Peptide retard debate

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Martin Shkreli
@MartinShkreliApr 22, 2026

The Spaces examined the current “peptide” craze, contrasting FDA‑approved therapeutics with unapproved, gray/black‑market compounds. Host Martin (a pharmacologist) argued that many colloquially labeled “peptides” (e.g., BPC‑157) lack evidence and have poor pharmacokinetics (short half‑life, rapid proteolysis), making self‑medication misguided. He distinguished rigorously engineered peptide drugs (e.g., GLP‑1 agonists) from unstable, research‑only mixtures, and predicted a shift to non‑peptidic small‑molecule GLP‑1R agonists (e.g., Lilly’s orforglipron) due to manufacturability, cost, and oral dosing. A lengthy debate unpacked compounding pharmacies, the 503A bulks list, and legal boundaries for prescribing: Dr. Cam (telemedicine CEO/psychiatry professor) clarified that compounding is permissible under narrow criteria (component of an FDA‑approved drug, a USP/NF monograph, or 503A bulks list), while Martin objected to expanding compounding to unproven agents and criticized “harm reduction” arguments for moving peptides into Category 1. They discussed evidence standards (double‑blind trials), off‑label practice (e.g., ketamine precedents), failures like intranasal oxytocin for autism, psychedelics’ promise pending data, and the overuse of SSRIs. An investor segment covered Eli Lilly’s GLP‑1 portfolio, market expectations, patent cliffs, and the challenge of redeploying cash flows. Overall, the session emphasized pharmacologic rigor, regulatory pathways, and patient safety over convenience or fashion.

Peptides, compounding, FDA, GLP‑1s, and pharma: a Twitter Spaces debrief

Participants and roles

  • Martin (host; pharmacologist/biotech entrepreneur): led the discussion, strongly critical of DIY “peptide” use and of unapproved gray/black‑market compounds; broadly pro‑evidence, pro‑regulatory standards; shared views on pharmacology, FDA pathways, and pharma economics.
  • Dr. Cam (telemedicine CEO; psychiatry professor): clarified how compounding pharmacies operate under U.S. rules; more open to physician‑supervised, off‑label and compounded options within legal frameworks.
  • Other participants (names not all stated):
    • Early caller (Charles): brief comment on generational drug culture (“dangerous drugs” then vs “placebos” now).
    • Multiple interlocutors questioned growth hormone secretagogues, BPC‑157, CJC‑1295, NAD+, GLP‑1 access/pricing, the 503A bulks list, and compounding.
    • One participant asked about Eli Lilly’s stock and pipeline (resitrutide, oral GLP‑1) and insulin pricing.

What “peptides” means here and why the definition matters

  • Martin drew a sharp distinction between:
    • Pharmaceutical peptides: drug‑class molecules with defined amino acid sequences that have been properly studied in clinical trials; examples include therapeutic hormones, engineered GLP‑1 analogs, oxytocin/vasopressin derivatives, etc.
    • The colloquial “peptides” that have become popular online: unapproved, minimally or un‑studied “research chemicals” (e.g., BPC‑157) often purchased from foreign websites or gray/black‑market vendors and self‑injected by healthy people.
  • His core concern: many people conflate the two. He stresses that “medicine is the stuff that works,” i.e., drugs with evidence and regulatory approval. Unapproved “peptides” marketed to healthy consumers typically lack credible evidence of safety/efficacy.

On GH secretagogues and CJC‑1295

  • A participant cited BPC‑157 and “growth hormone secretagogues,” mentioning CJC‑1295. Martin clarified:
    • Some GH secretagogues/releasing hormone analogs are FDA‑approved for specific indications (e.g., short stature, lipodystrophy); they are available by prescription.
    • That does not validate unapproved look‑alikes or research peptides; having a “similar class” does not confer evidence.

Martin’s pharmacology case against DIY “peptides”

  • Core thesis: Unapproved peptides used by healthy people are a bad idea; they are often unstable, rapidly degraded, and unlikely to have meaningful therapeutic effects. Even when a peptide is bioactive, if not engineered for appropriate pharmacokinetics, it will fail in practice.

PK/PD fundamentals and half‑life constraints

  • The bloodstream turns over in ~10–12 seconds; peptides face immediate protease degradation. For a drug to work:
    • It needs sufficient exposure (half‑life long enough) to bind its receptor in relevant tissues; and
    • The pharmacodynamic effect must persist appropriately.
  • He argued linear, short peptides (e.g., BPC‑157) are “dead within seconds” in circulation and are thus not plausible drugs unless heavily engineered. Peptides are bulky and typically do not cross membranes or the blood–brain barrier; they’re highly susceptible to peptidases.
  • Illustrative examples:
    • Antihistamines (e.g., loratadine): blockade must be sustained; a 5‑minute drug would be clinically useless for allergies.
    • Adenosine (short half‑life) is effective only as a continuous IV for specific cardiology uses; the instant infusion stops, effect stops.

Why pharma often prefers small molecules or large proteins over plain peptides

  • Small molecules: stable, manufacturable at scale, cell‑penetrant, with tunable half‑lives. Many peptide‑receptor interactions can be recapitulated by carefully designed, non‑peptidic small molecules (“skinning down” the pharmacophore), avoiding peptide bonds entirely.
  • Antibodies/large proteins: exquisitely specific, long half‑lives (often weeks to months), enabling practical dosing.
  • Peptides sit in an awkward middle: short half‑lives, poor tissue penetration, and metabolic liability. When pharma uses peptides, they often become “Frankenstein’d” with half‑life extensions (fatty acid acylation, Fc/albumin affinity, etc.) and other modifications Martin described as more like fusion constructs than simple peptides.

GLP‑1s as the notable exception—and why they’re exceptions

  • GLP‑1 receptor agonists work because they are deeply engineered: fatty‑acid modifications, albumin/Fc strategies, and other design features yielding once‑weekly dosing and strong efficacy.
  • Martin noted pharma ultimately produced a non‑peptide, oral GLP‑1 agonist (Lilly’s orforglipron), which illustrates the industry trend: capture the binding interactions with a small molecule to fix PK and manufacturing downsides.
  • He expects oral non‑peptide GLP‑1s to commoditize over time (once generic), rendering new peptide GLP‑1s unattractive in the long run.

Case study: intranasal oxytocin (and “nose‑to‑brain”)

  • Martin licensed intranasal oxytocin for autism from Novartis and described why the “nose‑to‑brain” transport thesis ultimately failed in an NIH study (negative Phase 3). Oxytocin is a 9‑mer with an extremely short half‑life; attempts to overcome this with delivery tricks did not translate into efficacy. He is skeptical of nostril‑to‑CNS “magic.”

Evidence, FDA approval, and off‑label use: the boundaries

  • Martin’s principle: If you’re healthy, avoid unapproved drugs. Almost everything legitimately needed exists among FDA‑approved options. Unapproved “peptides” lack evidence; bypassing the FDA is unsafe and undercuts the purpose of regulation.
  • He supports off‑label use of FDA‑approved drugs when medically justified (physicians routinely do this). Example: ketamine’s antidepressant signal emerged from academic trials; many physicians used IV ketamine (an approved anesthetic) off‑label for TRD before branded esketamine gained approval.
  • A participant raised NAD+ and other popular but unproven therapies. Martin emphasized the need for randomized, double‑blind, placebo‑controlled trials to establish efficacy and to counter human bias. Another participant reinforced the epistemology: RCTs are how we know whether something works.

Compounding pharmacies and the 503A “bulks list” debate

  • A long segment examined whether compounding offers a “safer” physician‑supervised alternative to overseas/black‑market “peptides.” Key points of clarification:
    • Dr. Cam: Legitimate 503A compounding pharmacies can generally compound a product if one of the following holds:
      1. The substance is a component of an FDA‑approved drug;
      2. It has a USP/NF monograph; or
      3. It’s on the FDA’s 503A bulks list (Category 1). Some items may be “under evaluation,” and rules evolve; items can also be moved to Category 2 (do not compound).
    • Compounding ≠ approval: compounded preparations aren’t “FDA‑approved” drugs; they fill niche needs (e.g., alternate dosage form, excipient avoidance) but cannot be promoted with efficacy claims. Many common compounded items are benign (e.g., melatonin, CoQ10) or are stereo‑isomers/variants of long‑known drugs (e.g., enclomiphene as a stereopure component of clomiphene).
    • BPC‑157 and similar unapproved “peptides”: Martin opposes legitimizing them via compounding. He sees placing such items on 503A lists as wrongheaded and believes it undermines the FDA’s evidentiary standard.
    • Harm‑reduction framing: Some participants argued that allowing compounding could curb black‑market risks (quality/sterility, dosing oversight). Martin rejects “special lanes” for drugs without evidence.
  • Prevalence and business model:
    • Disagreement over how big compounding is: estimates ranged from a sliver of volume (<1–3%) to larger peaks during GLP‑1 shortages. Martin views compounding as a small, sometimes abuse‑prone “cottage” sector with episodic regulatory run‑ins, not a mainstream channel.
    • Example companies: Empower Pharmacy mentioned; warning letters noted. Telehealth models that partner with compounders exist, but Martin emphasized they must stay within legal boundaries and avoid promotional overreach.

International angle: “Peptide” use in Russia/Asia, e.g., Semax

  • A participant cited reports of broader peptide integration overseas. Martin: every country has idiosyncratic approvals, but there’s no systematic global validation of “peptides” as a superior modality; small molecules and antibodies remain dominant for clear scientific and practical reasons.

GLP‑1 pipeline, Lilly stock, and pharma economics

  • On Lilly’s pipeline and oral GLP‑1:
    • Martin expects an oral small‑molecule GLP‑1 (referred to as orforglipron) to sell well: pill convenience, lower manufacturing cost versus injectable peptides. He anticipates robust demand but stresses patents and market timing are priced in by markets.
    • Resitrutide (multi‑agonist) and other pipeline assets were noted. He cautioned that weight loss likely has a physiological “speed/safety limit,” so the room for ever‑better agents may cap out.
  • Investing lens:
    • Pharma’s structural challenge: patents expire, revenues cliff, firms must constantly reinvent pipelines; management’s capital allocation is key (example criticism of Pfizer’s use of COVID windfall).
    • Warren Buffett’s aversion to pharma cited: hard to bet on who will recycle cash flows well.
    • Generics future: by the 2030s–2040s, GLP‑1s may commoditize (like statins and antihypertensives did), shifting the market to cheap oral options and lowering barriers to access.
  • Insulin pricing came up tangentially. Martin didn’t deeply analyze insulin’s current price dynamics here; his larger point was about sector economics, not policy pricing.

Psychedelics and FDA

  • Martin: psychedelics should be treated like any other drug; if RCTs show a favorable risk–benefit for specific indications (e.g., depression), FDA will (and has) approved novel mechanisms. He sees no anti‑psychedelic bias at FDA; approvals are a matter of evidence and safety, not politics.

Psychiatry: stagnation, off‑label strategies, and complexity

  • Martin and Dr. Cam agreed psychiatry has seen few breakthroughs compared with oncology. Serotonergic agents (SSRIs) have dominated for decades, and outcomes are mixed.
  • Martin attributed slow progress to scientific complexity—limited mechanistic understanding of brain‑to‑mind links. He views recent muscarinic and other mechanisms with caution (mixed data).
  • Dr. Cam described exploratory, legally compliant use of older agents (e.g., enclomiphene for hypogonadism) and tracking mood/anxiety outcomes; he favors giving patients options when evidence is emerging and risk is acceptable, while avoiding overpromising.

Regulatory framework and costs

  • FDA pathways and cost: Martin rejected “it costs billions” as a blanket figure; total costs vary widely (some approvals achieved for ~$100–200M, sometimes much less), though big programs can be expensive. The core is not price but producing solid evidence.
  • He underscored that FDA’s role is to determine whether drugs are safe and effective—not to set prices or decide access. Payers (insurers) drive coverage hurdles; patients may pursue cash‑pay workarounds, but that’s a payer issue, not a regulatory one.

Tone and ethics

  • Martin used strongly critical, sometimes abrasive language toward gray/black‑market “peptides” and self‑prescribing. His ethical stance: do no harm, don’t give unproven drugs to healthy people, and don’t erode evidence standards. He views compounding creep into unapproved “peptides” as a net negative.
  • Counter‑voices pushed harm‑reduction and physician discretion within compounding rules. Dr. Cam emphasized that legitimate compounders are constrained (USP monographs, components of approved drugs, or bulks list) and cannot market efficacy claims.

Key takeaways

  • “Peptides” as a social trend largely refers to unapproved research chemicals. Martin argues these are scientifically implausible or unproven, especially simple linear peptides with ultra‑short half‑lives (e.g., BPC‑157) used by healthy individuals.
  • Pharma’s sporadic success with peptides (notably GLP‑1s) reflects heavy engineering to fix peptide liabilities; the field is moving toward non‑peptide small molecules (e.g., oral GLP‑1 agonists) for stability, manufacturability, and convenience.
  • Off‑label use of FDA‑approved drugs under physician care is legitimate; bypassing approval entirely is not. RCTs remain the gold standard for knowledge.
  • Compounding pharmacies serve narrow, regulated roles; they are not a backdoor to legitimize unapproved “peptides.” The 503A bulks list is limited and evolving; placing “peptides” with no evidence on it is, in Martin’s view, a mistake.
  • GLP‑1s will likely become cheaper and oral over time; markets have priced much of this. Pharma investing hinges on pipeline reinvention and capital allocation, not just one class boom.
  • Psychiatry lags due to scientific complexity; the field welcomes new mechanisms supported by rigorous trials. Until then, cautious, ethical off‑label practice can help some patients—but should avoid hype.

Notable examples cited

  • Unapproved colloquial “peptides”: BPC‑157; CJC‑1295 (as an example of a non‑approved analog amid approved GH secretagogues).
  • Engineered peptide/peptide‑like successes: GLP‑1 RAs (e.g., semaglutide class), with fatty‑acid/Fc/albumin strategies; progression to oral non‑peptide GLP‑1 (orforglipron).
  • Short‑half‑life IV drug: adenosine (requires continuous infusion for effect in certain uses).
  • Off‑label precedent: ketamine for depression pre‑esketamine approval.
  • Failed peptide path: intranasal oxytocin for autism (negative NIH Phase 3; skepticism on “nose‑to‑brain”).
  • Regulatory references: NDA pathway; compounding under 503A; bulks list categories and “under evaluation” status; USP/NF monographs.

Practical guidance inferred from the discussion

  • If you are healthy, avoid unapproved “peptides.” If you have a legitimate medical need, speak with a physician about approved therapies (including off‑label uses where supported) rather than resorting to black‑market compounds.
  • Be wary of claims for short linear peptides with no robust clinical evidence; PK/PD realities are unforgiving.
  • For access/cost issues, discuss payer options or approved alternatives with your provider; compounding may be appropriate for formulation issues (e.g., excipient allergy, alternate dosage form), not as a replacement for evidence.
  • Watch the GLP‑1 landscape: engineered injectables work well; oral non‑peptide GLP‑1s may reshape access and economics over the next decade, but market pricing anticipates much of this.