Regulatory Framework of Terpenes for Dietary Supplements

Introduction

A diverse class of biomolecules that will be hard to miss this Halloween due to its flavorful and fragrant properties are terpenes. These organic hydrocarbons are produced by a variety of plant species and by some insects. Terpenes are responsible for the taste, aroma, and pharmacological activities of many plants like citrus fruits, coriander, eucalyptus, lavender, lemon grass and, peppermint species.4 Therefore, terpenes and terpenoids (i.e., terpenes that were subjected to heat or oxidation) are often isolated by hydrodistillation as oils (aka “essential oils”) and then used in foods, such as trick-or-treat candy, as well as in beverages and, cosmetics and even air fresheners. For example, the oil of the plant geranium (Pelargonium graveolens L’ Herit) which consists of aromatic terpenes including eugenol, citronellol, geraniol, and linalool is used as a natural perfume.1 Geranium plants are placed near outdoor paths so when people brush against the leaves, a scent is released into the air; moreover, geraniums have a large assortment of leaf types which are used in making potpourris, sachets, and flavorings.15

The pharmacological potential of terpenes also makes them appealing candidates for ingredients for dietary supplements; for instance, d-limonene, a terpene constituent of citrus peel has been claimed to have anti-cancer properties,16 although it is known to cause cancer in adult male rats. Along with the increase in popularity for terpenes as a dietary ingredient, the U.S. regulatory framework for dietary supplements is changing. As a result, it is important for companies to know which terpene ingredients qualify as a new dietary ingredient (NDI) and the procedures for submitting an NDI notification to the Food and Drug Administration (FDA).

Terpene as a dietary ingredient

A dietary ingredient is a vitamin; mineral; herb or other botanical; amino acid; or a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of substances as stated in the Dietary Supplement Health and Education Act of 1994. To determine if a terpene qualifies as a dietary ingredient it is important to know what plant, if any, from which the terpene was derived. Often, the same terpene can be produced from multiple sources; for instance, (E)‐β‐caryophyllene, a sesquiterpene (i.e., a terpene with three isoprene units), can be found in plants such as Cannabis and lima beans,2 and also in the multicolored Asian lady beetle, Harmonia axyridis.5 However, even though the structure of the terpene along with all the stereochemical details of a compound can be the same in both plant and insect species,2 where the terpene originated can effect whether it meets the definition as a dietary ingredient – the Asian lady beetle would likely not qualify, unless it could be demonstrated that it was eaten as a food at one time or another, by a significant number of people. Insects produce terpenes for roles in defense or attraction (sex pheromones),2 but this hardly makes them a staple item in anyone’s diet. In addition to insects and plants, terpenes can be produced synthetically and, by engineered microorganisms (Table 1).

Terpenes derived from a plant source would be a botanical ingredient and therefore would meet the definition of a dietary ingredient. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are ingredients in cannabis (Cannabis sativa) and are excluded from the dietary supplement definition under section 201(ff)(3)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). However, terpenes that are derived from parts of the cannabis plant that do not contain THC or CBD might be able to be marketed as dietary supplements since it will fall outside the scope of exclusion from the dietary supplement definition under section 201(ff)(3)(B) of the FD&C Act.11 The law only mandates the substance must have been part of the diet, not necessarily from what plant it is harvested.

With only a few exceptions, such as vanillin, a synthetic terpene is a synthetic copy of a terpene normally produced by an herb or other botanical. Because a synthetic terpene has never been part of an herb or other botanical, it would not qualify as a dietary ingredient under section 201(ff)(1)(C) of the FD&C Act. “As defined in the glossary, an herb or botanical includes only plants, algae, fungi, their exudates (secretions, such as sap or resin), and their physical parts”.10 However, “because the “dietary substance” category is defined in part by history of use, a synthetic copy of a botanical ingredient may qualify as a dietary ingredient under section 201(ff)(1)(E) if the synthetic copy has been used as a lawfully marketed ingredient in the conventional food supply”10 (Table 1).

Unlike a synthetic substance that usually has only one source from a synthesis pathway, a natural substance can have many sources, including non-food sources.6 For example, resveratrol, a substance commonly thought to only come from wine, is also obtained from Japanese knotweed, which is a non-food source.6 Therefore, a chemical, normally found in food can be used as a dietary ingredient, even if its origin is no longer a food.

Non-native terpenoids have been produced from metabolic engineered Escherichia coli and yeast, which do not normally produce terpenoids.17 However, there are several challenges with producing terpenoids from microorganisms including reducing the toxicity of terpenoids for yeast, since many monoterpenes have anti-microbial activity.17

NDIN Process

A “new dietary ingredient” is one that meets the definition of a “dietary ingredient” that was not marketed in the U.S. before October 15, 1994.10,13 If a terpene meets the “dietary ingredient” definition, as discussed previously and has not been marketed in the U.S. before October 15, 1994, it would be a “new dietary ingredient”. The Federal Food, Drug, and Cosmetic Act (the FD&C Act) requires that manufacturers and distributors who wish to market dietary supplements that contain “new dietary ingredients” notify the Food and Drug Administration about these ingredients, at least 75 days before the dietary ingredient is introduced or delivered for introduction into interstate commerce.12 In the Federal Register of September 23, 1997, the FDA established a procedure by which a manufacturer or distributor of dietary supplements or of a new dietary ingredient when submitting a NDIN to the FDA. The notification should include information necessary to characterize the NDI, such as specifying the part of the botanical that is the source of the new dietary ingredient.10 Information should also be submitted that demonstrates that a dietary supplement containing the new dietary ingredient will reasonably be expected to be safe,8 what FDA refers to as a “filing”. NDIN submissions can be mailed to the FDA or submitted electronically through the ePortal (COSM).12

Even though by law (DSHEA), the manufacturer is responsible for ensuring that its dietary supplement products are safe before they are marketed, there are no provisions in the law for FDA to “approve” dietary supplements for safety or effectiveness before they reach the consumer (e.g., “premarket approval”).13 Once the product is marketed, FDA has the burden of proof for showing that a dietary supplement is “unsafe” before it can take action to restrict the product’s use or removal from the marketplace.13 However, FDA has managed to circumvent this prohibition for premarket approval, by advantaging a provision in DSHEA that requires notification (i.e., the “filing”), by refusing to “file” a notification with which FDA disagrees.

Other Considerations

A product might be regulated as either an unapproved drug or a dietary supplement based on the claims made by company of the product. The product would fall under the requirements of dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) if the claim is a health claim, qualified health claim, nutrient content claim or a structure function claim; however, if the claim is it can treat, diagnose, prevent, or cure diseases (i.e., a drug claim), it would be regulated as a drug. That means dietary supplements should not make claims, such as “reduces pain” or “treats heart disease”.11 For example, the claim, “d-limonene prevents breast cancer” would not be permitted for dietary supplements. While a claim that a dietary supplement containing calcium would be permitted for “helps build strong bones”, but not for “prevents/treats osteoporosis”.

In a final rule issued by the FDA regarding the current good and manufacturing practice (cGMP) for dietary supplements, manufacturers are required to ensure the dietary supplement meets its specifications for identity, purity, quality, strength, and composition.9 Under section 402(f)(1)(B) of the FD&C Act, a dietary supplement is adulterated if it contains a new dietary ingredient for which there is inadequate information to provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury. The FDA can take action to remove adulterated or misbranded products from the market.11

Conclusion

Overall, all products marketed as dietary supplements must follow the laws and regulations governing dietary supplement products. Burdock Group can help companies with the NDIN submission process for any “new dietary ingredient” including terpenes, as well as provide any regulatory and safety guidance when bringing a dietary supplement product to market.

References:

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Beran, F.; Köllner, T.G.; Gershenzon, J. and Tholl, D. (2019) Chemical convergence between plants and insects: biosynthetic origins and functions of common secondary metabolites. New Phytologist. 223(1):52–67.
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Breitmaier, E. (2006) Terpenes: Importance, General Structure, and Biosynthesis. In Terpenes. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany p. 1–9.
Brown, A.E.; Riddick, E.W.; Aldrich, J.R. and Holmes, W.E. (2006) Identification of (-)-β-caryophyllene as a gender-specific terpene produced by the multicolored Asian lady beetle. Journal of Chemical Ecology. 32(11):2489–2499.
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FDA (1997) Premarket Notification for a New Dietary Ingredient. Federal Register. 62(184).
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FDA (2019a) FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD). (site visited on October 2, 2019).
FDA (2019b) How to Submit Notifications for a New Dietary Ingredient. (site visited on October 3, 2019).
FDA (2019c) Questions and Answers on Dietary Supplements. (site visited on October 3, 2019).
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Mahr, S. (2006) Herb of the Year 2006: Scented Geraniums. University of Wisconsin – Madison. (site visited on October 4, 2019).
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Zhang, Y.; Nielsen, J. and Liu, Z. (2017) Engineering yeast metabolism for production of terpenoids for use as perfume ingredients, pharmaceuticals and biofuels. FEMS Yeast Research. 17(8).