Hexarelin

Overview

Hexarelin (His-D-2MeTrp-Ala-Trp-D-Phe-Lys-NH2) is a synthetic hexapeptide growth hormone secretagogue developed by Mediolanum (Italy) in the 1990s. It is a potent ghrelin-receptor (GHSR-1a) agonist that also binds the CD36 scavenger receptor, giving it a cardioprotective signal distinct from other GHRPs. It is not FDA-approved for any indication and remains a research-only compound; its clinical development for GH deficiency and cardiac indications did not reach approval. A defining feature versus other GHRPs is rapid, pronounced tachyphylaxis with chronic daily dosing.

Mechanism of Action

Hexarelin binds GHSR-1a on pituitary somatotrophs and hypothalamic neurons, driving Gq/PLC/IP3 calcium signaling and pulsatile GH release while suppressing somatostatin tone. Like GHRP-6 and GHRP-2 it is non-selective: it meaningfully raises ACTH, cortisol, and prolactin — generally comparable to or greater than GHRP-2 and substantially more than ipamorelin. Separately from the GH axis, hexarelin binds the CD36 scavenger receptor on cardiomyocytes and microvascular endothelium, producing GHSR-1a-independent cardiovascular effects (coronary vasoactivity and preclinical cardioprotection in ischemia-reperfusion models). With repeated dosing the GH response desensitizes rapidly (tachyphylaxis), with attenuation developing over weeks and partial reversal after a washout.

Research Summary

Ghigo et al. (1994, PMID 8126144, JCEM) characterized hexarelin's GH-releasing activity across IV, SubQ, intranasal, and oral routes in healthy men, establishing it as a potent GH secretagogue. Rahim & Shalet (1998, PMID 10990150, Growth Horm IGF Res) demonstrated that twice-daily SubQ hexarelin in healthy elderly subjects caused ~45% attenuation of the GH AUC over 16 weeks, with partial recovery 4 weeks after discontinuation — the canonical human tachyphylaxis study. Bodart et al. (2002, PMID 11988484, Circulation Research) showed that hexarelin's cardiovascular action in perfused hearts is mediated by CD36 rather than GHSR-1a and is absent in CD36-null animals. Hexarelin has never been FDA-approved; grey-market use for body composition, recovery, or cardiac benefit is not clinically validated.

Dosing Information

Reported Side Effects

• Significant rise in ACTH, cortisol, and prolactin (more than ipamorelin; comparable to or greater than GHRP-2)
• Rapid tachyphylaxis — GH response attenuates with chronic daily dosing
• Increased appetite and hunger (ghrelin-receptor agonism)
• Water retention and transient facial flushing/warmth after injection
• Injection-site reactions (erythema, tingling, numbness)
• Impaired insulin sensitivity and hyperglycemia with sustained GH elevation
• Theoretical IGF-1-mediated concerns with long-term use

Research References

• Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man (1994)
• Does desensitization to hexarelin occur? (1998)
• CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart (2002)