Just under three years ago, the Food and Drug Administration deemed 19 peptide drugs too unsafe to be dispensed by compounding pharmacies, which mix components of approved drugs to create bespoke medication for people who have trouble taking commonly available products.

Now, under Health and Human Services Secretary Robert F. Kennedy Jr., the agency is poised to reverse itself. That’s despite few clinical studies supporting the effectiveness or safety of these peptides, which are amino acid chains meant to help regulate functions in the body and have become popular among fitness and longevity enthusiasts.

In February, Kennedy said the FDA acted illegally in 2023 when it categorized 19 peptides as too unsafe for compounders, whose final products aren’t tested or approved by the FDA. Kennedy, who described himself as a “big fan” of peptides, has used the therapies himself.

“It was illegal because they’re not supposed to do that unless there’s a safety signal,” Kennedy said on “The Joe Rogan Experience” podcast, referring to adverse events related to medications. “And they didn’t have a safety signal. They’re not allowed to look at efficacy. They’re not allowed to say, ‘Well, we don’t believe these are efficacious,’ or whatever. They can only look at safety.”

But three former FDA officials closely familiar with how the agency created the criteria to assess the peptides in the first place say Kennedy has mischaracterized their work. The agency’s 2023 decision to ban certain peptides was supported by numerous documented safety concerns, they said. FDA regulations also require the agency to assess both safety and effectiveness before approving a substance for compounding.

“It would be a disruption of the societal pact we have had since 1962 that drugs will be studied to see if they work before they are marketed in the U.S.,” said Janet Woodcock, a former FDA acting commissioner.

If Kennedy justifies reversal of the previous work by suggesting there were no safety concerns, it would give a false imprimatur of safety to more than a dozen unapproved, untested drugs, the officials said.

There’s been little new science on the 19 peptides since the FDA’s 2023 decision to categorize them as unsafe. But demand for the drugs has exploded as influencers have flooded social media with promises of sculpted physiques, glowing skin, luscious hair, rapidly healing injuries, youthful energy and blazing sex lives.

The demand has given rise to a burgeoning gray market, where wellness spas, multilevel marketers and telehealth websites ply the public with vials of “research grade” peptides labeled “not for human use.”

“More people want to use them,” said Lauren Colenso-Semple, a muscle physiology researcher and science communication specialist who follows scientific studies of peptides as part of her work. “That’s what’s changed.”

FDA-approved peptide drugs such as insulin and oxytocin have been available for decades. Newer ones such as semaglutide and tirzepatide, broadly known as GLP-1s, have exploded in popularity for weight loss and have shown promise for treating other conditions, such as addictions and neurodegenerative and liver diseases. The popularity of these drugs has led the public to become more comfortable with injectables and has helped drive attention to other gray-market peptides.

Last year, at a Las Vegas conference promising radical life extension, two women became critically ill after being injected with peptides the FDA had categorized as unsafe. Although Nevada regulators investigated and fined the health practitioners involved in administering the peptides, investigators weren’t able to determine the exact cause of the reaction. The doctor who ran the booth where the women became ill said he didn’t believe that the peptides caused their reactions but apologized for the incident and said he would review his practices.

The Alliance for Pharmacy Compounding, one of the largest industry associations lobbying for the FDA to change its stance on peptides, acknowledges it knows little about the safety of individual peptides being sold to the public. (Its CEO says it is an advocacy organization, not a scientific one.) But the group argues the public would be safer if peptides were handled by regulated compounding pharmacies instead of the gray market. The FDA should forgo the usual human clinical trials in order to bring about this shift, a spokesperson for the alliance said.

“Where we don’t have research, clinical trials, what we’ve got a ton of, is, shall we say, testimonials, patient affidavits, attesting to the wonders of the drug,” said Scott Brunner, the alliance’s chief executive officer. “And RFK Jr. is one of those testifiers.”

On the Rogan podcast, Kennedy wasn’t clear on exactly how the FDA would let compounders start dispensing peptides, describing it only as “some kind of action” to make “about 14” peptides “more accessible.” Nor has he specified which peptides he wants to make available. (Neither the FDA nor HHS responded to ProPublica’s requests for more information.) But several regulatory shortcuts exist and, ultimately, Kennedy could simply declare the ingredients are legal.

“He has all of the authority,” said Woodcock, likening such a declaration to former HHS Secretary Kathleen Sebelius’ unilateral 2011 reversal of the FDA’s decision to lift age restrictions on the emergency contraception Plan B. (A judge ultimately found Sebelius’ move to be arbitrary and capricious and nullified it.)

“The secretary can do anything they want.”

The Bulks List

The FDA’s road to regulating compounding pharmacies — and by extension the peptides they seek to dispense — has been long and tedious. Much of the regulatory fight has focused on which ingredients compounders should be allowed to use.

Under a 1997 law, the first passed by Congress to regulate the industry, compounders can only use ingredients that are a component of an approved drug, have what’s known as a USP monograph (essentially a third-party certified recipe for a drug used mainly by manufacturers of generics), or are listed as approved substances by the FDA.

This FDA list, known as “the bulks list,” is at the center of the ongoing peptide debate.

Litigation and pressure from the industry and lawmakers delayed for decades the creation of the bulks list, leaving compounders in limbo on scores of substances, not just peptides.

“Everything was a fight. It was a huge fight,” said one former FDA official who has spent more than 30 years working on compounding policies. The former official asked not to be named to avoid a public debate with the industry.

The need for the list took on new urgency in 2012, when more than 60 people died from fungal meningitis infections contracted from a drug produced at a compounding facility and dispensed to hundreds of people. Congress passed another law further regulating large compounders that sell medications to doctors’ offices and hospitals rather than individual patients. The new law also prompted the agency to move more quickly on establishing the bulks list.

The FDA asked the industry to nominate substances for inclusion on the list. It did so, nominating thousands of ingredients, including, for example, purified water and asparagus.

“They put in everything,” the official said. “Literally thousands of nominations with absolutely no justification for why it needed to be there.”

Each substance would have to be reviewed individually before it could be added to the bulks list. The agency would have to solicit public comment and an advisory committee of health and pharmacy experts would have to review the FDA’s research.

Reviewing them “was a massive effort. The agency proceeded glacially, but really we were speeding as fast as we could,” the official said.

In 2017, under pressure to move more quickly, the FDA came up with an interim solution. It substantially narrowed the list of nominated ingredients, quickly reviewed each remaining substance and placed them into three categories. The first was substances with enough of a safety track record that the agency felt comfortable letting compounders use them while the final list was assembled. The second category included substances considered too risky for compounding. And the third included those without enough supporting information for the FDA to make an informed decision and therefore wouldn’t be used for compounding.

This categorization didn’t constitute a formal regulation; rather the agency was using its discretion not to go after compounders who used ingredients it deemed safe — those from the first category.

In 2023, the FDA placed 19 peptides in Category 2, which already included a handful of substances the agency considered to be dangerous.

This is what Kennedy has called “the war on peptides.”

In explaining its decisions, the FDA pointed to well-established research in peptide drug development that injectable peptides carry the risk of causing immune reactions. Such reactions can range from responses with “no clinical manifestations” to irritating rashes to life-threatening conditions such as anaphylactic shock, which constricts breathing and impairs motor function.

Peptides occur naturally in the body but break down quickly after serving their purpose. Peptide drugs, on the other hand, are manufactured to last longer in the body to create a therapeutic response, such as controlling appetite or promoting the growth of new blood vessels, bone density or muscle.

“Now that it’s been tweaked to make it something else, the immune system can recognize it as foreign and there’s the potential issue of having an unwanted immune response,” Colenso-Semple said.

The manufacturing process can also introduce impurities — like bacteria or heavy metals — into peptide drugs. They also are sensitive to environmental conditions and can change chemical composition if stored at the wrong temperatures or shaken too vigorously, increasing the risk of an immune response or decreasing their effectiveness. And when a substance is injected, as opposed to taken orally, it bypasses most of the body’s natural defenses.

The risk of an immune response is common to peptide drugs in general. But individual peptides also present specific potential risks.

The FDA reviewed data to assess these risks and found limited human studies on a few peptide therapies; most have only been studied in animals or in clinical populations like HIV patients. What human data the FDA did find for individual peptides indicated the potential for harm. Subjects in studies of six individual peptides — growth hormone releasing peptide-2, ibutamoren mesylate, ipamorelin, CJC-1295, AOD-9604 and melanotan II — experienced adverse events, including death. (It wasn’t proven whether the deaths were caused by the peptides or by something else.) Ultimately, the FDA decided not enough data existed to allay the known safety concerns.

“Of course any adverse event can be a flag,” said another former FDA official who worked in the compounding division when the peptides were categorized as unsafe. The former official asked not to be named because they work in public health and don’t want to antagonize the current administration. “Also, if there is no clinical data for a substance, and an awareness that the substance has the propensity for harm, that could make it an appropriate placement on the Category 2 list.”

Are They Safe?

Putting the peptides on the unsafe list didn’t change much for compounders. Because those peptides aren’t components of an approved drug and don’t carry a USP monograph, compounders weren’t allowed to dispense them anyway.

“All that did was put an exclamation point on it,” Brunner said. In the months after the FDA’s announcement, his organization repeatedly warned its members not to dispense peptides.

But the listing prompted at least two peptide companies to sue the FDA, arguing it was dragging its feet on creating the bulks list of allowed compounding substances. To date, only six substances have made it through the process to be put on the list, none of which are peptides and none of which are injectables. As the lawsuit wound its way through federal court, the FDA agreed to accelerate the review of four peptides named in the lawsuit: CJC-1295, AOD-9604, thymosin-alpha and ipamorelin acetate. It also decided to move forward on two other peptides not listed in the complaint: kisspeptin and ibutamoren mesylate. Online marketing claims these peptides help with, among other things, weight loss, muscle-building, anti-aging, insomnia, tissue repair and sexual dysfunction. Marketers also claim thymosin-alpha, one of the more studied peptides, can help with immune function, Lyme disease and COVID-19.

In the final months of the Biden administration, the FDA convened the expert advisory committee and presented its research on the six peptides. In reports up to 158 pages long, the agency detailed the science behind the immune response risk in synthetic peptides, listed documented adverse events associated with the drugs and summarized the limited research on human subjects. In each case, the FDA recommended against putting the peptide on the bulks list for compounders.

“I can’t imagine anybody looking at this data and being comfortable” making these available to the public, Colenso-Semple said.

The peptide industry was given just 10 minutes before the committee to present arguments that the six peptides were safe. Speakers offered anecdotal evidence from their own and others’ practices. Even though peptides can’t legally be used by compounders, many were dispensing the drugs because the FDA has been lax in enforcing its regulations.

“Many of the peptides that have been placed on Category 2 have been used successfully by thousands of our practitioners treating hundreds of thousands of patients who utilize these compounds to energize cellular function and give the body what it needs to help address sickness and disease, including obesity, diabetes and addiction,” said Dan DeNeui, CEO of one of the peptide companies that sued the FDA.

His wife, Terri DeNeui, a nurse practitioner and founder of their company Evexias Health Solutions, presented information from a survey of 508 patients treated with various peptides that said 19% reported uncomfortable side effects and less than 1% experienced an adverse event.

They also contended peptides would be more safely dispensed by regulated compounders than on the gray market — the argument now being made by the Alliance for Compounding Pharmacies. The active ingredients in the drugs would be manufactured at an FDA-registered facility subject to inspection, and compounders are overseen by state boards of pharmacies to ensure sterile conditions.

That’s “a heck of a lot better than what many consumers are doing,” getting advice in chat rooms and “ordering some substance that purports to be a peptide and may or may not be,” Brunner told ProPublica.

While that argument addresses quality-control concerns associated with the gray market, it doesn’t confront the fundamental question of whether peptides are safe.

“They’re totally unapproved drugs,” said one of the former FDA officials. “Would you let a pharmaceutical company do this? No. No way.”

In the end, the advisory committee sided with the FDA and endorsed its initial decision that the six peptides were too risky to be dispensed to the public.

What Happens Now?

Unhappy with the advisory committee’s decision, the compounding industry has amplified its argument that the FDA review process for the bulks list is broken. The advisory committee had few working compounders on it and didn’t give those who opposed the decision on peptides enough time to present its arguments, industry advocates say.

With a new administration, whose health secretary has used peptides himself and is trying to advance alternative health practices, they see an opportunity. They hope the FDA will appoint more members with compounding experience to the committee and ease enforcement on peptides while it continues the established regulatory process.

“Given the scale of demand — demand that is going to be met, if not by a state licensed compounding pharmacy, then by the black and gray markets — we believe the lens that the FDA is using related to these peptides, at least some of the peptides, is the wrong lens,” Brunner said. “They’re wanting research, clinical trials. They’re wanting a certain amount of certitude that, frankly, is appropriate for most drugs, but not for this moment.”

Regulatory shortcuts exist that would allow the FDA to skip the more laborious approval process. The FDA could simply remove the peptides from Category 2, those it considers unsafe. It could place them in Category 1, allowing them to be used in compounding. Or it could announce it’s changing its enforcement strategy and not going after compounders who work with these substances.

None of that would be safe for the public, Woodcock contends. Congress intended for the FDA to “refer to a substantive body of evidence about the safety and effectiveness” of ingredients put on the bulks list, she said.

“This wasn’t supposed to be a route for unapproved drugs to get into the market,” she said. “Not even Congress was thinking that.”