Pentapeptide-18 (Leuphasyl)

Also known as: Leuphasyl, Pentapeptide-18, Tyr-D-Ala-Gly-Phe-Leu

Evidence: Preclinical

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Overview

Leucine-enkephalin analog pentapeptide (Tyr-D-Ala-Gly-Phe-Leu) sold as Leuphasyl for expression lines; evidence is manufacturer data, one small emulsion study and in vitro work.

Pentapeptide-18 is a leucine-enkephalin analog with D-alanine at position 2, marketed by Lipotec as Leuphasyl. The efficacy figures in circulation, including synergy with acetyl hexapeptide-8, come from manufacturer documents rather than peer-reviewed trials (Errante et al., 2020). A small Romanian study tested 0.5, 1 and 2% emulsions over the brow and periorbital muscles to choose a concentration; it was not placebo-controlled (Dragomirescu et al., 2014). Recent independent work is computational and in vitro (Akhan et al., 2026). The comparison to injected botulinum toxin is marketing, not a measured equivalence.

Benefits

Expression-line reduction (manufacturer data, not peer reviewed), no keratinocyte cytotoxicity up to 1 mg/mL (in vitro)

Dosing reference

Research dose: Topical, 0.5 to 2% emulsions in the one published human study; whether this is pure peptide or supplier solution is not stated in the abstract.

Topical only. The one published study compared 0.5, 1 and 2% emulsions applied over the facial muscles rather than on the wrinkles. Other human data are manufacturer-run, often with acetyl hexapeptide-8.

Mechanism

Proposed. The manufacturer describes binding to enkephalin receptors on nerve terminals that lowers acetylcholine release at the neuromuscular junction, independent of and additive to the SNARE mechanism of acetyl hexapeptide-8 (Errante et al., 2020; Dragomirescu et al., 2014). No peer-reviewed study has measured receptor binding, acetylcholine release or muscle activity after topical use. Docking studies predict binding to MMP-13 and signalling proteins, which is untested in cells (Akhan et al., 2026).

Evidence

Preclinical: animal or in vitro data only

Emulsions at 0.5, 1 and 2% applied over the corrugator and orbicularis muscles to find an optimal concentration; uncontrolled, effect sizes not given in the abstract (Dragomirescu et al., 2014)
Manufacturer data report expression-line reduction and synergy with acetyl hexapeptide-8; a review cites them as company documents, not peer-reviewed trials (Errante et al., 2020)
No cytotoxicity in HaCaT keratinocytes up to 1 mg/mL; docking predicts MMP-13 binding (Akhan et al., 2026)
Analogs with a terminal D-tyrosine reduced melanin in MNT-1 cells and a 3D skin model; the parent was the comparator (Park et al., 2020)
Human-trial status: no published randomized or placebo-controlled human trial; efficacy figures are manufacturer data

References

Side effects

No cytotoxicity in keratinocytes up to 1 mg/mL (Akhan et al., 2026); the small emulsion study assessed tolerability but its abstract gives no results (Dragomirescu et al., 2014). The sequence is an opioid-peptide analog; systemic effects have not been studied. Commonly reported (anecdotal): mild irritation.

Storage

Storage: Room temperature, away from light
Lyophilized: 2 years at room temp
Reconstituted: N/A (ready to use)

Pharmacology

Half-life: No published pharmacokinetic data in any species
Bioavailability: Not measured; in silico ADME only (Akhan et al., 2026). Penetration to muscle is unproven
Molecular weight: 569.66 Da
Sequence: Tyr-[D-Ala]-Gly-Phe-Leu