Leuphasyl: Expression Line Peptide Profile

Every time you smile, frown, or squint, the muscles beneath your skin contract. Repeat this thousands of times over the years, and you get expression lines — the forehead creases, crow's feet, and frown lines that etch themselves into the face. Cosmetic peptides have been racing to find gentler alternatives to botulinum toxin injections, and one candidate has emerged with a unique mechanism: Leuphasyl.

Unlike most anti-wrinkle peptides that target the machinery of muscle contraction directly, Leuphasyl works upstream — at the level of the nerve itself. It's designed to mimic enkephalin, a naturally occurring opioid peptide in the body, and intercept the signal before it even tells the muscle to contract. Think of it as turning down the volume on facial movements rather than paralyzing the muscle outright.

This article breaks down what Leuphasyl is, how it works at the cellular level, what the research actually shows, and how it compares to other peptides in the anti-wrinkle toolkit.

Quick Facts
What Is Leuphasyl?
How Leuphasyl Works: The Enkephalin Pathway
Upstream vs. Downstream: How Leuphasyl Differs from Argireline
Clinical Evidence: What the Studies Show
Synergy with Other Peptides
Safety and Tolerability
How to Use Leuphasyl
Frequently Asked Questions
Bottom Line
References

Quick Facts

Category	Details
INCI Name	Pentapeptide-18
Other Names	Leuphasyl®, Pentapeptide-18
Peptide Type	Enkephalin-mimetic, neuropeptide
Sequence	Tyr-D-Ala-Gly-Phe-Leu (YAGFL)
Mechanism	Opioid receptor-mediated reduction of acetylcholine release
Primary Use	Expression lines (forehead, crow's feet)
Developer	Lipotec (now part of Lubrizol)
Concentration	Typically 0.05%–0.5% in formulations (2% minimum for visible effects in some studies)
Evidence Level	Moderate — clinical data available, but limited independent replication

What Is Leuphasyl?

Leuphasyl, also known as Pentapeptide-18, is a synthetic peptide composed of five amino acids: tyrosine, D-alanine, glycine, phenylalanine, and leucine. Its sequence — Tyr-D-Ala-Gly-Phe-Leu — was intentionally designed to mimic the structure of enkephalins, the body's naturally occurring opioid peptides.

Enkephalins are neurotransmitters that regulate pain, mood, and, relevant here, muscle activity. Specifically, met-enkephalin (Tyr-Gly-Gly-Phe-Met) and leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) bind to opioid receptors on neurons and reduce neuronal excitability. When enkephalins bind to these receptors at the neuromuscular junction — the site where nerve meets muscle — they reduce the release of acetylcholine, the neurotransmitter that tells muscles to contract.

Leuphasyl borrows this mechanism. By structurally resembling enkephalin, it binds to the same opioid receptors and triggers the same inhibitory cascade. The result: fewer signals reach the muscle, less contraction occurs, and expression lines soften.

Leuphasyl was developed by Lipotec, a Spanish peptide research company now part of Lubrizol's personal care division. It's been marketed since the mid-2000s as a Botox-like topical ingredient, though its effects are substantially gentler and slower to appear.

Unlike Argireline, which blocks the assembly of proteins required for neurotransmitter release, Leuphasyl acts earlier in the signaling chain — at the receptor level, before acetylcholine vesicles are even mobilized.

How Leuphasyl Works: The Enkephalin Pathway

To understand how Leuphasyl reduces wrinkles, you need to follow the chain of events that leads to muscle contraction in the first place.

Facial movements start with a nerve impulse traveling down a motor neuron. When that impulse reaches the neuromuscular junction, it triggers the release of acetylcholine into the synaptic cleft — the tiny gap between nerve and muscle. Acetylcholine crosses this gap, binds to receptors on the muscle cell, and initiates contraction. Repeat this thousands of times a day, and the skin above the muscle folds into permanent lines.

Leuphasyl interrupts this process at the very beginning: the decision to release acetylcholine.

Step 1: Binding to Opioid Receptors

Leuphasyl binds to enkephalin receptors — specifically, delta (δ) and mu (μ) opioid receptors — on the surface of the presynaptic neuron (the nerve cell side of the neuromuscular junction). These receptors are G-protein-coupled receptors, meaning they're linked to signaling molecules inside the cell called G-proteins.

When Leuphasyl docks onto these receptors, it activates them just as natural enkephalins would.

Step 2: G-Protein Activation and Ion Channel Modulation

Receptor activation triggers the release of G-protein subunits (alpha, beta, gamma) inside the neuron. These subunits go to work on two types of ion channels:

Calcium (Ca²⁺) channels: The G-protein closes voltage-gated calcium channels, preventing calcium from entering the neuron.
Potassium (K⁺) channels: The G-protein opens potassium channels, allowing potassium to leave the neuron.

Both actions make the neuron less excitable. Calcium influx is required for neurotransmitter vesicles to fuse with the cell membrane and release their contents. Without enough calcium, acetylcholine vesicles don't fuse, and acetylcholine doesn't get released.

This mechanism has been documented in studies on enkephalin's effects on calcium channels in neuroblastoma cells, where enkephalin reversibly blocked the long-lasting calcium current needed for neurotransmitter release.

Step 3: Reduced Acetylcholine Release

With calcium entry blocked, acetylcholine release drops. The muscle receives fewer "contract" signals. This reduction in acetylcholine has been shown to occur in multiple tissue types, including the human neocortex and the frog neuromuscular junction, where enkephalin reduced quantal transmitter release.

Step 4: Muscle Relaxation

Less acetylcholine means less muscle contraction. The facial muscle stays more relaxed, and the skin above it experiences less mechanical stress. Over time, this translates to shallower expression lines.

The beauty of this mechanism is that it doesn't paralyze the muscle. It modulates the signal. Facial expressions remain intact, just slightly muted.

Upstream vs. Downstream: How Leuphasyl Differs from Argireline

If you've read about anti-wrinkle peptides, you've probably come across Argireline (acetyl hexapeptide-8). Both Leuphasyl and Argireline reduce muscle contraction, but they work at different stages of the process.

Argireline targets the SNARE complex — a group of proteins responsible for docking acetylcholine vesicles to the cell membrane. When Argireline mimics part of SNAP-25 (a SNARE protein), it competes for binding sites and disrupts vesicle fusion. This prevents acetylcholine from being released into the synaptic cleft.

Leuphasyl works earlier. It acts at the receptor level, before the vesicles are even mobilized. By activating opioid receptors, it prevents the calcium influx that's needed for vesicle fusion in the first place.

Here's the analogy: Argireline unplugs the USB cable after it's been inserted. Leuphasyl removes the USB port from the equation.

This difference in mechanism is why the two peptides are often combined. Leuphasyl reduces the release signal upstream, and Argireline blocks the release machinery downstream. The result is a more complete inhibition of acetylcholine release than either peptide achieves alone.

Clinical data supports this. In a 28-day study, wrinkle depth decreased by 11.64% with Leuphasyl, 16.26% with Argireline, and 24.62% with both combined — a clear synergistic effect.

Clinical Evidence: What the Studies Show

Leuphasyl's efficacy has been evaluated in several small clinical studies, most of them conducted or sponsored by Lipotec. The data is promising but limited. Independent replication is sparse, and most studies involve small sample sizes.

28-Day Study: Leuphasyl Alone

A cream containing 0.05% Leuphasyl was applied twice daily to the eye area of 14 volunteers, aged 39 to 64, for 28 days. Wrinkle depth was measured using profilometry.

Results:

Mean reduction in wrinkle depth: 11.64%
Maximum reduction in some subjects: 23.55%

This study established that Leuphasyl has measurable anti-wrinkle effects when used alone, though the magnitude was modest compared to injectables.

Combination Study: Leuphasyl + Argireline

The same study also tested Leuphasyl in combination with Argireline (acetyl hexapeptide-3).

Results:

Leuphasyl alone: 11.64% reduction
Argireline alone: 16.26% reduction
Leuphasyl + Argireline: 24.62% reduction (maximum: 46.53%)

The combination produced a synergistic effect — the combined reduction was greater than the sum of the individual reductions. This supports the idea that blocking acetylcholine release at two different points in the pathway is more effective than targeting one alone.

Other Clinical Data

A separate study evaluated three concentrations of Pentapeptide-18 — 0.5%, 1%, and 2% — on 20 volunteers over two months. Researchers found that 2% was the minimum concentration needed for visible wrinkle reduction and that the peptide was free of side effects.

An independent 12-week study on 30 women aged 40–55 with moderate facial wrinkles documented a 27% reduction in wrinkle volume and a 21% improvement in skin elasticity with twice-daily application of a topical formulation containing Pentapeptide-18.

While these results are encouraging, it's worth noting that most of the published data comes from the manufacturer or manufacturer-affiliated researchers. More independent, peer-reviewed studies would strengthen confidence in these findings.

Synergy with Other Peptides

Leuphasyl is rarely used in isolation. It's most commonly formulated alongside other anti-wrinkle peptides, particularly Argireline, Matrixyl, and Syn-Ake.

Argireline + Leuphasyl: As discussed, this is the most studied combination. By targeting both the receptor-mediated signal (Leuphasyl) and the vesicle release machinery (Argireline), the two peptides work together to reduce acetylcholine release more completely. The clinical data supports a synergistic effect, with combined reductions exceeding the sum of individual effects.

Matrixyl + Leuphasyl: Matrixyl (palmitoyl pentapeptide and palmitoyl tetrapeptide-7) works by stimulating collagen synthesis, not by reducing muscle contraction. Combining Matrixyl with Leuphasyl addresses wrinkles from two angles: Leuphasyl reduces the mechanical stress that creates dynamic wrinkles, while Matrixyl rebuilds the dermal matrix to improve skin structure. Some formulations pair both peptides with hyaluronic acid to boost hydration and plump the skin.

Syn-Ake + Leuphasyl: Syn-Ake mimics the effects of snake venom peptides by blocking nicotinic acetylcholine receptors on the muscle side of the neuromuscular junction. Leuphasyl reduces acetylcholine release from the nerve; Syn-Ake blocks its reception at the muscle. Together, they cover both ends of the signal.

Copper Peptides + Leuphasyl: Copper peptides like GHK-Cu stimulate wound healing, collagen production, and antioxidant defenses. Pairing them with Leuphasyl combines neuropeptide-based wrinkle reduction with broader skin regeneration effects.

The trend in cosmetic peptide formulations is toward multi-peptide cocktails, with each peptide addressing a different aspect of aging. Leuphasyl fits into this strategy as the upstream neuromodulator.

Safety and Tolerability

Leuphasyl has a strong safety profile in the available literature. The peptide is designed to act locally at the neuromuscular junction and doesn't penetrate deep into systemic circulation. Because it mimics a naturally occurring peptide (enkephalin), the body recognizes it as structurally familiar.

Reported side effects:

None in the clinical studies reviewed.
No irritation, redness, or adverse reactions noted at concentrations up to 2%.

One of the advantages of Leuphasyl over botulinum toxin injections is that it doesn't paralyze muscles. It modulates nerve signaling, which means facial expressions remain natural. There's no risk of a "frozen" look or drooping if applied incorrectly.

That said, the long-term safety data is limited. Most studies tracked participants for only 28 days to 12 weeks. We don't have robust data on what happens with years of continuous use.

Who should avoid it?

There are no formal contraindications, but pregnant or breastfeeding individuals should consult a healthcare provider before using any cosmetic peptide.
Individuals with known sensitivity to peptide-based skincare ingredients should patch-test first.

The absence of reported side effects doesn't mean side effects are impossible — it means the available data hasn't captured them yet.

How to Use Leuphasyl

Leuphasyl is typically found in serums, creams, and gels designed for expression-line-prone areas: the forehead, between the brows, and around the eyes (crow's feet).

Typical concentrations:

0.05%–0.5% in most commercial products
2% or higher in clinical-grade formulations

Application:

Apply to clean, dry skin.
Target areas where expression lines form (forehead, crow's feet, frown lines).
Use twice daily for best results (morning and evening).
Pair with Argireline or other anti-wrinkle peptides for synergistic effects.

What to expect:

Results take time. Most studies show visible effects after 4 to 8 weeks of consistent use.
Effects are subtle compared to injectables. Don't expect Botox-level wrinkle smoothing.
Continued use is required to maintain results. If you stop, expression lines will gradually return.

Formulation considerations: Peptides are notoriously unstable. They degrade in the presence of strong acids, high heat, and certain preservatives. Look for products stored in opaque, airtight containers and formulated at a pH that supports peptide stability (usually around 5–7).

Because Leuphasyl works by penetrating the skin and reaching the neuromuscular junction, formulation matters. Peptides are large molecules, and not all of them penetrate effectively. Lipophilic modifications (like palmitoylation, seen in Palmitoyl Tripeptide-1) or delivery systems (liposomes, microneedling) can improve absorption.

Frequently Asked Questions

Is Leuphasyl the same as Botox? No. Botox is botulinum toxin, a neurotoxin that blocks acetylcholine release by cleaving SNAP-25 proteins. Leuphasyl is a synthetic peptide that reduces acetylcholine release by activating opioid receptors. Botox is injected; Leuphasyl is applied topically. Botox produces dramatic, near-total muscle relaxation; Leuphasyl produces subtle modulation.

How long does it take to see results? Most studies show measurable effects after 4 to 8 weeks of twice-daily use. Some individuals may notice subtle improvements earlier; others may take longer.

Can I use Leuphasyl with retinoids or vitamin C? Yes. There are no known interactions between Leuphasyl and retinoids, vitamin C, or other common skincare actives. In fact, combining neuropeptides with collagen-stimulating ingredients (retinoids, Matrixyl) may address wrinkles from multiple angles.

Does Leuphasyl work on static wrinkles? Leuphasyl is designed to reduce dynamic wrinkles — lines caused by muscle movement. It won't directly repair static wrinkles caused by collagen loss, sun damage, or loss of skin elasticity. For those, you'd need ingredients that stimulate collagen synthesis (Matrixyl, Palmitoyl Tetrapeptide-7, retinoids) or improve skin structure.

Is it safe to use Leuphasyl around the eyes? Yes. Most clinical studies applied Leuphasyl to the crow's feet area (around the eyes) with no adverse effects. Avoid getting the product directly in the eye, but topical application to the surrounding skin is considered safe.

What's the difference between Leuphasyl and Snap-8? Snap-8 (acetyl octapeptide-3) is an extended version of Argireline. Both Snap-8 and Argireline target the SNARE complex to prevent acetylcholine release. Leuphasyl works at the receptor level, before vesicle mobilization. Snap-8 may penetrate deeper and work longer, but the mechanisms are fundamentally similar to Argireline — just at different degrees of potency.

Can Leuphasyl prevent wrinkles from forming? Theoretically, yes. By reducing the frequency and intensity of muscle contractions, Leuphasyl could slow the formation of new expression lines. But this is speculative. Most studies measure existing wrinkle reduction, not prevention. Long-term studies would be needed to confirm preventive effects.

How does Leuphasyl compare to Syn-Ake? Syn-Ake blocks acetylcholine receptors on the muscle side of the neuromuscular junction, mimicking the effects of snake venom peptides. Leuphasyl works on the nerve side, reducing acetylcholine release. Both reduce muscle contraction, but at different targets. They're often combined for a more complete anti-wrinkle effect.

Is Leuphasyl vegan? Yes. Leuphasyl is a synthetic peptide, not derived from animal sources. It's produced through chemical synthesis in a lab.

Bottom Line

Leuphasyl is a synthetic pentapeptide designed to mimic enkephalin, a naturally occurring neurotransmitter that reduces neuronal excitability and acetylcholine release. By binding to opioid receptors at the neuromuscular junction, Leuphasyl reduces the signal that tells facial muscles to contract. This leads to fewer dynamic wrinkles — particularly in expression-prone areas like the forehead and around the eyes.

The peptide has a unique mechanism compared to other anti-wrinkle ingredients. While Argireline blocks vesicle fusion and Syn-Ake blocks acetylcholine receptors on the muscle, Leuphasyl works upstream at the receptor level on the nerve. This makes it a natural candidate for combination formulations, where its effects can be amplified by peptides that target different steps in the contraction pathway.

The clinical evidence is promising but limited. Studies show 11%–27% reductions in wrinkle depth with consistent use, and synergistic effects when combined with Argireline. The peptide appears safe and well-tolerated, with no reported adverse effects in the available literature.

That said, Leuphasyl is not a Botox replacement. Its effects are subtle, slow to appear, and require ongoing use. It's best suited for individuals looking for a gentle, topical approach to expression lines — or as part of a broader anti-aging regimen that includes collagen-stimulating peptides like Matrixyl or copper peptides.

If you're building a peptide-based skincare routine, Leuphasyl fits into the neuropeptide category alongside Argireline, Snap-8, and Syn-Ake. Pair it with collagen-supporting peptides and a solid sunscreen, and you've covered multiple mechanisms of wrinkle formation and prevention.

Disclaimer: This article is for educational purposes only and does not constitute medical advice. Leuphasyl is a cosmetic ingredient, not a drug. It has not been evaluated by the FDA for the treatment of wrinkles or any medical condition. Consult a dermatologist or healthcare provider before starting any new skincare regimen, especially if you have sensitive skin, allergies, or underlying health conditions.

References

Physiology, Enkephalin. StatPearls [Internet]. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK557764/
The Efficiency and Safety of Leuphasyl—A Botox-Like Peptide. Cosmetics 2013, 1(2), 75-81. https://www.mdpi.com/2079-9284/1/2/75
Block of calcium channels by enkephalin and somatostatin in neuroblastoma-glioma hybrid NG108-15 cells. Proc Natl Acad Sci U S A. 1987 Jan;84(1):289-93. https://pmc.ncbi.nlm.nih.gov/articles/PMC387236/
Opioid receptor-mediated control of acetylcholine release in human neocortex tissue. Naunyn Schmiedebergs Arch Pharmacol. 1996 Nov;354(5):586-92. https://pubmed.ncbi.nlm.nih.gov/8938656/
Enkephalin reduces quantal content at the frog neuromuscular junction. Nature. 1983 Dec 8-14;306(5943):556-8. https://pubmed.ncbi.nlm.nih.gov/6823319/
Enkephalins modulate inhibitory neuromuscular transmission in circular muscle of human colon via delta-opioid receptors. J Pharmacol Exp Ther. 1992 Jan;260(1):456-62. https://pubmed.ncbi.nlm.nih.gov/1966052/
Leuphasyl® Peptide Solution. Lipotec (Lubrizol). Technical datasheet. https://www.lipotec.com/en/products/leuphasyl-reg-peptide/
Investigating the effects of Argireline in a skin serum containing hyaluronic acids on skin surface wrinkles. J Cosmet Dermatol. 2023. https://pmc.ncbi.nlm.nih.gov/articles/PMC10665711/
Enkephalins and Pain Modulation: Mechanisms of Action and Therapeutic Perspectives. Biomolecules 2024, 14(8), 926. https://pmc.ncbi.nlm.nih.gov/articles/PMC11353043/
Peptides: Emerging Candidates for the Prevention and Treatment of Skin Senescence: A Review. Pharmaceutics 2025. https://pubmed.ncbi.nlm.nih.gov/39858482/

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