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LL-37

Also known as human cathelicidin, hCAP-18/LL-37, CAP-18, CAMP gene product

Endogenous antimicrobial peptide; the phase 2b trial in leg ulcers missed its primary endpoint.

early-clinical Recovery & tissue research chemical

At a glance

Category
Recovery & tissue
Status
research chemical
Route
in clinical research exclusively topical (gel) and, on one occasion, intratumoural; on the grey market subcutaneous
Half-life
Not known for exogenously administered LL-37. As a cationic peptide it is subject to rapid proteolysis and binding to serum components; the clinical research was topical, so systemic pharmacokinetics have never been determined
Onset
the wound studies treated over a period of 4 weeks
Molecular weight
4493 g/mol
Sequence
LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES

An endogenous human peptide, but not approved as a medicine anywhere, in any formulation. Clinical development (topical, in venous leg ulcers) never got past phase 2 2. The FDA lists "Cathelicidin LL-37" among bulk drug substances that may present significant safety risks - previously category 2 under the interim 503A/503B policies, now in the "nominated but withdrawn" table - noting immunogenicity risk, characterisation difficulties, and that "nonclinical research findings suggest detrimental effects on male reproduction and that this drug can be protumorigenic in some tissues" 6. Sold as a 'research chemical'.

Doping status: Not listed by WADA

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

LL-37 is the only human cathelicidin. It is the active C-terminal fragment of the pro-protein hCAP-18, which is stored in the specific granules of neutrophils and cleaved off extracellularly by proteinase 3. It is an amphipathic alpha helix with a net charge of roughly +6.

The direct antimicrobial action rests on physical membrane disruption: the positively charged helix binds to negatively charged microbial membranes and its hydrophobic face inserts into the bilayer. The spectrum covers Gram-positive and Gram-negative bacteria, fungi and enveloped viruses. Because the mechanism is physical, resistance is relatively difficult to develop.

Immunomodulation runs via formyl peptide receptor 2 (FPR2/FPRL1), the first identified functional receptor for LL-37. This drives chemotaxis of neutrophils, monocytes, eosinophils and T cells. LL-37 also promotes angiogenesis through upregulation of VEGF and migration of epithelial cells during wound closure.

The inflammatory effect is concentration-dependent and bidirectional: inhibitory at low concentrations (less TNF-alpha from LPS-stimulated macrophages), pro-inflammatory at high concentrations. This is essential for understanding both the trial results and the risks.

What the research shows

The clinical history of LL-37 is one of an early positive signal that did not hold up in a larger trial. The widely cited sixfold improvement in healing comes from a study with 34 participants; the subsequent phase 2b with 148 participants missed its primary endpoint 12. For systemic or subcutaneous administration there is no human efficacy evidence whatsoever.

Research in humans

Phase 1/2 in venous leg ulcers (2014, n=34): randomised, double-blind and placebo-controlled, with topical administration twice weekly at concentrations of 0.5, 1.6 and 3.2 mg/ml 1. At 0.5 mg/ml the healing rate was roughly six times higher than placebo (p=0.003) with a 68% reduction in wound area; at 1.6 mg/ml roughly threefold (p=0.088, not significant); at 3.2 mg/ml no difference from placebo 1. Phase 2b in hard-to-heal venous leg ulcers (2021, n=148): the primary endpoint was not met — complete wound closure in 26.5% (0.5 mg/ml), 24.7% (1.6 mg/ml) and 25.3% (placebo) 2. A post-hoc analysis showed improvement in wounds larger than 10 cm², but post-hoc subgroups are hypothesis-generating and not evidence. In addition there is a small phase 1 dose-finding study of intratumoural injection in melanoma with cutaneous metastases (NCT02225366), registered as completed; I have not been able to find a publication with results.

Animal and lab research

Extensive preclinical and in vitro work on antimicrobial activity, wound healing, angiogenesis and immunomodulation, plus mechanistic models for psoriasis. That broad preclinical base did not translate into a positive phase 2b.

Caveats. The dose-response relationship is inverted: the highest concentration did no better than placebo. That is a substantial argument against dosing higher. The positive finding from the small study was not replicated in the larger, adequately designed trial — the classic pattern of an early chance result. The entire body of human evidence concerns topical wound care; subcutaneous administration has never been studied in humans, at any dose.

What it is used for

  • Topical for hard-to-heal venous leg ulcers - studied to phase 2b, where complete wound closure was 26.5% at 0.5 mg/ml, 24.7% at 1.6 mg/ml and 25.3% on placebo, so the primary endpoint was not met 2
  • Used in practice for chronic or resistant infections and gut complaints, without clinical support
  • Used in practice topically for acne and skin infections

Dosing

Dose
Clinically studied: topical gel at 0.5, 1.6 or 3.2 mg/ml. Grey market: varied subcutaneous protocols
Frequency
twice weekly topically in the studies
Route
topically on the wound
Duration
4 weeks in the studies
  • 0.5 mg/ml was the effective concentration in the small phase 1/2 study; 3.2 mg/ml did no better than placebo 1. More is demonstrably not better here, which fits the concentration-dependent tipping point from anti-inflammatory to pro-inflammatory.
  • For systemic subcutaneous administration in humans there is no dose-finding research, no pharmacokinetics and no safety study; every published human exposure has been topical gel on a wound 12. The only injected human exposure was intratumoural in a very small study. The FDA likewise states it lacks sufficient safety information on cathelicidin LL-37 to know whether it would cause harm when administered to humans 6.
  • With a cationic peptide, endotoxin contamination in unregulated material is a specifically relevant risk, precisely because of its own immunomodulatory activity.
  • The subcutaneous self-injection pattern that circulates is set out as a circulating protocol below. The only studied route is a topical gel on a wound 12; what circulates is injected grey-market powder with no human dose-finding, pharmacokinetic or safety data behind it 6. It is recorded because readers encounter it, not because it is validated.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Topical gel for hard-to-heal venous leg ulcers (phase 1/2)

published trial

Source: Wound Repair and Regeneration, 2014

Weeks 1-4LL-37 gel applied to the ulcer twice weekly
Concentrations tested0.5, 1.6 and 3.2 mg/ml
Result by concentration0.5 mg/ml improved healing; 3.2 mg/ml did no better than placebo

The inverted dose-response fits the concentration-dependent switch this peptide shows from anti-inflammatory to pro-inflammatory behaviour. Note what the schedule actually is: a gel on an open wound, twice a week. It provides no basis for the subcutaneous protocols sold on the grey market, for which no dose-finding, pharmacokinetic or safety study exists in humans.

Research-chemical subcutaneous self-injection (circulating)

user protocol — not validated

Source: Peptide forums and research-chemical vendor labelling; no pharmaceutical product exists

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Reported amountsroughly 100-250 mcg subcutaneously, daily or a few times a week, from reconstituted grey-market powder — figures vary between sellers and posters with no common basis
Reported reasonschronic or antibiotic-resistant infections, gut complaints, acne and vague 'immune' support
Reported cycleshort runs of a few weeks; no consistent schedule circulates

Every published human exposure to LL-37 was a gel applied to a wound 12; the label study is a topical one, whereas what circulates is subcutaneous injection. There is no dose-finding study, no pharmacokinetics and no safety study for subcutaneous LL-37 in humans, at any dose. The microgram figures that circulate are arithmetic from a reconstituted vial, not studied doses, and the trials give a positive reason to distrust dosing higher: the concentration that helped was the lowest one, and the highest did no better than placebo, matching this peptide's switch from anti-inflammatory to pro-inflammatory as concentration rises 1. Injecting a cationic peptide from unregulated powder makes endotoxin contamination specifically dangerous, because the molecule has its own immunomodulatory activity. The FDA states it lacks sufficient safety information on cathelicidin LL-37 to know whether it would cause harm in humans, and cites nonclinical findings of detrimental effects on male reproduction and protumorigenic effects in some tissues 6. This is recorded because it circulates, not because any injected dose has been shown to be safe or effective.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
5 mg
Solvent
bacteriostatic water (0.9% benzyl alcohol)
Storage
Reconstituted 2-8 °C, protected from light. Powder in the freezer. Shelf-life figures are convention, not stability data.

Worked example

5 mg vial + 2 ml bacteriostatic water = 2.5 mg/ml. 250 mcg = 0.1 ml, that is 10 units on a U100 insulin syringe. The 250 mcg here is an arithmetic illustration of the dilution, not a studied dose: no dose-finding, pharmacokinetic or safety study of subcutaneous LL-37 exists in humans. The concentrations that were studied, 0.5 to 3.2 mg/ml, describe a gel applied to a wound and are not a quantity to inject.

Do not shake. These vial sizes and instructions come from grey-market suppliers; no pharmaceutical presentation exists.

Work it out for LL-37

Safety

Side effects

  • Well tolerated topically in the studies: reactions at the ulcer and adjacent skin were mostly mild or moderate, with no consistent difference between treatment groups. In the phase 2b, twelve non-fatal serious adverse events occurred in eleven patients (7.4%), none assessed as related to study drug; adverse events judged possibly related numbered six across four patients (2.7%) 2
  • Flare-up of type I interferon-driven inflammation, particularly in psoriasis and rosacea — see contraindications
  • Pro-inflammatory effects at higher concentrations, in line with the loss of effect at 3.2 mg/ml in the study 1
  • Mast cell activation and histamine-like reactions are reported anecdotally with injection; this cannot be confirmed from a published source
  • For systemic administration there is no human safety dataset at all; the FDA records no adequate safety information for this peptide and cites nonclinical findings of detrimental effects on male reproduction and protumorigenic effects in some tissues 6

Do not use if

  • Psoriasis — the most important contraindication 3. LL-37 is overexpressed in psoriatic skin, where it binds released self-DNA and converts it into a powerful TLR9 stimulus for plasmacytoid dendritic cells. These release interferon-alpha, which sets off a self-amplifying autoimmune reaction in the skin. LL-37 is moreover recognised as a T-cell autoantigen in psoriasis. Anyone with psoriasis is administering a molecule that is mechanistically involved in their own disease.
  • Rosacea — comparable involvement in the disease mechanisms has been described
  • Systemic lupus erythematosus and other conditions with an interferon signature; LL-37-specific T cells have been linked to autoantibody production in SLE
  • Active malignancy: the tumour biology is unsettled. LL-37 has been described as promoting local invasion in melanoma 4 and proliferation in hepatocellular carcinoma, while other models have shown antitumour activity instead. The effect appears to depend on context and tumour type. The FDA cites nonclinical findings that the drug "can be protumorigenic in some tissues" 6
  • Pregnancy and breastfeeding: no data

Interactions

Not systematically studied. No interaction studies exist. Theoretically, potentiation is conceivable with concurrent use of agents that affect innate immunity or the interferon response.

Sources