Leuphasyl

Lipotec's (now Lubrizol's) trade name for pentapeptide-18 (H-Tyr-D-Ala-Gly-Phe-Leu-OH), a metabolically stabilized leu-enkephalin analog sold as a topical cosmetic ingredient and studied for softening expression lines by damping neurotransmitter release at the neuromuscular junction.

Also referenced as: Pentapeptide-18, [D-Ala2]-Leu-enkephalin, [D-Ala2]-Leucine-enkephalin, H-Tyr-D-Ala-Gly-Phe-Leu-OH, Tyr-D-Ala-Gly-Phe-Leu

Also appears in: Longevity

What is Leuphasyl?

Leuphasyl is the trade name — originally Lipotec’s, now Lubrizol’s, following Lubrizol’s 2012 acquisition of Lipotec SAU of Barcelona — for pentapeptide-18, the synthetic pentapeptide H-Tyr-D-Ala-Gly-Phe-Leu-OH (CAS 64963-01-5). Structurally it is leu-enkephalin, one of the two endogenous opioid pentapeptides isolated from brain in 1975, with the glycine at position 2 replaced by D-alanine — a substitution introduced in the mid-1970s specifically to slow enzymatic breakdown of the sequence.

In cosmetic chemistry it belongs to the small group of “neuromodulating” or so-called botox-like topical peptides, and its INCI name is Pentapeptide-18; the EU cosmetic ingredient database lists its declared function as skin conditioning. It reaches the research-peptide market as a topical raw material, typically listed alongside the other expression-line peptides — Argireline (acetyl hexapeptide-8), SNAP-8, and Vialox — and frequently sold as a blend with Argireline rather than on its own.

How it works

• Leu-enkephalin was one of the two pentapeptides identified as the brain’s natural opiate-receptor ligands (Hughes et al., Nature, 1975;258(5536):577-580); binding and bioassay work shortly afterward separated multiple opioid receptor populations and showed the enkephalins act preferentially at the receptor type those authors designated δ, in contrast to morphine’s μ profile (Lord et al., Nature, 1977;267(5611):495-499). Pentapeptide-18 is a stabilized analog of that endogenous ligand.
• Opioid receptors are Gi/Go-coupled. Activation inhibits adenylyl cyclase and lowers cAMP, opens inwardly rectifying potassium channels, and inhibits voltage-gated calcium channels; the net presynaptic effect is less neurotransmitter released per impulse (Al-Hasani & Bruchas, Anesthesiology, 2011;115(6):1363-1381).
• The specific observation the cosmetic rationale rests on was made at the neuromuscular junction: enkephalin reversibly reduced the quantal content of transmitter release from motor nerve terminals in frog cutaneous pectoris muscle, apparently by acting on presynaptic inward calcium current (Bixby & Spitzer, Nature, 1983;301(5899):431-432). Less acetylcholine per impulse would mean a weaker contraction of the mimetic muscle beneath an expression line. That experiment used Met-enkephalin in amphibian tissue, not pentapeptide-18 in human facial muscle.
• The D-alanine at position 2 is why this analog is used instead of plain leu-enkephalin. Native enkephalins are deactivated rapidly by rat and human plasma and by brain homogenate, principally through aminopeptidase cleavage at the Tyr1-Gly2 bond (Hambrook et al., Nature, 1976;262(5571):782-783). The stabilizing value of the D-Ala2 substitution was established on the met-enkephalin side of the family: [D-Ala2]-Met-enkephalinamide binds opiate receptors almost as tightly as met-enkephalin itself while resisting degradation by brain enzymes (Pert et al., Science, 1976;194(4262):330-332). That analog carries a C-terminal amide in addition to the D-Ala2 substitution; pentapeptide-18 takes only the D-Ala2 half of that design onto a leu-enkephalin backbone with a free acid terminus, so the parallel is a design rationale rather than a measured result for this exact molecule.

Research status

Leuphasyl has no drug-development record. A ClinicalTrials.gov search for “pentapeptide-18” or “Leuphasyl” returns zero registered studies, and the indexed literature is thin: PubMed returns four records for “pentapeptide-18” and three for “Leuphasyl” — six distinct papers once the overlap between the two searches is removed — and none of them is a controlled clinical trial. The single human use study is not among those six; it appeared in a cosmetic-science journal PubMed does not index, which is worth knowing before treating a PubMed count as the whole evidence base.

That human study is Dragomirescu et al., Cosmetics, 2014;1(2):75-81. Twenty volunteers, minimum age 30, applied one of three oil-in-water emulsions containing 0.5%, 1%, or 2% Leuphasyl for two months over the corrugator supercilii and the orbicularis oculi, with wrinkles imaged once a week on a two-dimensional pro-derm Analyser. Only the 2% formulation produced a meaningful change — a mean reduction in measured wrinkle trajectory of 34.7% in the frontal, inter-eyebrow region and 28.4% periorbitally — while 0.5% and 1% did not. The paper describes no vehicle-only control arm, no randomization, and no blinding of the instrumental assessment; the authors also state plainly that their 2D methodology “does not permit us to evaluate the wrinkles depth” (Dragomirescu et al., 2014), so the headline percentages describe the length of a line on an image rather than its depth, against no placebo. The same paper mislabels the compound “pentapeptid-3” and calls Argireline by its older name, acetyl hexapeptide-3. Its authors concluded that results reported in the literature for Argireline were superior to their own, and that a Leuphasyl/Argireline mix would be ideal for a synergic effect — which is the reasoning behind the Argireline/Leuphasyl pairing sold today.

The indexed literature is preclinical, formulation, or computational work:

• Park et al., Sci Rep, 2020;10(1):262 — adding D-tyrosine to a terminus of pentapeptide-18 conferred anti-melanogenic activity in human MNT-1 melanoma cells, primary melanocytes, and the epidermal basal layer of a 3D human skin model. This tests a modified derivative, not pentapeptide-18 itself.
• Pawłowska et al., Int J Mol Sci, 2024;25(18):10078 — solid lipid nanoparticles co-loaded with retinol and pentapeptide-18, characterized for particle size, polydispersity, and four-week storage stability at three temperatures. A raw-material study with no efficacy endpoint.
• Pawłowska et al., Life (Basel), 2024;14(10):1212 — the same group’s follow-up, working those nanocarriers into semi-solid cosmetic preparations and assessing physicochemical characteristics and shelf-life stability. Formulation work again, not a wrinkle trial.
• Akhan et al., Comput Biol Chem, 2026;123:108952 — density functional theory calculations, FTIR/ATR-FTIR/Raman characterization, and molecular docking and dynamics against protein targets implicated in skin aging. Computational and spectroscopic only; no cell or human data.
• Akhan et al., Chem Biodivers, 2026;23(5):e02546 — docking and molecular dynamics for Leuphasyl and Vialox against the collagen-degrading matrix metalloproteinases MMP-1, MMP-8, and MMP-13 and against SIRT-1, reporting stronger Leuphasyl interaction with MMP-13. It also carries the only published cell-based safety data on the compound: no cytotoxicity in HaCaT keratinocytes at concentrations up to 1 mg/mL.
• Akhan et al., Cell Biochem Biophys, 2026 (online ahead of print, doi 10.1007/s12013-026-02095-z) — in vitro and in silico screening of venom-derived and biomimetic neurotransmitter-inhibitor pentapeptides for anticancer activity, a line of inquiry unrelated to the cosmetic use case.

None of those six tests whether the ingredient softens an expression line on a human face. The MMP and SIRT-1 docking work in particular proposes a matrix-remodeling rationale that is separate from — not evidence for — the neuromuscular mechanism the product is marketed on.

Widely repeated efficacy figures — a percentage wrinkle-depth reduction after roughly a month, usually quoted for a Leuphasyl plus Argireline combination — originate in the ingredient supplier’s own in-vivo panel data reported in trade literature. They have not been published in a peer-reviewed journal or independently replicated.

The largest gap is delivery. No published skin-permeation or pharmacokinetic study locates intact pentapeptide-18 anywhere near the neuromuscular junction of a facial mimetic muscle after topical application. Human epidermis does carry opioid receptors — δ-opioid receptor signaling regulates keratinocyte differentiation and epidermal homeostasis through ERK-dependent inhibition of the transcription factor POU2F3 (Neumann et al., J Invest Dermatol, 2015;135(2):471-480) — so a plausible epidermal target exists, but that is a different mechanism from the muscle-relaxation claim the ingredient is marketed on.

Common dosage forms

Leuphasyl is a topical-only compound in practice. Cosmetic ingredient suppliers sell it as an aqueous peptide solution containing a low percentage of active for formulators to dose into creams, serums, and emulsions. Research vendors list it as lyophilized powder in the tens-to-hundreds-of-milligrams range, labeled for topical use, and it is commonly offered pre-blended with Argireline or with SNAP-8. Finished consumer products declare it on the ingredient panel as Pentapeptide-18. It is not sold in the injectable vial or IU formats used for metabolic and growth-hormone-axis peptides.

Key considerations

• Regulatory status: Pentapeptide-18 is a cosmetic ingredient that has never been reviewed as a drug. FDA does not approve cosmetic ingredients, and the agency states that “cosmeceutical” has no meaning under the law; a product marketed with claims of relaxing muscles or otherwise affecting the structure or function of the body can be regulated as an unapproved drug regardless of how it is positioned. The EU cosmetic ingredient database lists PENTAPEPTIDE-18 with a declared function of skin conditioning.
• Evidence gap: one small, uncontrolled 60-day study in 20 people, zero registered clinical trials, six indexed PubMed papers — none of them a wrinkle-efficacy study — and no permeation or pharmacokinetic data. The distance between the cell-level and amphibian-tissue mechanism and a measured cosmetic outcome in human skin has not been closed.
• The mechanism is borrowed rather than demonstrated in skin: the transmitter-release evidence comes from amphibian neuromuscular preparations and central opioid pharmacology. Facial mimetic muscle sits well below the epidermis, and the 2014 authors themselves attributed their weaker periorbital result to the large group of muscle fibers involved in the orbicularis oculi, against the single dominant corrugator supercilii at the inter-eyebrow site.
• Naming confusion is unusually dense here: Leuphasyl, pentapeptide-18, and [D-Ala2]-Leu-enkephalin are the same molecule. It is not DADLE ([D-Ala2, D-Leu5]-enkephalin, CAS 63631-40-3), which carries a D-leucine at position 5 and is used as a δ-selective research probe. Listings and older papers that call it “pentapeptide-3” collide with Vialox / Pentapeptide-3V (Gly-Pro-Arg-Pro-Ala), a structurally unrelated snake-venom-derived pentapeptide that acts as a curare-like nicotinic acetylcholine receptor antagonist. And it is distinct from Argireline (acetyl hexapeptide-8, older name acetyl hexapeptide-3), a SNAP-25 fragment mimetic that acts earlier in the same contraction cascade, which is why the two are sold together.
• Safety data are thin rather than reassuring: no adverse effects were reported in the published cosmetic literature at 0.5-2% topical use, but that base is a single 20-person study with no control arm, and the authors’ claim that the peptide is free of side effects rests on that same uncontrolled observation. The only cell-based safety datapoint is a 2026 docking paper reporting no HaCaT keratinocyte cytotoxicity up to 1 mg/mL. There is no published sensitization, systemic-exposure, or regulatory toxicology assessment, and no data at all on non-topical routes. Because the parent molecule is an opioid receptor agonist, systemic exposure would sit in a different risk category than for a structural or matrikine cosmetic peptide.