two key limitations. First, it also allows states to be the primary regulators of hemp in their states and take a more restrictive approach to the sale of hemp and hemp-derived products, which many states were already doing even before the bill’s passage, and continue to do.15  Second, the legislation clearly states that “Nothing in this subtitle shall affect or modify…the Federal Food, Drug, and Cosmetic Act…”16 In other words, the 2018 Farm Bill did not affect FDA’s position on CBD, nor its authority to regulate CBD as a food or dietary ingredient under the FD&C Act. In fact, just hours after the President signed the bill, FDA issued a statement reiterating its position on CBD. However, it also stated that the agency is “committed to pursuing an efficient regulatory framework for allowing product developers that meet the requirements under our authorities to lawfully market these types of products.”17 The statement specifically cites the agency’s authority to issue a regulation allowing the use of previously approved drug ingredients subsequently in supplements and food. This is significant because it would mark the first time FDA used this authority. While other ingredients are used in both drugs and supplements and foods (e.g., fish oil and niacin), in those cases, the use of the ingredients as a food or supplement pre-dated their use as drugs, and, therefore, the IND Preclusion did not apply. 

 

The agency has made similar public statements with respect to CBD in recent months and has formed a working group on CBD. They are engaging with the US Congress to address this matter in an efficient manner, recognizing that a formal administrative rulemaking would likely take years to finalize.18 In April 2019, FDA also announced a public hearing and comment period to obtain scientific data and information about the safety, manufacturing, product quality, marketing, labeling and sale of products containing cannabis or cannabis-derived compounds, including CBD.19 Notably, Members of Congress also have weighed in on CBD and have asked FDA to prioritize the regulatory pathway for CBD and its use in food and supplements.20

 
Current and Future Prospects for CBD   

 

That both FDA and Congress are seeking swift resolution is a positive sign and could make the prospect of legislation more likely than rulemaking. There are concerns, however, as this issue may be “derailed” by other Congressional priorities as well as debates over the details of what the framework for CBD in supplements and food will look like. For example, any such framework is likely to include limitations around the use of CBD in these products, such as daily dosages limits. Such action by FDA also could create a precedent for other ingredients since, historically, FDA has not set dosage levels for individual ingredients. In addition, the intent of the IND Preclusion is to protect pharmaceutical manufacturers’ investment in the study of drug ingredients, so the pharmaceutical industry may decide to weigh in on any legislative or regulatory proposal concerning CBD.

 

Some industry stakeholders have cited FDA’s position on red yeast rice dietary supplements as a model for how to approach CBD. In that case, FDA found the makers of red yeast rice supplements with enhanced or added lovastatin could not be marketed as a dietary supplements due to FDA’s approval of a lovastatin as a drug, which preceded the marketing of red yeast rice products as dietary supplements or food.21 Unlike the case of CBD, the date upon which the lovastatin drug was approved was a determining factor, rather than the date when substantial clinical investigations were authorized and made public. The red yeast rice matter eventually ended up in court, where a federal appeals court agreed with FDA’s conclusions that lovastatin’s approval as a new drug preceded its marketing as a food or dietary supplement, and that lovastatin-enhanced red yeast rice products are not dietary supplements under the FD&C Act.22

 

A key difference between those red yeast rice supplements and current CBD supplements is that the levels of lovastatin in those products were concentrated to almost the same level as FDA-approved drugs containing lovastatin. In the case of current CBD products, the vast majority, if not all CBD supplements and food, contain levels of CBD that are significantly less than the amount of CBD in the FDA-approved drug Epidiolex.23 Epidiolex is an isolated, pure and nearly 100% CBD formulation; it is distinguished from full spectrum hemp extracts containing naturally occurring and very low levels of CBD. FDA has unofficially signaled that full spectrum hemp extracts, where the CBD content is not concentrated or manipulated, do not present the same regulatory considerations as CBD isolate and may not be subject to the IND Preclusion.

 

Another unknown is how states will choose to regulate CBD and other hemp products since, as discussed above, the 2018 Farm Bill does not preempt state law and expressly gives states the ability to impose stricter requirements on the growth, processing, manufacturing and sale of hemp-derived products, including CBD.24 Even prior to the passage of the 2018 Farm Bill, some states opted to regulate CBD and other hemp-derived ingredients in a restrictive manner. For example, in July 2018, the California Department Public Health issued an FAQ on industrial hemp and CBD in food products stating CBD derived from hemp is prohibited for use in food or dietary supplements, while continuing to allow the sale of CBD derived from marijuana that is sourced from, produced and sold by those with commercial cannabis licenses.25 The document further states that “[u]ntil the FDA rules that industrial hemp-derived CBD oil and CBD products can be used as a food or California makes a determination that they are safe to use for human and animal consumption, CBD products are not an approved food, food ingredient, food additive or dietary supplement.”26 In recent months, states such as North Carolina and South Carolina have taken similar positions.27,28 Other states, such as Idaho and South Dakota, prohibit the use of CBD generally, regardless of whether it is added to food products.29,30 State regulation will continue to have a significant impact on the CBD marketplace, as companies will be required to navigate through a patchwork of varied laws before they can determine whether their hemp-derived CBD product is compliant at the state level.

 

Despite FDA’s view and state pronouncements on CBD, the market for hemp-derived CBD supplements and food continues to grow. It is estimated the CBD market will be $16 billion by 2025, even in the face this regulatory uncertainty.31 Importantly, CBD appears to be a safe ingredient at the levels sold in dietary supplements and food products. In 2018, the World Health Organization issued a report concluding that CBD is safe,32 and FDA made similar findings regarding CBD in its scheduling recommendation to DEA regarding Epidiolex.33  

 
Conclusion

Although FDA has clear authority and the tools necessary to take enforcement action based solely on the IND Preclusion, such a move by the agency would likely trigger a legal challenge from industry. FDA’s position has been limited to public statements, Warning Letters and the marijuana FAQ—arguably none of which would be considered final agency actions allowing the issue to be decided by a court. The timing is uncertain, but the recent FDA announcements and Congress’ interest in establishing a regulatory pathway for CBD have encouraged the industry to invest in this product category. In the coming months. The details of the regulatory pathway for hemp-derived CBD are expected to be the subject of intense discussions between FDA and interested stakeholders.

 
References

  1. Warning Letters and Test Results for Cannabidiol-Related Products, 2 April 2019. FDA website. https://www.fda.gov/newsevents/publichealthfocus/ucm484109.htm.  Accessed 7 June 2019.
  2. FDA Warning to Natural Alchemist, 31 October 21. FDA website.  https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm583205.htm. Accessed 7 June 2019.
  3. Federal Food Drug and Cosmetic Act (FD&C Act), 21 USC 321(ff)(3)(B)(ii).
  4. FDA Regulation of Cannabis and Cannabis-Derived Products: Questions and Answers, 2 April 2019. FDA website. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm. Accessed 7 June 2019.
  5. GW Pharma Press Release. FDA Accepts Investigational New Drug (IND) Application for Sativex®, 30 January 2006. https://www.gwpharm.com/about/news/fda-accepts-investigational-new-drug-ind-application-sativexr. Accessed 7 June 2019.
  6. Op cit 4.
  7. Statement from FDA Commissioner Scott Gottlieb, MD, on signing of the Agriculture Improvement Act and the agency’s regulation of products containing cannabis and cannabis-derived compounds, 20 December 2018. FDA website. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-signing-agriculture-improvement-act-and-agencys. Accessed 7 June 2019.
  8. Op cit 3.
  9. Op cit 5.
  10. Agriculture Improvement Act of 2018, Pub. L. No. 115-334, H.R. 2, 115th Cong. https://www.congress.gov/115/bills/hr2/BILLS-115hr2enr.pdf. Accessed 7 June 2019.
  11. Agriculture Improvement Act of 2018, Section12619 (amending the Controlled Substances Act, Section 802(16)). Section 10113 defines “hemp” as “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol [THC] concentration of not more than 0.3 percent on a dry weight basis.”
  12. Controlled Substances Act, 21 USC 802(16).
  13. Drug Enforcement Administration (DEA) Statement. Clarification of the New Drug Code (7350) for Marijuana Extract. https://www.deadiversion.usdoj.gov/schedules/marijuana/m_extract_7350.html. Access 7 June 2019.
  14. Statement of Principles on Industrial Hemp, 81 FR 53395 (12 August 2016). https://www.federalregister.gov/documents/2016/08/12/2016-19146/statement-of-principles-on-industrial-hemp. Accessed 7 June 2019.
  15. Agriculture Improvement Act of 2018, Section 10113 (amending the Agricultural Marketing Act of 1946, Section 297B(a)(3)).
  16. Ibid at Section 10113 (amending the Agricultural Marketing Act of 1946, Section 297D(c)(1)).
  17. Op cit 7.
  18. Drotleff L. “FDA Commissioner: Rules for CBD in Food, Supplements Could Take Years.” 22 March 2019. Hemp Industry Daily. https://hempindustrydaily.com/fda-commissioner-rules-for-cbd-in-food-supplements-could-take-years/. Accessed 7 June 2019.
  19. Scientific Data and Information About Products Containing Cannabis or Cannabis-Derived Compounds; Public Hearing; Request for Comments, 84 FR 12969 (2 April 2019). https://www.federalregister.gov/documents/2019/04/03/2019-06436/scientific-data-and-information-about-products-containing-cannabis-or-cannabis-derived-compounds. Accessed 7 June 2019.
  20. Letter from Senators Wyden and Merkley to FDA Commission Gottlieb. 6 January 2019. https://www.wyden.senate.gov/imo/media/doc/011519%20FDA%20CBD%20Hemp%20Letter.pdf. Access 7 June 2019.
  21. FDA Warning Letter to Ip-6 International Inc., 23 April 2014. FDA website. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/ip-6-international-inc-04232014. Accessed 7 June 2019.
  22. Pharmanex, Inc. v. Shalala, 221 F.3d 1151 (10th Cir. 2000); 2001 US Dist. LEXIS 4598 (D. Utah Mar. 30, 2001) (district court opinion on remand).
  23. EPIDIOLEX® (cannabidiol) Oral Solution—the First FDA-Approved Plant-Derived Cannabinoid Medicine: Now Available by Prescription in the US. 1 November 2018. http://ir.gwpharm.com/news-releases/news-release-details/epidiolexr-cannabidiol-oral-solution-first-fda-approved-plant. Accessed 7 June 2019.
  24. Op cit 15.
  25. California Department of Public Health, FAQ—Industrial Hemp and Cannabidiol (CBD) in Food Products, 6 July 2018. https://www.cdph.ca.gov/Programs/CEH/DFDCS/CDPH%20Document%20Library/FDB/FoodSafetyProgram/HEMP/Web%20template%20for%20FSS%20Rounded%20-%20Final.pdf. Accessed 7 June 2019.
  26. Ibid.
  27. Regulators Notify Industry Regarding CBD Products in the Marketplace. 8 February 2019. https://www.ncagr.gov/paffairs/release/2019/RegulatorsnotifyindustryregardingCBDproductsinthemarketplace.htm. Accessed 7 June 2019.
  28. SCDA Regulators to Notify Industry Regarding CBD and Hemp in Food and Feed Products in the Market Place. 20 February 2019. https://agriculture.sc.gov/scda-regulators-to-notify-industry-regarding-cbd-and-hemp-in-food-and-feed-products-in-the-market-place/. Accessed 7 June 2019.
  29. Idaho Office of Drug Policy Position Statement on CBD. February 2019. https://odp.idaho.gov/wp-content/uploads/sites/58/2019/02/CBD-position-edits-1-14-2019.pdf. Accessed 7 June 2019.
  30. Attorney General Ravnsborg Clarifies Questions Regarding Industrial Hemp and CBD (Cannabidiol) Oil. 25 March 2019. https://atg.sd.gov/OurOffice/Media/pressreleasesdetail.aspx?id=2167. Accessed 7 June 2019.
  31. Dorbian I. “CBD Market Could Pull In $16 Billion By 2025, Says Study.” Forbes. 12 March 2019. https://www.forbes.com/sites/irisdorbian/2019/03/12/cbd-market-could-pull-in-16-bln-by-2025-says-study/. Accessed 7 June 2019.
  32. Cannabidiol (CBD) Critical Review Report. Expert Committee on Drug Dependence. World Health Organization. Fortieth Meeting. Geneva, 4-7 June 2018. https://www.who.int/medicines/access/controlled-substances/WHOCBDReportMay2018-2.pdf?ua=1. Accessed 7 June 2019.
  33. Letter from Brett P. Giroir, MD, Assistant Secretary for Health, Department of Health and Human Services to Robert W. Patterson, Acting Administrator, Drug Enforcement Administration. 16 May 2018.  https://www.votehemp.com/wp-content/uploads/2018/10/HHS-FDA-recommendation-DEA-CBD-2018-0014-0002.pdf. Accessed 7 June 2019.
  34.  

About the Authors
 
Rend Al-Mondhiry, JD, is senior counsel at Amin Talati Upadhye, where she advises clients in the dietary supplement, food and cosmetic industries on a broad range of FDA and FTC regulatory and compliance matters. She can be contacted at Rend@amintalati.com.
 
Ashish Talati, JD, is partner at Amin Talati Upadhye, where he leads the firm’s food and drug industry practice. He is one of the industry’s foremost experts on FDA regulatory matters, counseling clients on matters of regulatory compliance, helping them anticipate and address regulatory issues in their day-to-day business operations and strategic planning. He can be reached at ashish@amintalati.com.

Cite as: Al-Mondhiry R and Talati A. “Update on the Regulatory Status of Cannabidiol in Food and Dietary Supplements and Future Prospects.” Regulatory Focus. June 2019. Regulatory Affairs Professionals Society.



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