Introduction

Peptides are not experimental compounds. They are the original therapeutics of modern medicine. Insulin, introduced in 1921, is a peptide. So are oxytocin, vasopressin, ACTH, growth hormone, and glucagon. All of endocrine physiology — and much of immunology, metabolism, and tissue repair — is peptide‑driven. These molecules are not fringe; they are the vocabulary biology uses to coordinate systems.

The past decade has expanded this domain. Peptides that support microvascular repair, immune recalibration, mitochondrial stability, and metabolic control have become subjects of serious academic investigation. Their mechanisms are clear, their activity is physiologic, and their potential spans orthopedics, gastroenterology, neurology, immunology, and metabolism.

Against this backdrop, the FDA’s 2023 decision to restrict dozens of peptides appears, at first glance, inexplicable. No adverse‑event clusters had emerged. No new toxicology data had surfaced. Several of the banned compounds were under active examination at major research institutions. And yet they were designated “significant safety concerns” and effectively removed from clinical use.

Understanding that decision — and what it implies — requires stepping back from the molecules themselves. The peptide story exposes a deeper issue: a structural mismatch between the biological realities of human repair and the regulatory‑economic architecture that governs pharmaceuticals.

Peptides: A Brief History Grounded in Physiology

Peptides entered medicine long before small‑molecule pharmacology matured. Insulin transformed metabolic disease. Oxytocin and vasopressin shaped obstetrics and cardiovascular medicine. ACTH and growth hormone clarified the relationship between stress, growth, and endocrine reserve. These therapies worked because they echoed internal signalling — short, modular instructions that tissues already knew how to interpret.

That pattern continues. Modern metabolic drugs — semaglutide, tirzepatide, and related GLP‑1 (glucagon‑like peptide‑1) analogues — are peptides. Their mechanism is explicitly physiologic: GLP‑1 amplifies satiety signalling and moderates glucose kinetics. The success of these drugs is not despite their peptide nature, but because of it.

The same logic underlies newer domains of peptide research. Academic centers have explored peptides in areas where traditional pharmacology struggles:

• Case Western has documented spinal‑cord regeneration with the ISP peptide, allowing axons to grow through inhibitory scar tissue.
• Johns Hopkins has examined metabolic peptides that modulate AMPK (AMP‑activated protein kinase) and mitochondrial stress responses.
• Yale now incorporates immune‑metabolic recalibration into its Long COVID program, reflecting pathways that peptides such as Thymosin‑α1, VIP (vasoactive intestinal peptide), and MOTS‑c directly influence.
• International trials during COVID evaluated Thymosin‑α1 for immune stabilization and improved outcomes.
• NAD⁺ (nicotinamide adenine dinucleotide) research — structurally adjacent to peptide physiology — is being pursued by multiple academic groups as a foundational lever in metabolic and post‑viral dysfunction.

These are not fringe institutions. They represent the center of American biomedical science. Their interest in peptides reflects a simple reality: the mechanisms make sense.

Why Regulation and Economics Diverge From Biology

The FDA’s regulatory framework was built for an earlier pharmacologic era — one defined by synthetic small molecules, single‑target mechanisms, and linear disease categories. Drugs were expected to act on a narrow receptor, produce a measurable change in an isolated endpoint, and fit neatly into a proprietary commercial model.

Peptides disrupt that template. They tend to:

• act across systems rather than single pathways,
• restore function instead of suppressing symptoms,
• degrade into amino acids rather than persisting as foreign chemistry,
• and most critically, cannot be patented in their natural form.

This last point is decisive. Modern pharmaceutical development depends on exclusivity — a period during which a company can recoup the cost of large clinical trials through protected revenue. Natural peptides offer no such protection. They are inexpensive to produce, physiologic in action, and often reduce the need for long‑term pharmacotherapy.

A regulatory system funded in part by industry fees and structured around proprietary chemistry is therefore structurally disincentivized from advancing — or even accommodating — these molecules. It is not a matter of intent. It is a matter of architecture.

The 2023 Peptide Ban: A Structural Outcome, Not a Scientific One

In this context, the FDA’s 2023 reclassification becomes clearer. Dozens of peptides — some endogenous, some well‑studied, some in active academic development — were designated “significant safety concerns” and rendered ineligible for compounding.

What changed scientifically? Nothing.

There were no new human toxicity findings. No mechanistic revelations. No accumulation of adverse events. The decision did not map to evidence.

It mapped to incentives.

The restricted peptides were those that had become widely used, clinically versatile, physiologically coherent, and increasingly visible to the public — precisely the characteristics that conflict with a chronic‑care pharmaceutical model. Their growth through compounding pharmacies further bypassed the proprietary delivery channels on which major drug revenues depend.

This is why the decision, while scientifically unjustifiable, is structurally predictable. The molecules most aligned with human biology are the least aligned with the economic substrate of modern drug regulation.

The Modern Medicine Paradox

The paradox becomes sharper when contrasted with the regulatory treatment of high‑risk synthetic drugs. Over the past several decades, the FDA has approved — and often defended — medications later shown to have catastrophic safety profiles: Vioxx, with tens of thousands of cardiovascular deaths; Fen‑Phen, causing irreversible valvular damage; Rezulin, withdrawn for hepatic failure; opioids, which precipitated a national epidemic; atypical antipsychotics, associated with profound metabolic deterioration; SSRIs (selective serotonin reuptake inhibitors), approved without long‑term safety data and later given suicidality warnings.

These drugs fit the FDA’s structural model. They were proprietary, patent‑protected, and developed within the familiar economic architecture.

Peptides, in contrast, do not fit that architecture — and were restricted despite clean safety histories. To an uninvolved observer, the asymmetry appears illogical. Within the system’s incentive structure, it is entirely consistent.

COVID and Long COVID: A Case Study in System Failure

COVID exposed the limitations of organ‑specific medicine, but Long COVID made those limitations unavoidable. Patients with persistent post‑viral symptoms presented with a pattern that basic science could already explain: NAD⁺ depletion, mitochondrial dysfunction, cytokine amplification, gastrointestinal barrier disruption, autonomic instability, and immune imbalance. These are not random findings; they are signatures of systemic dysregulation.

They are also domains where peptide and NAD⁺ biology are most relevant.

Mechanistic interventions such as Thymosin‑α1, NAD⁺ restoration, VIP, BPC‑157, MOTS‑c, and SS‑31 align directly with the pathways disrupted in post‑viral illness. While clinical practice struggled to interpret these patterns, academic centers moved toward them. Yale’s Long COVID program exemplifies this shift, focusing on immune‑metabolic recalibration. International studies reported benefits of Thymosin‑α1 in acute COVID. NAD⁺ depletion was documented repeatedly as a mechanistic consequence of infection. Hopkins and Case Western continued advancing peptide‑based approaches for metabolic and neural repair.

The scientific trajectory and the regulatory trajectory diverged. Evidence moved in one direction; policy moved in another.

A System Misaligned With Biology

Peptides were restricted not because they are unsafe, but because they are incompatible with the regulatory and economic model that governs modern pharmaceuticals. They restore function, reduce chronic drug dependence, and lack the intellectual property structure required to justify large trials. In a system optimized for long‑term prescription revenue and proprietary chemistry, these properties become liabilities.

COVID and Long COVID revealed the cost of this misalignment. When faced with immune‑metabolic collapse — a domain where peptide and NAD⁺ biology offers coherent mechanistic interventions — the medical system defaulted to fragmentation and symptomatic treatment. Academic centers adjusted. Regulation did not.

The peptide paradox is therefore not about individual molecules. It is a diagnostic of a broader problem: biology has evolved, evidence has advanced, but regulation remains anchored to an older economic logic. Until those systems realign, the therapies most capable of restoring physiology will remain the least accessible — not because they pose risk, but because they challenge a model built to manage, rather than resolve, chronic disease.