Leuphasyl

Overview

Leuphasyl (also called Pentapeptide-18 or Pentapeptide-3, INCI usage varies between sources) is a synthetic pentapeptide marketed as a cosmeceutical anti-wrinkle ingredient. A tier-4 profile states it was developed by Lipotec S.A(vendor claim). (now Lubrizol) in Barcelona in the mid-2000s as an enkephalin analog¹¹. Its reported sequence is H-Tyr-D-Ala-Gly-Phe-Leu-OH; a vendor page lists molecular formula C29H39N5O7, molecular weight ~569.65 g/mol, and CAS 64963-01-5¹⁰, and an ingredient guide adds FDA UNII PO4D55T1IG.

What the sources describe

A tier-1 MDPI review describes Leuphasyl as a botox-like pentapeptide used in cosmetic science that inhibits neuromuscular synapses in mimic muscles by acting like enkephalins, linking the enkephalin receptor to nerve cells to modulate acetylcholine release in the synaptic space, resulting in muscle relaxation and reduction of expression wrinkles³. Sources describe it as based on the natural enkephalin opioid pentapeptides leucine-enkephalin and methionine-enkephalin, first identified by Hughes et al. in 1975, with a D-alanine substitution at position 2 said to increase resistance to enzymatic degradation while preserving receptor binding^8,9.

Several profiles contrast its mechanism with botulinum toxin: they state it acts upstream at the receptor level (presynaptically) rather than by cleaving SNARE proteins, and describe it as preserving partial muscle motility and avoiding the frozen appearance associated with injections. Profiles also distinguish it from Argireline (Acetyl Hexapeptide-8) and SNAP-8 (Acetyl Octapeptide-3), which are described as acting post-synaptically on SNARE complex assembly⁵.

Reported clinical and preclinical findings

• The MDPI review reports that three emulsions (0.5%, 1%, 2%) were formulated and applied at the mimic-muscle level over the corrugator supercilii (eyebrow zone) and orbicularis oculi (periorbital zone), with regression of wrinkles between the eyebrows evaluated using the pro-derm Analyser imagistic method⁴.
• The Dragomirescu et al. (2014) study (Cosmetics/MDPI, published 8 April 2014, vol. 1, pp. 75–81) describes Leuphasyl as a botox-like peptide applied topically at the mimic-muscle level, showing efficiency in reducing wrinkles between the eyebrows, reports an optimal application concentration, describes it as safe for topical use, and reports improvements in skin hydration, elasticity, and texture¹. A tier-3 profile attributes to this study a ~34.7% forehead wrinkle-depth reduction at 2% Leuphasyl over 60 days(vendor claim).
• A tier-4 profile reports that manufacturer-sponsored split-face studies showed statistically significant reductions in crow's-foot wrinkle depth after 28 days of twice-daily topical application versus vehicle control, and that in vitro studies published in Cosmetics (MDPI, 2014) confirmed receptor-mediated modulation of Ca2+ channels consistent with enkephalin activity(vendor claim).
• Reported wrinkle-reduction figures vary between sources and are worth reading with that caveat in mind. A vendor page reports 5% Leuphasyl reduced wrinkles by about 11% after 28 days, and about 25% (up to 47%) when paired with 5% Argireline³; a tier-3 profile reports ~11–12% alone; and tier-4 profiles report up to 47% combined with Argireline and a 34.7% frontal wrinkle-depth reduction at a 2% minimum effective concentration. Manufacturer data reported across profiles indicates combining Leuphasyl with Argireline produces greater wrinkle reduction than either alone².

Additional reported activities (preclinical / in silico)

Computational and in vitro studies report interactions beyond the neuromuscular mechanism: binding to TGF-β, TNF-α, MAPK, PI3K/AKT and NF-κB targets implicated in skin aging, interactions with AKT-1 and MAPK14/p38α, and targeting of matrix metalloproteinases MMP-1, MMP-8 and MMP-13 with the strongest interaction reported for MMP-13. An in silico study describes strong docking affinity to EGFR and PI3K and reports cytotoxic effects in MDA-MB-231 and PC3 cells in MTT assays, suggesting possible selective anticancer effects. Separately, in vitro work reports that adding terminal D-tyrosine to pentapeptide-18 conferred anti-melanogenic activity — reducing melanin content and tyrosinase activity in MNT-1 melanoma cells and primary melanocytes and in a 3D human skin model; a tier-3 profile likewise suggests potential melanin suppression and skin brightening in D-tyrosine-containing analogs(vendor claim). Formulation studies report that solid lipid nanoparticles/lipid nanocarriers can co-deliver retinol and pentapeptide-18 as a stable anti-aging combination, with semi-solid formulations showing reduced sebum secretion and reduced facial wrinkles.

Evidence caveats

Multiple sources note the clinical evidence base is thin and primarily manufacturer-sponsored; one tier-4 profile explicitly states that no independent peer-reviewed clinical trials existed as of 2026. Reported wrinkle-reduction percentages and their associated concentrations are inconsistent across sources, and sources disagree on the INCI name (Pentapeptide-18 vs Pentapeptide-3) and whether the sequence contains D-alanine. Collagen/elastin enhancement and skin-brightening (D-tyrosine analogs⁹) claims rest on limited or analog-specific sourcing, and the anticancer, MMP, and aging-pathway findings are in silico or in vitro only.

Safety and Side Effects

Leuphasyl is not regulated as a drug by the FDA and is marketed as a cosmetic ingredient⁶.

Sources generally characterize it as well tolerated at cosmetic concentrations:

• A tier-4 profile states that the MDPI study concluded Leuphasyl is safe with no adverse effects and preserves facial expressivity unlike botulinum toxin, and an ingredient guide similarly reports that efficiency tests showed it is less effective than Botox injections but is safe, has no adverse effects, and preserves facial expressivity(vendor claim).
• A tier-3 profile describes a complete safety profile without neurological side effects, characterizing it as very safe with no reported systemic toxicity or significant skin irritation at standard cosmetic concentrations(vendor claim).
• The Dragomirescu et al. study reports Leuphasyl demonstrates safety for topical use.
• In vitro toxicity work reports no cytotoxicity on the HaCaT keratinocyte cell line at concentrations up to 1 mg/mL, and in silico ADME/toxicity predictions suggesting favorable pharmacokinetic and safety profiles; another study reports favorable ADMET properties.

Reported potential adverse effects

A tier-4 profile lists rare skin irritation at high concentrations and very rare contact sensitization as potential adverse effects(vendor claim). Formulation studies report that lipid nanoparticles reduced the irritating effect of retinol seen in classic retinoid therapies when the two were co-formulated.

Important caveats

• Bioavailability through intact skin is unresolved. A vendor page notes limited topical bioavailability owing to the peptide's hydrophilic nature and molecular size, and ADMET modeling indicated limited oral bioavailability and minimal blood-brain-barrier penetration(vendor claim). A tier-3 profile flags whether meaningful receptor engagement occurs through intact skin at cosmeceutical concentrations as the central unresolved question(vendor claim).
• In vitro cytotoxicity note. An in silico/in vitro study reports Leuphasyl exhibited cytotoxic effects in MDA-MB-231 and PC3 cancer cell lines in MTT assays, framed as a possible selective anticancer effect rather than a toxicity concern; this is a cell-line finding, not a human safety observation.
• The safety statements above derive largely from manufacturer-sponsored or in silico/in vitro sources, with no independent peer-reviewed clinical trials reported as of 2026.

Dosing and Formulation

No medical dose has been established for Leuphasyl. It has no regulatory drug label — it is marketed as a topical cosmetic ingredient⁶. The figures below are what the sources report for cosmetic formulation and use, not medical guidance, and reported effective concentrations vary between sources.

Topical formulation concentrations (as reported)

• The MDPI review reports three emulsions formulated at 0.5%, 1%, and 2% applied to the skin at the mimic-muscle level.
• A vendor page states 2% Leuphasyl is the lowest concentration shown to give significant wrinkle reduction in cosmetic testing, with measurable improvement over roughly 2 months of daily use, and describes topical application as a cream, gel, or lotion that works mainly where placed¹.
• A tier-4 profile states finished formulations use 1–5% concentration, with the manufacturer recommending combination with Argireline at an equal concentration for enhanced effect(vendor claim).
• A tier-3 profile suggests typical topical use at 3–10%, potent effects at 2% without irritation, ~2–4 weeks for visible wrinkle reduction at 4%, and a 28–60 day cycle length, with example regimens of 5% twice daily for expression lines and 10% once daily at night(vendor claim). These figures come from a community/expert-opinion profile, not from a trial.

Manufacturer technical data sheet (LEUPHASYL Solution)

The manufacturer TDS states LEUPHASYL is synthesized under cGMP with a final freeze-drying step and incorporated into emulsions, gels, and sera at temperatures below 40 °C, recommending 3 to 10% of LEUPHASYL Solution in the final formulation for significant anti-wrinkle activity. The Solution is described as containing 0.5 g/L peptide powder (0.05% powder) with 0.5% Caprylyl Glycol preservative, with a shelf life of at least twelve months at room temperature or eighteen months at 4 °C; the TDS lists the INCI name as Pentapeptide-3.

Storage and handling (as reported)

• A tier-3 profile provides storage guidance: -20 °C or below for freezer storage (ideally -80 °C for long-term, up to 2–3 years), 2–8 °C for short-term storage, use of reconstituted solutions within 4 weeks (28 days) for optimal potency, and mentions a 0.9% benzyl alcohol preservative(vendor claim).
• Formulation studies report that lipid nanoparticle dispersions of retinol and pentapeptide-18 remained stable over 4 weeks of storage at 4, 25, and 45 °C, and that semi-solid preparations were stable regardless of storage temperature with 25 °C recommended.

Combination use

Multiple sources report an additive or synergistic effect when Leuphasyl is combined with Argireline (Acetyl Hexapeptide-8), with combined regimens reported to reach greater wrinkle reduction than either alone^2,3. No human trial in the provided claims has independently validated any of these formulation regimens outside manufacturer-sponsored studies.

What these percentages actually mean

The percentage figures across these sources are not directly comparable, because they may refer to two different things. The manufacturer's technical data sheet supplies Leuphasyl as a dilute trade solution that contains only 0.05% actual peptide powder, and its recommendation of 3–10% of that solution in a final formulation therefore works out to only roughly 0.0015–0.005% peptide by weight in the finished product. Vendor and community figures quoted as "2%", "5%", or "10% Leuphasyl" do not state whether they mean percent of the dilute trade solution or percent of pure peptide. If they refer to the trade solution — as the manufacturer's own numbers do — the true peptide dose is far lower than the headline percentage implies. Because the sources do not reconcile this point, the concentration figures reported here should be read with that ambiguity in mind.

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   Tier 1Web · semanticscholar.org
2. 2.
   Retinol and Oligopeptide-Loaded Lipid Nanocarriers as Effective Raw Material in Anti-Acne and Anti-Aging Therapies.(opens in a new tab)

   Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2024
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   Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2026
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   Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2024
9. 9.
   D-tyrosine adds an anti-melanogenic effect to cosmetic peptides.(opens in a new tab)

   Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
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