Copper Tripeptide

Copper tripeptide, or GHK-Cu, is the most well-studied peptide cosmeceutical. Its anti-aging efficacy has been verified in several independent trials, and it also appears to be a potent wound-healing agent.


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments


Wrinkle treatment


Reduced fine lines and coarse wrinkles, likely through modulating collagen production and degradation.


Skin lightening


Delivers clearer skin, and reduces blemishes such as mottled hyperpigmentation.


Increased skin thickness


Increases epidermal thickness by inducing dermal keratinocyte proliferation.


Increased skin elasticity


GHK-Cu containing liquid foundation, cream concealer, face and eye creams have been shown to improve skin elasticity and firmness.


Tighter skin


Improves skin laxity (looseness) after 12 weeks of treatment.




Inhibits lipid peroxidation and quenches the toxic products of lipid and fatty acid peroxidation.




Accelerates wound healing and tissue remodeling in animals, but no studies have been conducted on humans so far.

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Table of contents:

1. Sources

GHK is a sequence of 3 amino acids found in human plasma, where it was first isolated.[1] It has a high affinity for copper, with the amino acids glycine and lysine playing major roles in copper binding, forming GHK-Cu.[2] It is GHK-Cu, and not GHK itself, that exerts biological effects.[3][4]

2. Bioavailability

The ability of GHK-Cu to penetrate the stratum corneum is a key factor in its cosmeceutical activity, as it needs to reach viable, living skin to exert its effects.[4]

In vitro experiments have demonstrated that GHK-Cu readily penetrates a model membrane made of stratum corneum lipids[5][6] as well as through the stratum corneum of human skin.[7] Moreover, the tripeptide deposits copper in the stratum corneum, epidermis and dermis during its passage, potentially forming a skin reservoir.[7]

3. Effects on the skin

The anti-aging efficacy of GHK-Cu has been confirmed in several independent trials. In one such study on 67 volunteers, GHK-Cu was found to improve skin clarity and laxity, reduce fine lines, coarse wrinkles and mottled hyperpigmentation, and increase skin density and thickness.[8]

A GHK-Cu containing liquid foundation and cream concealer improved the appearance and elasticity of the skin and increased epidermal thickness, in an 8-week study.[9]

Furthermore, facial creams containing GHK-Cu also delivered sustained improvements in skin clarity, laxity, thickness, wrinkles and fine lines in a double-blind, placebo-controlled trial over 12 weeks.[10] Similarly, an eye cream containing GHK-Cu improved fine lines, skin texture, skin elasticity, thickness and the overall appearance of the skin around the eyes in a separate controlled, 12 week study.[11] The facial cream was also found to provide more benefits than a retinol-containing cream, while the eye cream was more effective than a product containing Vitamin K.[10][11]

Another comparative study also discovered that GHK-Cu applied to the thigh increased pro-collagen synthesis in 70% of the subjects, which was higher than the effects of topical tretinoin (40%), vitamin C (50%) and melatonin (50%).[12]

GHK-Cu is known to stimulate the synthesis of collagen and glycosaminoglycans in human fibroblasts.[13][14] GHK-Cu's cosmetic benefits have also been linked to its antioxidant and anti-inflammatory actions and to its ability to revive the proliferative potential of epidermal stem cells.[4] The exact mechanisms of action have yet to be elucidated, however.

3.2 Antioxidant effect

GHK-Cu suppresses oxidative damage by inhibiting lipid peroxidation[15] and by quenching the toxic products of fatty acid and lipid peroxidation.[16][17] Since lipid peroxidation plays an important role in UV-induced skin damage and skin aging,[18][19][20] GHK-Cu should have a protective effect against skin aging and photodamage.[4]

3.3 Stem cell activation

Epidermal stem cells are undifferentiated, slow cycling cells that give rise to transient stem cells that in turn differentiate into all types of cells found in the skin.[21]

Both GHK-Cu and copper-free GHK have been shown to induce changes in epidermal basal cells that are characteristic of epidermal stem cells and increase the proliferation of keratinocytes.[22][23] Because recent findings suggest that epidermal stem cells are intrinsically resistant to aging[21] and that local environmental factors rather than cellular senescence may be responsible for the age-related decline in proliferative capacity of stem cells,[24] the ability of GHK-Cu and GHK to restore the proliferative potential of epidermal stem cells makes it a powerful player in skin repair and rejuvenation.[4]

3.4 Wound healing

A series of animal studies have demonstrated GHK-Cu's effects on wound healing and tissue remodeling. In rabbits, topical GHK-Cu facilitated wound contraction, more rapid filling of open wounds with granular tissue and improved vessel growth.[25][26] In rats and dogs, topical GHK-Cu also accelerated the healing of open wounds and pad wounds respectively.[27][28]

GHK-Cu modulates the activities of various metalloproteinases, enzymes that facilitate the breakdown of proteins of the extracellular matrix.[3][29] It also stimulates anti-proteases, indicating that it maintains a balance between matrix synthesis and breakdown, preventing excessive skin damage.[4]

Injection of GHK-Cu into the wounds of rats also resulted in increased production of collagen I, the glycosaminoglycans dermatan sulfate and chondroitin sulfate, and the proteoglycans biglycan and decorin.[30] The increase in decorin is particularly notable, since decorin regulates the assembly of collagen fibrils and decreases the level of TGF-β1, which is known to increase scarring.[31][32]

In addition, GHK-Cu has been shown to increase the viability of fibroblasts and to induce an increase in the production of basic fibroblast growth factor during irradiation with LED light.[33] Since fibroblasts are the key cells in the repair and renewal processes of the skin, the ability of GHK-Cu to increase the functional activity of fibroblasts may explain in part its wound healing and rejuvenation properties.[4] GHK-Cu also attracts immune and endothelial cells to the site of injury, which is another explanation for its effect in promoting wound healing.[34]

Although no studies have yet been conducted to assess the wound healing ability of GHK-Cu on human skin, it is thought that GHK-Cu may be helpful in managing skin healing after plastic surgery, especially in patients of advanced age and in patients with underlying health conditions.[4] GHK-Cu also appears to have a soothing effect on the skin, as treatment with GHK-Cu skin care products following laser resurfacing significantly enhanced patient satisfaction, though it did not reduce or resolve post-treatment erythema.[35]

4. Side Effects

While there are no published reports on the long-term safety and tolerability of topical GHK-Cu as used in cosmetic products, GHK-Cu has been shown to exert its effects at very low, non-toxic concentrations.[13][14] GHK-containing creams have also been shown to be well-tolerated, non-allergenic, and not irritating to the eyes.[4][11]

Scientific References

  1. Pickart L, Thaler MM. Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver. Nat New Biol. (1973)
  2. Conato C, et. al. Copper complexes of glycyl-histidyl-lysine and two of its synthetic analogues: chemical behaviour and biological activity. Biochim Biophys Acta. (2001)
  3. Siméon A, et. al. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci. (2000)
  4. Pickart L, Margolina A. GHK–Copper Peptide in Skin Remodeling and Anti-Aging. SOFW Journal. (2010)
  5. Mazurowska L, Mojski M. ESI-MS study of the mechanism of glycyl-l-histidyl-l-lysine-Cu(II) complex transport through model membrane of stratum corneum. Talanta. (2007)
  6. Mazurowska L, Mojski M. Biological activities of selected peptides: skin penetration ability of copper complexes with peptides. J Cosmet Sci. (2008)
  7. Hostynek JJ, Dreher F, Maibach HI. Human skin retention and penetration of a copper tripeptide in vitro as function of skin layer towards anti-inflammatory therapy. Inflamm Res. (2010)
  8. Gorouhi F, Maibach HI. Role of topical peptides in preventing or treating aged skin. Int J Cosmet Sci. (2009)
  9. Appa Y, et. al. A clinical evaluation of a copper-peptide-containing liquid foundation and cream concealer designed for improving skin condition. American Academy of Dermatology 6th Annual Meeting. (2002)
  10. Leyden JJ, et. al. Skin care benefits of copper peptide containing facial cream. American Academy of Dermatology 6th Annual Meeting. (2002)
  11. Leyden JJ, et. al. Skin care benefits of copper peptide containing eye creams. American Academy of Dermatology 6th Annual Meeting. (2002)
  12. Abdulghani AA, et. al. Effects of topical creams containing vitamin C, a copper-binding peptide cream and melatonin compared with tretinoin on the ultrastructure of normal skin - A pilot clinical, histologic, and ultrastructural study. Disease Management and Clinical Outcomes. (1998)
  13. Maquart FX, et. al. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. (1988)
  14. Wegrowski Y, Maquart FX, Borel JP. Stimulation of sulfated glycosaminoglycan synthesis by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. Life Sci. (1992)
  15. Miller DM, et. al. Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation. Adv Exp Med Biol. (1990)
  16. Beretta G, et. al. Glycyl-histidyl-lysine (GHK) is a quencher of alpha,beta-4-hydroxy-trans-2-nonenal: a comparison with carnosine. insights into the mechanism of reaction by electrospray ionization mass spectrometry, 1H NMR, and computational techniques. Chem Res Toxicol. (2007)
  17. Beretta G, et. al. Acrolein sequestering ability of the endogenous tripeptide glycyl-histidyl-lysine (GHK): characterization of conjugation products by ESI-MSn and theoretical calculations. J Pharm Biomed Anal. (2008)
  18. Smith KJ, Dipreta E, Skelton H. Peroxisomes in dermatology. Part I. J Cutan Med Surg. (2001)
  19. Tanaka N, et. al. Immunohistochemical detection of lipid peroxidation products, protein-bound acrolein and 4-hydroxynonenal protein adducts, in actinic elastosis of photodamaged skin. Arch Dermatol Res. (2001)
  20. Polte T, Tyrrell RM. Involvement of lipid peroxidation and organic peroxides in UVA-induced matrix metalloproteinase-1 expression. Free Radic Biol Med. (2004)
  21. Giangreco A, et. al. Epidermal stem cells are retained in vivo throughout skin aging. Aging Cell. (2008)
  22. Kang YA, et. al. Copper-GHK increases integrin expression and p63 positivity by keratinocytes. Arch Dermatol Res. (2009)
  23. Choi HR, et. al. Stem cell recovering effect of copper-free GHK in skin. J Pept Sci. (2012)
  24. Rubin H. The disparity between human cell senescence in vitro and lifelong replication in vivo. Nat Biotechnol. (2002)
  25. Cangul IT, et. al. Evaluation of the effects of topical tripeptide-copper complex and zinc oxide on open-wound healing in rabbits. Vet Dermatol. (2006)
  26. Gul NY, et. al. The effects of topical tripeptide copper complex and helium-neon laser on wound healing in rabbits. Vet Dermatol. (2008)
  27. Canapp SO Jr, et. al. The effect of topical tripeptide-copper complex on healing of ischemic open wounds. Vet Surg. (2003)
  28. Swaim SF, et. al. Effect of locally injected medications on healing of pad wounds in dogs. Am J Vet Res. (1996)
  29. Siméon A, et. al. Expression and activation of matrix metalloproteinases in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. J Invest Dermatol. (1999)
  30. Siméon A, et. al. Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J Invest Dermatol. (2000)
  31. Sayani K, et. al. Delayed appearance of decorin in healing burn scars. Histopathology. (2000)
  32. Zhang Z, et. al. Recombinant human decorin inhibits cell proliferation and downregulates TGF-beta1 production in hypertrophic scar fibroblasts. Burns. (2007)
  33. Huang PJ, et. al. In vitro observations on the influence of copper peptide aids for the LED photoirradiation of fibroblast collagen synthesis. Photomed Laser Surg. (2007)
  34. Pickart L. The human tri-peptide GHK and tissue remodeling. J Biomater Sci Polym Ed. (2008)
  35. Miller TR, et. al. Effects of topical copper tripeptide complex on CO2 laser-resurfaced skin. Arch Facial Plast Surg. (2006)