Peptide of the Week: GHK-Cu, the Copper Tripeptide

GHK-Cu is one of the most familiar peptides in skin care, and one of the most discussed in injectable "regenerative" circles. It is also a good example of how a real, decades-old research history can be stretched well past what the data show.

This week we look at where GHK-Cu comes from, what the wound and skin studies found, how to read the gene-expression claims, and why the evidence for creams says little about injections.

What it is

GHK is a tripeptide: a chain of just three amino acids, glycine, histidine and lysine. It binds copper tightly, and the copper-bound form is called GHK-Cu. The plain form is sold separately as GHK (Basic).

Natural occurrence

GHK was first described in 1973 as an activity in human albumin, a blood protein (Pickart 2012). A 1980 study found that it forms complexes with copper and increases copper uptake into cultured liver-cancer cells, which led researchers to propose it acts as a copper carrier (Pickart 1980).

GHK has been reported in human plasma, saliva and urine, with levels that decline with age (Pickart 2015). The GHK sequence also appears inside type I collagen, which led one group to suggest it may be released by enzymes at a wound site (Maquart 1988).

Wound-healing studies

Cells and animals

In fibroblast cultures (the cells that make connective tissue), GHK-Cu increased collagen production at very low concentrations, with the effect peaking at 1 nanomolar (Maquart 1988). In rats with implanted wound chambers, injecting GHK-Cu into the chambers increased collagen, total protein and other connective-tissue components in a concentration-dependent way (Maquart 1993).

Human wound trials

Human wound results are mixed:

• Diabetic foot ulcers. In a multicenter, randomized, evaluator-blinded, placebo-controlled trial, a GHK-Cu gel increased closure of plantar ulcers (98.5% median closure versus 60.8% with vehicle) and, in ulcers treated right after debridement, lowered infection rates (7% versus 34%) (Mulder 1994).
• Venous leg ulcers. In a randomized, evaluator-blinded trial of 86 patients, a 0.4% copper-tripeptide cream did no better than placebo. Silver sulfadiazine cream outperformed both (Bishop 1992).

Both trials are more than 30 years old, and we found no larger modern trials that settled the question.

Skin studies

The strongest cosmetic claims appear in review articles. One review states that GHK in cosmetic products has been found to tighten skin, improve elasticity and density, and reduce fine lines, photodamage and hyperpigmentation (Pickart 2015).

The controlled trials we could find are smaller and more modest. In a randomized study of skin care after CO2 laser resurfacing, 13 patients completed the trial. Blinded evaluators and computer analysis found no significant difference in redness, wrinkles or overall skin quality between the GHK-Cu and non-GHK-Cu regimens. Patients using GHK-Cu did report higher satisfaction (Miller 2006).

GHK-Cu is often combined with other cosmetic peptides, as in the GHK-Cu + Argireline stack. Related copper peptides in our library include AHK-Cu.

The gene-expression claims

You will often read that GHK-Cu "resets" thousands of genes. It helps to know where that comes from.

The independent finding. A team at Boston University and the University of British Columbia profiled lung tissue from smokers with COPD and identified a gene-expression pattern linked to emphysema. Using the Connectivity Map, a database of how compounds change gene activity in cells, they identified GHK as able to reverse that pattern. In lab tests, GHK also restored collagen remodeling by fibroblasts taken from COPD lungs (Campbell 2012). The authors called for further studies of the effects on disease progression.

The broader claims. The larger statements, that GHK can up- and down-regulate at least 4,000 human genes and is "essentially resetting DNA to a healthier state," come from review articles by Loren Pickart, lead author of the 1980 copper study above, and colleagues (Pickart 2015; Pickart 2014; Pickart 2018). One of these reviews describes GHK's known actions as all appearing "health positive" (Pickart 2018).

Many of the most-cited GHK reviews come from this single author group, and the most expansive claims have not been independently confirmed in people. A change in gene activity in cells or in a database analysis is a hypothesis about what a compound might do. It is not evidence of a clinical benefit.

Topical vs injectable: the evidence gap

Nearly all of the human evidence for GHK-Cu involves topical use: gels on wounds and creams on skin.

• Topical absorption. In a lab study using isolated human skin, copper from the tripeptide passed through the skin layers and some was retained in the tissue (Hostynek 2011). This was an in vitro test, not a study in living people.
• Injection in animals. In a rat model of knee-ligament reconstruction, an independent group injected GHK-Cu into the joint weekly for four weeks. Knee laxity was smaller than with saline at 6 weeks but not at 12 weeks, and the authors concluded the benefit did not last once treatment stopped (Fu 2015).
• Injection in people. We found no controlled human trial of injected GHK-Cu on its own in PubMed.

So the claim that injecting GHK-Cu does what creams are said to do rests on extrapolation. The route, dose, exposure and safety profile of an injection are all different from a cream, and they have not been studied in controlled human trials.

For how GHK-Cu compares with a peptide often paired with it, see GHK-Cu vs BPC-157 and the GLOW stack.

The bottom line

GHK-Cu is a real, naturally occurring peptide with a credible early research history in wound healing and collagen biology. The human evidence is limited to a few small, mostly older topical trials with mixed results. The gene-expression claims rest largely on one author group's reviews plus one independent computational study, and there are no controlled human trials of injectable use.

If you are tracking the research on this or other peptides, each peptide page lists its research status and PubMed-verified studies.

Sources

• The human tripeptide GHK-Cu in prevention of oxidative stress and degenerative conditions of aging: implications for cognitive health. Oxid Med Cell Longev, 2012. PMID 22666519
• Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature, 1980. PMID 7453802
• GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. Biomed Res Int, 2015. PMID 26236730
• Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett, 1988. PMID 3169264
• In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds. J Clin Invest, 1993. PMID 8227353
• Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl-l-histidyl-l-lysine copper. Wound Repair Regen, 1994. PMID 17147644
• A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers. J Vasc Surg, 1992. PMID 1495150
• Effects of topical copper tripeptide complex on CO2 laser-resurfaced skin. Arch Facial Plast Surg, 2006. PMID 16847171
• A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. Genome Med, 2012. PMID 22937864
• GHK and DNA: resetting the human genome to health. Biomed Res Int, 2014. PMID 25302294
• Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data. Int J Mol Sci, 2018. PMID 29986520
• Human skin penetration of a copper tripeptide in vitro as a function of skin layer. Inflamm Res, 2011. PMID 20721598
• Tripeptide-copper complex GHK-Cu (II) transiently improved healing outcome in a rat model of ACL reconstruction. J Orthop Res, 2015. PMID 25731775

This article is for educational and research purposes only and is not medical advice.