PeptideJournal
Regulatory & Legal11 min read

FDA GRAS Status & Peptides: Supplement Pathway

**If you've spent any time looking into peptide supplements, you've probably encountered the term "GRAS." It sounds reassuring — Generally Recognized as Safe.

If you've spent any time looking into peptide supplements, you've probably encountered the term "GRAS." It sounds reassuring — Generally Recognized as Safe. But the reality behind that acronym is far more complicated than the supplement industry would like you to believe, and the FDA is about to make it even more so.

Table of Contents

What GRAS Actually Means

GRAS stands for Generally Recognized as Safe. It's a designation under the Federal Food, Drug, and Cosmetic Act (FD&C Act) that exempts certain substances from the standard food additive approval process. If a substance has GRAS status, it can be added to food — and, by extension, used in certain supplement contexts — without going through the full premarket approval that the FDA requires for new food additives or drugs.

The key phrase is "generally recognized." A GRAS determination isn't the FDA saying a substance is safe. It means that qualified scientific experts, based on publicly available data, have concluded that the substance is safe for its intended use. The standard is "reasonable certainty of no harm" — the same standard that applies to food additives, but achieved through a different pathway.

Here's what trips people up: GRAS status applies to food ingredients and food-contact substances. It was never designed as a pathway for therapeutic peptides. When someone tells you a peptide is "GRAS approved," the first question should be: GRAS for what use, and in what form?

How a Substance Gets GRAS Status

There are two routes to GRAS status, and the difference between them matters enormously.

FDA-Notified GRAS (the formal route). A company prepares a detailed GRAS notice — typically hundreds of pages of toxicology data, exposure estimates, and expert panel evaluations — and submits it to the FDA for review. If the FDA has no objections, it issues a "no questions" letter. As of 2025, approximately 1,240 GRAS notices have been filed with the agency. This process costs anywhere from $200,000 to over $1 million and takes 12 to 24 months.

Self-Affirmed GRAS (the informal route). A company convenes its own expert panel, reviews the evidence internally, and concludes that a substance is safe. No FDA filing is required. No public record is created. The FDA may never know the substance is in the food supply. This pathway has been legal — and controversial — since the FDA finalized its GRAS rule in 2016.

The difference is stark. An FDA-notified GRAS substance has been reviewed by the agency. A self-affirmed GRAS substance has only been reviewed by experts the company hired. Both carry the same legal weight under current law, but that's about to change.

Which Peptides Have GRAS Status

Very few peptides have formal GRAS status, and the ones that do are food-derived proteins — not the therapeutic peptides that most people searching this topic care about.

Collagen peptides are the most prominent example. Several collagen products have been the subject of GRAS notices. GRN No. 1171, filed by Spherix Consulting Group, covers a non-animal Type 21 collagen polypeptide produced through fermentation. Other bovine- and marine-derived collagen hydrolysates have received "no questions" letters for use in foods and beverages. These GRAS determinations cover collagen as a food ingredient — they don't make collagen a regulated therapeutic.

Creatine monohydrate (GRN No. 931) has GRAS status for use in food, though creatine is an amino acid derivative rather than a peptide in the strict sense.

Casein phosphopeptides and certain bioactive milk peptides have been the subject of GRAS determinations for use in food applications.

What does not have GRAS status? Essentially every therapeutic peptide that people actually want to know about: BPC-157, CJC-1295, ipamorelin, thymosin alpha-1, TB-500, selank, semax, and semaglutide. None of these are GRAS. None are dietary supplements. They are unapproved drugs, or in the case of semaglutide, an FDA-approved prescription medication.

The Supplement vs. Drug Pathway

Understanding why most peptides can't use the supplement pathway requires understanding what a "dietary supplement" actually is under federal law.

The Dietary Supplement Health and Education Act (DSHEA) of 1994 defines dietary ingredients as vitamins, minerals, herbs or botanicals, amino acids, and dietary substances used to supplement the diet. Amino acids are explicitly included. Peptides — chains of amino acids — fall into a gray area.

Here's where it gets complicated:

Natural peptides found in food (like collagen fragments or casein-derived peptides) can potentially qualify as dietary ingredients if they were marketed before October 15, 1994, or if a New Dietary Ingredient (NDI) notification has been filed and accepted by the FDA.

Synthetic peptides are almost never dietary supplements. The FDA has consistently taken the position that synthetic peptides designed for therapeutic effects are drugs, not supplements. If a peptide was studied as a drug before it was ever marketed as a supplement, it's excluded from the supplement category under the prior drug exclusion clause of DSHEA.

The drug pathway requires an Investigational New Drug (IND) application, three phases of clinical trials, a New Drug Application (NDA), and FDA approval. This process takes 10 to 15 years and costs an average of $1 to $2 billion. There are approximately 80 FDA-approved peptide drugs on the market, including insulin, semaglutide, tirzepatide, and leuprolide.

The supplement pathway requires only an NDI notification (75 days before marketing) if the ingredient is new, and the manufacturer bears the burden of establishing safety. No efficacy data is required. The FDA can only pull a supplement off the market after proving it's unsafe — the opposite of the drug pathway, where the manufacturer must prove safety and efficacy before marketing.

The supplement pathway is cheaper, faster, and requires far less evidence. That's exactly why the FDA guards the boundary between supplements and drugs so aggressively.

The Self-GRAS Problem

Self-affirmed GRAS has been called a loophole, and for good reason. Under the current system, a company can hire its own panel of experts, have them review data on a substance, and declare it GRAS — without ever telling the FDA. The substance can then be added to food products and sold nationwide.

This matters for peptides because some companies have attempted to use the self-GRAS pathway to market peptide-containing products without FDA review. The logic goes: if the peptide is GRAS, it's a food ingredient, not a drug, and the FDA's drug approval requirements don't apply.

The FDA doesn't buy this argument. The agency has repeatedly stated that GRAS status for a substance as a food ingredient does not make that same substance legal as a drug or therapeutic agent. A collagen peptide that's GRAS for use in a protein bar doesn't become a regulated medicine because someone puts it in a capsule and markets it for joint repair.

But the self-GRAS system creates enforcement gaps. Because the FDA doesn't know about every self-affirmed GRAS determination, it can't proactively stop products from reaching market. The agency estimates that hundreds of substances are currently self-affirmed GRAS without any FDA notification.

FDA Enforcement and the Current Reality

The FDA has been tightening its grip on peptides from multiple directions.

On the compounding side, the agency placed numerous therapeutic peptides on Category 2 of the 503A bulks list in late 2023 and 2024, designating them as substances that "raise significant safety risks." BPC-157, TB-500, CJC-1295, ipamorelin, and others were effectively banned from compounding pharmacies. Even after five peptides were procedurally removed from Category 2 in September 2024, the Pharmacy Compounding Advisory Committee (PCAC) voted against adding any of them to the approved bulks list.

On the supplement side, the FDA has issued warning letters to companies marketing peptides as dietary supplements with therapeutic claims. The agency's position is clear: if a product is marketed to diagnose, treat, cure, or prevent disease, it's a drug regardless of what the label says. "Research use only" disclaimers don't provide protection when products are sold with syringes and reconstitution supplies, or when the marketing clearly targets human therapeutic use.

In 2025, the FDA expanded Import Alert 66-78 to cover 12 additional unapproved peptides, signaling increased scrutiny of imported peptide products. The agency's own testing found that up to 40% of online and compounded peptides contained incorrect dosages or undeclared ingredients.

What the GRAS Overhaul Means for Peptides

The FDA is pursuing a fundamental overhaul of the GRAS system that could eliminate the self-affirmed pathway entirely.

In late 2025, the FDA published proposed rules to amend 21 CFR Parts 170 and 570. The proposed changes would remove the self-affirmation pathway for new GRAS determinations, require mandatory GRAS notice submission and FDA review before market entry, establish a publicly accessible GRAS inventory, and formalize procedures for the FDA to determine when a substance doesn't meet GRAS criteria.

HHS Secretary Robert F. Kennedy Jr. directed the FDA commissioner to explore rulemaking that would eliminate self-affirmed GRAS. The "Better Food Disclosure Act of 2025," introduced in the Senate, would deem any GRAS food substance unsafe unless the HHS Secretary includes it on an official GRAS list. Under this legislation, the FDA would have 180 days to evaluate each GRAS notice.

For peptides, these changes mean the already narrow GRAS pathway gets narrower. Companies that have relied on self-affirmed GRAS to market peptide-containing food products would need to submit formal GRAS notices. Products that can't survive FDA scrutiny would be pulled.

The American Herbal Products Association (AHPA) has pushed back, calling self-affirmed GRAS "an important, legal, and rigorous pathway" and urging the FDA to develop any changes in consultation with industry. Legal challenges are expected — the FDA has previously acknowledged that it "lacks express statutory authority to require companies to submit GRAS notices."

But the direction is clear: more oversight, not less, is coming to the GRAS system.

FAQ

Can I buy peptide supplements legally?

You can legally buy certain peptide-containing supplements — primarily collagen peptides and some bioactive peptides derived from food sources. What you cannot legally buy as a supplement are synthetic therapeutic peptides like BPC-157, CJC-1295, or TB-500. These are classified as unapproved drugs. Products marketing these peptides as supplements are doing so in violation of federal law, even if they carry "research use only" disclaimers.

Does GRAS status mean the FDA tested a peptide and found it safe?

No. GRAS means that qualified experts have reviewed publicly available evidence and concluded the substance is safe for its intended use. For FDA-notified GRAS, the agency reviews the submission and may issue a "no questions" letter — but this isn't the same as FDA testing or approval. For self-affirmed GRAS, the FDA may not even know the substance exists.

Why can't therapeutic peptides use the supplement pathway?

Therapeutic peptides fail the supplement pathway for several reasons: many were studied as drugs before being marketed as supplements (triggering the prior drug exclusion), synthetic peptides don't qualify as "dietary ingredients" under DSHEA, and any product marketed with therapeutic claims is legally a drug regardless of labeling. The FDA has consistently enforced these boundaries.

Will the GRAS overhaul help or hurt peptide availability?

For therapeutic peptides, the GRAS overhaul is largely irrelevant — these peptides were never legitimately GRAS to begin with. For food-derived peptides like collagen, the overhaul could create new costs and delays if companies must submit formal GRAS notices for products that were previously self-affirmed. But it also means consumers can have more confidence that GRAS-labeled products have actually been reviewed by the FDA.

What's the difference between GRAS, NDI, and NDA?

GRAS applies to food ingredients with a long history of safe use. NDI (New Dietary Ingredient) notifications apply to supplement ingredients marketed after October 1994. NDA (New Drug Application) is the full drug approval pathway. Most therapeutic peptides need the NDA pathway — they're too novel for GRAS, too synthetic for NDI, and too therapeutic for supplements.

The Bottom Line

GRAS status and the supplement pathway are real regulatory categories — but they don't do what many people hope they do for peptides. The GRAS pathway covers food ingredients with strong safety histories, like collagen peptides and creatine. It was never designed to be a shortcut for therapeutic peptides, and the FDA has aggressively enforced that boundary.

The coming GRAS overhaul will likely eliminate the self-affirmed pathway, which will close one of the few remaining routes companies have used to market peptide products without FDA review. For consumers, this is broadly a good thing: it means that when a product says "GRAS," there will be a better chance the FDA has actually reviewed the evidence.

If you're interested in therapeutic peptides, the honest answer is that talking to your doctor about FDA-approved options or clinical trial access is the safest and most legally sound path. The supplement aisle isn't where you'll find what the science has actually validated.

References

  1. FDA. "Generally Recognized as Safe (GRAS)." U.S. Food and Drug Administration. https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-gras

  2. FDA. "GRAS Notices." U.S. Food and Drug Administration. https://www.fda.gov/food/generally-recognized-safe-gras/gras-notices

  3. FDA. "Questions and Answers on Dietary Supplements." U.S. Food and Drug Administration. https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements

  4. NutraIngredients. "Eliminating self-affirmed GRAS? FDA advancing proposals to amend food ingredient regulations." September 2025. https://www.nutraingredients.com/Article/2025/09/09/fda-moves-ahead-with-proposals-to-amend-gras-regulations/

  5. NutraIngredients. "FDA releases HFP priorities: All eyes on modernizing dietary supplement oversight, GRAS, NDIs." January 2026. https://www.nutraingredients.com/Article/2026/01/26/fda-releases-hfp-priorities-all-eyes-on-modernizing-dietary-supplement-oversight-gras-ndis/

  6. Beveridge & Diamond. "The Trump Administration's First Unified Agenda for FDA Promises Major Changes for the GRAS Pathway." 2025. https://www.bdlaw.com/publications/the-trump-administrations-first-unified-agenda-for-fda-promises-major-changes-for-the-gras-pathway-food-ingredients-and-cosmetics/

  7. Frier Levitt. "Regulatory Status of Peptide Compounding in 2025." https://www.frierlevitt.com/articles/regulatory-status-of-peptide-compounding-in-2025/

  8. FDA. "Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A." https://www.fda.gov/media/174456/download

  9. NIH Office of Dietary Supplements. "Dietary Supplement Health and Education Act of 1994." https://ods.od.nih.gov/About/DSHEA_Wording.aspx

  10. Epstein Becker Green. "Eliminating the GRAS Pathway: An Update." https://www.healthlawadvisor.com/eliminating-the-gras-pathway-an-update