Peptides are short chains of amino acids that are present in virtually every living organism. They are a fundamental feature of life in animals, plants, fungi and microorganisms, primarily serving as signaling molecules.
Their powerful physiological effects have sparked broad curiosity from the dietary supplement industry. In the United States, for example, industry bodies are now pushing the FDA to consider expanding the scope of the definition of dietary ingredients to include peptides.
However, clear differentiation is needed between peptides used in supplement applications and those used as drugs or ‘gray market’ injectables. This was discussed in a recent webinar hosted by the Council of Responsible Nutrition (CRN) which explored emerging peptide science, innovation and opportunities for the dietary supplement industry.
What is the definition of a peptide?
Typically, peptides are defined as having a chain length of somewhere between two and 50 amino acids, but these numbers are not concrete. There are some peptides longer than 50 amino acids which are still considered peptides due to their biological role.
The defining feature of peptides is their mechanism: They are bioactive signaling molecules that regulate specific biological functions. Meanwhile, amino acids are singular units which are the building blocks of proteins and peptides, and proteins are structural and functional molecules with a highly complex structure, containing 50-1000+ amino acids.
Proteins carry peptides in the amino acid chain, but peptides within the chain are not active until they are freed, explained Nora Khaldi, CEO and founder of Nuritas, during CRN’s webinar. Nuritas is a biotechnology company that uses artificial intelligence and genomics to discover and unlock natural bioactive peptides from food and plant sources.
“Proteins are simply carriers of peptides,” Khaldi said. “Within the protein chain, there are different fragments of peptides, and once they are cleaved out of the protein, they become an activated peptide.”
Once activated, peptides carry messages. In fact, most signals in the human body come from peptides, regulating major processes such as metabolism, immune response, appetite and tissue repair.
One of the most well-known examples is the GLP-1 (glucagon-like peptide-1) hormone. GLP-1 is a short peptide built from 30 to 31 amino acids. It is released immediately after eating a meal, triggering insulin release, slowing down gastric emptying and signaling fullness and satiety to the brain. Once the signal is emitted, the peptide is destroyed and transformed into amino acids or nutrients. This is a natural process, which pharmaceutical companies have synthetically replicated and modified to make the feeling of fullness long-lasting to induce weight loss.
While GLP-1 targets satiety, all peptides behave differently, with some offering muscle repair properties or protection against skin aging, for example.
The method used to produce a peptide influences both its behavior and its regulation.
Methods of peptide discovery and production
AI is being increasingly being used both to discover peptides and to determine the most effective way to release them from proteins.
“In one apple, there’s about 30 billion peptides, and it’s very hard to test them one at a time in the lab,” Khaldi said. “So you have to use different techniques within AI to discover the peptide, to discover what protein it belongs to and how you actually get it out of that protein in the most effective way.”
Following discovery, peptides can be produced in three ways: synthetically, through hydrolysis or through bio-fermentation. Each production method results in different end outcomes.
Synthetically produced peptides are mostly used in drug formulations, such as GLP-1s. This chemical method involves manually assembling amino acids to improve stability and bioavailability.
Hydrolysis, on the other hand, involves breaking down the bonds of larger molecules to split them into smaller, more bioavailable parts. This is a common method used to produce peptides for dietary supplements. For example, collagen peptides are small fragments of collagen and milk casein hydrolysates are broken down milk proteins.
Bio-fermentation can also be used to produce peptides by using microorganisms such as bacteria and yeast. This method allows manufacturers to duplicate specific sequences of peptides and is often used to produce peptides such as human insulin and human growth hormone (somatropin).
“None of these methods would give you a completely pure molecule,” Khaldi said. “Your level of purity augments [...], and there’s always going to be things within the ‘soup’ at the end of the production method.”
Both the production method and the formulation process are therefore integral to the efficacy of the end product.
To ensure the best possible outcome, there are a number of factors to consider, according to Michael Anthonavage, vice president of product development and innovation at Vitaquest. This includes physiochemical considerations, bioavailability and GI stability, compatibility with other ingredients, the delivery format and taste. Formulators must also consider how the manufacturing process could alter the final product.
“Each stage of the manufacturing process will present a different challenge,” he said during the CRN webinar. “As you scale up, your instruments are going to generate heat, they’re going to generate pressure, and all these things will work against you in your peptide manufacturing. So, you have to test along the way to make sure you’re not losing the activities of your peptide.”
Developing and producing peptides is therefore a complex process, one that can take years, particularly for pharmaceutical companies developing new peptide-based drugs. It can also take anywhere from several months to several years for a novel ingredient to gain regulatory approval, depending on the jurisdiction, making the path to commercialization both lengthy and complex.
What determines whether a peptide is regulated as a supplement or a drug?
One of the most significant questions surrounding peptides is how they are regulated. Peptides encompass a broad range of ingredients, and Luca Bucchini, a regulatory expert in EU food law and managing director of Hylobates Consulting, said this has contributed to widespread confusion.
“Regulatory uncertainty stems from the technological transition from traditional protein hydrolysates (such as collagen or whey peptides, which are macronutrients with an established history of safe food use) to short-chain, synthetic sequence-specific peptides engineered for targeted biological or metabolic signaling,” he said. “Peptides are small parts of proteins so at first sight one would think that they could be regulated as proteins. However, some have such strong bioactivity that they require different regulation.”
While some peptides are regulated as dietary supplement or cosmetic ingredients and some as approved drugs, others occupy a largely unregulated ‘gray market’, where they are commonly sold under the guise of being ‘for research purposes’.
Examples of peptides sitting under different regulatory frameworks
Peptides used in dietary supplements:
- Collagen peptides
- Whey protein hydrolysates
- Casein Phosphopeptides (CPP)
Peptides regulated as approved drugs:
- Insulin
- GLP-1 drugs (semaglutide/tirzepatide)
- Enfuvirtide (fuzeon)
Unregulated peptides circulating the ‘gray market’
- BCP-157 (marketed as an agent to improve injury recovery)
- TB-500 (marketed as a systemic tissue repair booster)
- CJC-1295 (marketed for systemic body composition and anti-aging)
During the CRN webinar, Ashish Talati, founding member and FDA & FTC attorney at Talati Law, said one of the most common questions from peptide developers is: “Can my peptide legally be marketed as a dietary supplement?”
To answer this question, he said they must ask themselves a series of questions: Is it a lawful dietary ingredient? Has its identity been established? Is the safety evidence adequate? Are the claims compliant?
The format is also very important. The general regulatory principle is that a dietary/food supplement is an orally ingested product, while an injectable product generally falls into a different regulatory category, typically a medicinal/drug product or biologic, depending on the jurisdiction.
The Dietary Supplement Health and Education Act (DSHEA), which regulates dietary supplements in the United States, categorically bans injectables as being classed as supplements, however peptides are not explicitly included in the scope of the definition of dietary ingredients.
Bucchini noted that in Europe, peptides must also be orally delivered to be classified as a food supplement, but that oral peptides which illicit strong bioactivity require different regulation.
“Under [EU law], if a substance exerts a significant pharmacological, immunological or metabolic action, human medicines legislation takes legal precedence over food law,” he said. “In other words, if a peptide has a strong effect on the body, it has to be authorized as a medicine. It is important to understand that it is not so much the nature of peptide that matters but the fact that these peptides have on the body.”
In APAC, each country operates under its own regulatory framework.
As in Europe, Australian regulations require peptides marketed as supplements to avoid claims that they can cure or treat disease or otherwise imply a therapeutic use. They must also meet applicable safety requirements.
In Singapore, the Health Sciences Authority maintains a structured therapeutic products regime, including special access controls for unregistered therapeutic products, while in Hong Kong, the Department of Health Drug Office regulates pharmaceutical products by reference to therapeutic presentation and pharmacological, immunological or metabolic action. It requires medicines to be registered before sale and enforces controls on unregistered pharmaceutical products and therapeutic advertising.
Dr. Teresa Nicoletti, PhD, a scientist and partner at Australian law firm Mills Oakley’s Health and Life Sciences group, said that while regulators are responding to the rise of peptides in different ways, online supply, cross-border importation, prescription-only substances and products promoted through wellness or performance-enhancement channels are coming under increased scrutiny.
“The precise regulatory route differs by jurisdiction, but the recurring themes are consumer safety, unlawful therapeutic claims, unapproved medicines, misleading product presentation and the difficulty of enforcing national laws against borderless online supply,” she said.
The rise of unregulated peptides
While peptide-based drugs and supplements are gaining traction, the ‘gray market’ is the category generating the most noise and is what consumers are most likely to find when searching for peptides to purchase online. A quick Google search returns dozens of websites selling peptides ‘for research purposes only’, but these products can be bought easily by consumers without proving research intent.
In the European Union, ‘research only’ disclaimers do not protect companies from enforcement action, Bucchini said.
“European health and law enforcement authorities actively invalidate ‘research use only’ (RUO) or ‘not for human consumption’ disclaimers used to evade food and drug oversight,” he said. “Under EU and UK case-law, product status is determined by objective composition, physiological action and commercial presentation. Disclaimers are legally void when products are sold directly to consumers in unit-dose formats (e.g., capsules, pre-filled vials, nasal sprays).”
Why are most therapeutic peptides designed to be injected rather than ingested?
The digestive system breaks down proteins and peptides into smaller fragments. If taken orally, many peptides are rapidly degraded in the gastrointestinal tract before they can be absorbed into the bloodstream.
Injections bypass the GI system, allowing peptides to reach the bloodstream intact. Advances in formulation technology have enabled some peptides to be delivered orally, but this is often expensive to do and difficult to achieve.
The same is true in the U.S. and Asia-Pacific region (APAC), with the U.S. Food and Drug Administration (FDA) recently tightening enforcement on online shops selling illegal peptides to consumers, and Australia’s Therapeutic Goods Administration (TGA) following suit. In fact, the TGA—with help from local police forces—recently seized more than $120,000 of illicit peptide and anabolic steroid products from two residential premises in New South Wales.
The owner of the properties allegedly imported and relabeled the products before selling them online via social media. The products include retatrutide, CJC-1295 and a combination of BPC-157 and TB-500.
Nicoletti said the TGA’s crackdown on illegal selling is necessary to protect public health, given unapproved peptides can cause liver damage, severe allergic reactions, inflammation and other health complications.
“The supply of unapproved, poorly labeled products that are not subject to Australian regulatory standards poses a serious public health issue,” she said. “Consumers who self-administer these peptides by subcutaneous or intramuscular injection may have no reliable way of determining what is in the vial, where it was made, whether it is sterile or whether it is otherwise safe.”
Despite it being illegal to sell unregulated injectable peptides directly to consumers, the practice is still widespread. In response, regulators in the United States are beginning to consider alternative approaches.
Last month, an FDA advisory board recommended easing access to certain peptides, including BPC-157, KPV and TB-500. If the FDA accepts these recommendations, these peptides will allow specialized pharmacies to compound these peptides into patient-specific medications with a valid prescription.
Proponents of this proposal argue that this pathway would reduce harm to consumers by providing a legal, regulated channel for people who currently buy unverified and unregulated peptides online.
