Abstract
A comprehensive scientific review of Growth Hormone Releasing Peptide-6 (GHRP-6), one of the earliest synthetic ghrelin mimetics, covering its discovery, hexapeptide structure, GH secretion mechanisms, pronounced appetite stimulation, gastroprotective properties, cardioprotective effects, and clinical research history.
Growth Hormone Releasing Peptide-6 (GHRP-6) is a synthetic hexapeptide with the amino acid sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 that stimulates growth hormone (GH) release from the anterior pituitary gland. Developed in the 1980s by Cyril Bowers at Tulane University, GHRP-6 was among the first synthetic peptides demonstrated to potently release GH through a mechanism distinct from growth hormone-releasing hormone (GHRH). Its discovery and characterization played a pivotal role in the identification of the growth hormone secretagogue receptor (GHS-R1a) and ultimately contributed to the discovery of ghrelin, the endogenous ligand for this receptor. GHRP-6 remains one of the most extensively studied GH secretagogues, with a research history spanning over three decades and a pharmacological profile that includes significant effects beyond GH release.
The structural design of GHRP-6 emerged from systematic structure-activity relationship studies beginning with the observation that certain enkephalin analogs could release GH. Bowers and colleagues modified the Met-enkephalin backbone, incorporating D-amino acids and aromatic residues to optimize GH-releasing potency while eliminating opioid activity. The resulting hexapeptide—GHRP-6—was selected from hundreds of analogs as having optimal GH-releasing potency and pharmacological properties. The inclusion of D-tryptophan at position 2 and D-phenylalanine at position 5 confers resistance to enzymatic degradation and enables productive interaction with the GHS-R1a binding pocket.
GHRP-6 activates the GHS-R1a receptor (ghrelin receptor), a G protein-coupled receptor predominantly expressed in the hypothalamus (arcuate nucleus) and anterior pituitary (somatotroph cells). Receptor binding activates the Gq/11 signaling cascade, leading to phospholipase C activation, phosphatidylinositol bisphosphate hydrolysis, and intracellular calcium mobilization through IP3-mediated release from the endoplasmic reticulum and subsequent store-operated calcium entry. The resulting calcium transient triggers GH vesicle exocytosis from somatotroph cells. At the hypothalamic level, GHRP-6 stimulates GHRH release and suppresses somatostatin secretion, amplifying the GH-releasing signal. This dual mechanism—direct pituitary stimulation plus hypothalamic facilitation—produces a GH response that exceeds what either mechanism alone could achieve.
The GH-releasing potency of GHRP-6 is well characterized across multiple clinical studies. Intravenous administration of GHRP-6 at 1 microgram per kilogram body weight produces peak GH concentrations of approximately 25 to 50 nanograms per milliliter in healthy young adults, with the peak occurring at 15 to 30 minutes post-injection and GH returning to baseline within 2 to 3 hours. The dose-response relationship is sigmoidal, with a threshold dose of approximately 0.3 micrograms per kilogram, half-maximal response at approximately 0.5 to 1 microgram per kilogram, and plateau at approximately 2 micrograms per kilogram. While GHRP-6 is less potent than GHRP-2 on a microgram-per-microgram basis for GH release, it remains a robust and reliable GH secretagogue.
Perhaps the most distinctive pharmacological feature of GHRP-6 is its pronounced stimulation of appetite and food intake. Among the classical GHRPs, GHRP-6 produces the strongest orexigenic response, with subjects consistently reporting intense hunger beginning 15 to 30 minutes after injection and lasting 30 to 60 minutes. This appetite stimulation is mediated through activation of hypothalamic GHS-R1a receptors expressed on neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons in the arcuate nucleus. These neurons constitute the primary orexigenic pathway in the brain, and their activation drives food-seeking behavior, increases meal size, and shifts food preference toward calorie-dense options. The appetite-stimulating effect of GHRP-6 has been investigated as a potential therapeutic approach for conditions characterized by pathological appetite suppression, including cancer cachexia, AIDS wasting syndrome, anorexia nervosa, and appetite loss in the elderly.
GHRP-6 exhibits notable effects on the gastrointestinal system that extend beyond appetite stimulation. Research has demonstrated significant gastroprotective properties of GHRP-6 in experimental models of gastric injury. In rodent models of ethanol-induced, stress-induced, and NSAID-induced gastric ulceration, GHRP-6 pre-treatment substantially reduced ulcer formation, decreased gastric acid secretion, and enhanced mucosal blood flow. These gastroprotective effects are attributed to multiple mechanisms: stimulation of gastric mucosal prostaglandin synthesis, enhancement of mucosal blood flow through nitric oxide-dependent vasodilation, upregulation of protective heat shock proteins (particularly HSP70), and anti-oxidative effects that scavenge reactive oxygen species. A series of studies conducted at the Center for Genetic Engineering and Biotechnology (CIGB) in Havana, Cuba, demonstrated that GHRP-6 promotes healing of established gastric ulcers and prevents recurrence, effects that are independent of its GH-releasing properties.
The cytoprotective and tissue-repair properties of GHRP-6 extend beyond the gastric mucosa. Research has shown that GHRP-6 promotes wound healing, reduces fibrosis, and accelerates tissue repair in multiple organ systems. In models of liver fibrosis, GHRP-6 reduced collagen deposition, attenuated hepatic stellate cell activation, and improved liver function markers. In skin wound models, GHRP-6 accelerated wound closure, enhanced granulation tissue formation, and improved the quality of scar tissue. These tissue-repair effects appear to involve activation of the PI3K/Akt and MAPK signaling pathways, upregulation of growth factors including vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), and modulation of the inflammatory response toward a pro-resolution phenotype.
Cardiovascular effects of GHRP-6 have been extensively studied and reveal a significant cardioprotective profile. In isolated heart preparations and in vivo models of myocardial ischemia-reperfusion injury, GHRP-6 reduces infarct size, preserves cardiac contractility, and attenuates cardiomyocyte apoptosis. These cardioprotective effects are mediated through activation of the reperfusion injury salvage kinase (RISK) pathway, involving PI3K/Akt and ERK1/2 signaling, which converges on mitochondrial preservation and inhibition of the mitochondrial permeability transition pore. Importantly, the cardioprotective doses of GHRP-6 are substantially lower than GH-releasing doses, and the cardiac protection is maintained in hypophysectomized animals, confirming a GH-independent mechanism. GHRP-6 also has direct effects on cardiac electrophysiology, binding to cardiac GHS-R1a receptors and modulating calcium handling in cardiomyocytes.
The neuroendocrine profile of GHRP-6 includes effects on pituitary hormones beyond GH. GHRP-6 stimulates modest prolactin release (approximately 30 to 60 percent above baseline) and ACTH/cortisol secretion (approximately 20 to 40 percent above baseline). These effects are less pronounced than those of GHRP-2 and hexarelin, making GHRP-6 somewhat more selective for GH release among the classical GHRPs. The lower prolactin stimulation is particularly relevant for chronic protocols where sustained prolactin elevation could produce unwanted effects.
The anti-inflammatory and immunomodulatory properties of GHRP-6 have been documented in multiple experimental systems. GHRP-6 reduces the production of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) and enhances anti-inflammatory cytokine production (IL-10). In models of systemic inflammation and sepsis, GHRP-6 improved survival, reduced organ damage, and attenuated the cytokine storm. These effects involve modulation of NF-kB signaling, inhibition of NLRP3 inflammasome activation, and promotion of regulatory T cell responses.
Clinical research with GHRP-6 has explored multiple applications. As a diagnostic tool, GHRP-6 has been used in GH stimulation testing, though GHRP-2 is generally preferred for this indication due to its greater potency. In combination with GHRH, the GHRP-6 plus GHRH test has been proposed as one of the most reliable provocative tests for GH deficiency, with excellent sensitivity and specificity. Chronic administration studies in elderly subjects have demonstrated sustained GH and IGF-1 elevation with improvements in body composition, though tachyphylaxis (gradual reduction of response) was observed over several weeks of continuous use.
The safety profile of GHRP-6 from clinical studies is generally favorable. The most commonly reported side effects include intense but transient hunger (which some subjects find uncomfortable), injection site reactions, mild facial flushing, and transient dizziness. The effects on glucose metabolism are similar to other ghrelin receptor agonists—acute hyperglycemia and insulin suppression following injection—but these are transient and generally not clinically significant with pulsatile dosing. The long-term safety of chronic GHRP-6 administration has not been established in large-scale clinical trials.
In summary, GHRP-6 is a historically significant GH secretagogue with a diverse pharmacological profile that extends well beyond GH release. Its pronounced appetite stimulation, gastroprotective properties, tissue-repair promotion, cardioprotective effects, and anti-inflammatory actions make it a multifaceted peptide with potential applications across numerous therapeutic areas. While its GH-releasing potency is surpassed by GHRP-2 and hexarelin, its broader tissue-protective profile and relatively favorable hormonal selectivity maintain its relevance in contemporary research.
