GHRP-6

Growth Hormone Releasing Peptide-6 (GHRP-6) is a synthetic hexapeptide and one of the first growth hormone secretagogues (GHSs) developed for research. Consisting of six amino acids — His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 — GHRP-6 acts as a potent agonist of the growth hormone secretagogue receptor type 1a (GHS-R1a), the same receptor targeted by the endogenous hormone ghrelin. Its discovery in the early 1980s by Cyril Bowers and colleagues opened an entirely new avenue for studying growth hormone regulation. GHRP-6 stimulates GH release through a mechanism distinct from and complementary to growth hormone-releasing hormone (GHRH). While GHRH acts via the GHRH receptor on pituitary somatotrophs, GHRP-6 activates the ghrelin/GHS-R1a pathway. This dual-pathway system allows GHRP-6 to produce robust GH release when used alone and synergistic amplification when combined with GHRH analogs such as Sermorelin or CJC-1295. Beyond its GH-releasing properties, GHRP-6 has attracted research interest for its effects on appetite stimulation, gastroprotection, and potential cardioprotective activity. Its strong appetite-stimulating effect—a direct consequence of ghrelin receptor activation in the hypothalamus—distinguishes it from more selective secretagogues like Ipamorelin and has made it a valuable tool for studying ghrelin-mediated feeding behavior.

GHRP-6 exerts its biological effects through multiple receptor-mediated and downstream pathways: **Ghrelin Receptor (GHS-R1a) Agonism**: GHRP-6 binds to and activates the growth hormone secretagogue receptor 1a on anterior pituitary somatotrophs, triggering intracellular calcium mobilization and phospholipase C activation. This results in the rapid exocytosis of growth hormone-containing secretory vesicles. **Hypothalamic Action**: GHRP-6 also acts centrally at the hypothalamic level, stimulating the release of GHRH from arcuate nucleus neurons and suppressing somatostatin tone. This dual site of action — pituitary and hypothalamic — amplifies the overall GH response beyond direct pituitary stimulation alone. **Appetite and Orexigenic Signaling**: Through GHS-R1a activation in hypothalamic feeding centers, GHRP-6 robustly stimulates appetite via NPY/AgRP neuron activation. This ghrelin-like orexigenic effect is more pronounced with GHRP-6 than with later-generation secretagogues such as GHRP-2 or Ipamorelin. **Cortisol and Prolactin Release**: Unlike Ipamorelin, GHRP-6 produces modest but measurable increases in cortisol and prolactin at effective GH-releasing doses. This is attributed to non-selective activation of corticotroph and lactotroph pathways at the pituitary level. **Cytoprotective Effects**: GHRP-6 has demonstrated GH-independent protective effects on gastric mucosa and myocardial tissue. These appear to be mediated through CD36 receptor interactions and anti-oxidative, anti-inflammatory signaling pathways distinct from GHS-R1a activation.

GHRP-6 has one of the longest research histories among synthetic GH secretagogues: **Growth Hormone Release Potency**: Foundational studies by Bowers et al. established that GHRP-6 produces dose-dependent GH release in humans, with peak GH levels 3-6 fold above baseline within 15-30 minutes of subcutaneous administration. The GH response is amplified 2-3 fold when co-administered with GHRH, confirming the synergistic interaction between the two pathways. **Appetite and Metabolic Effects**: Clinical research has documented significant increases in appetite and food intake following GHRP-6 administration, mediated by ghrelin receptor activation in hypothalamic feeding centers. Studies show approximately 30% increase in meal-initiated caloric intake, making it a research tool for studying orexigenic pathways and a candidate for treating cachexia and wasting syndromes. **Gastroprotection**: Preclinical research has demonstrated that GHRP-6 protects against ethanol-induced and NSAID-induced gastric mucosal damage in rodent models. This cytoprotective effect appears to operate through antioxidant mechanisms and reduction of inflammatory mediators, independently of GH release. **Cardioprotective Research**: Studies in animal models of myocardial ischemia-reperfusion injury have shown that GHRP-6 reduces infarct size and preserves cardiac function. This effect involves CD36 receptor-mediated signaling and has stimulated interest in GHRP-6 analogs for cardiovascular research. **Comparative Secretagogue Studies**: Head-to-head comparisons with GHRP-2 and Ipamorelin have clarified GHRP-6's relative position: it produces robust GH release comparable to GHRP-2 but with greater appetite stimulation and more pronounced cortisol/prolactin co-release than the more selective alternatives.

Research protocols for GHRP-6 are well-established from decades of clinical investigation: **Typical Research Doses**: Most studies employ 100-300 mcg per administration via subcutaneous injection. The saturation dose for maximal GH release is approximately 100 mcg (or ~1 mcg/kg body weight), beyond which additional peptide produces diminishing returns on GH secretion. **Administration and Timing**: Subcutaneous injection on an empty stomach is standard. Administration 2-3 times daily (morning, post-exercise, and bedtime) is common in research protocols. Food intake — particularly fats and carbohydrates — blunts the GH response and should be avoided for 30 minutes before and after injection. **Combination Protocols**: GHRP-6 is frequently combined with GHRH analogs (Sermorelin, CJC-1295 without DAC) at equimolar or 1:1 microgram doses. This combination produces synergistic GH release substantially exceeding either peptide alone, and is the most common multi-peptide research design in the GH secretagogue literature. **Important Disclaimer**: GHRP-6 is available for research purposes only. All dosing parameters cited here are derived from published preclinical and clinical research literature. Human therapeutic dosing has not been established by regulatory agencies, and these parameters should not be construed as clinical recommendations.

GHRP-6's side effect profile is well-documented from extensive research use: **Observed Effects**: The most prominent effect is a substantial increase in appetite occurring 15-30 minutes post-injection, driven by ghrelin receptor activation in hypothalamic feeding centers. This can be intense, particularly in the first weeks of use. Other commonly reported effects include injection site redness, transient flushing, headache, dizziness, and water retention. Cortisol and prolactin elevations are measurable but typically modest at standard research doses. **Potential Concerns**: Sustained appetite stimulation may lead to unintended caloric surplus and weight gain if not accounted for. The cortisol and prolactin co-release, while modest, distinguishes GHRP-6 from more selective alternatives and may be undesirable in certain research contexts. As with all GH-elevating agents, theoretical considerations apply regarding glucose metabolism and proliferative conditions. **Research Limitations**: While GHRP-6 has been studied in humans for over 30 years, the majority of data comes from short-term pharmacodynamic studies rather than long-term safety trials. Comprehensive chronic-use safety data across diverse populations is limited. Long-term effects on insulin sensitivity, pituitary function, and cardiovascular parameters require further investigation.