Hexarelin
examorelin, EP-23905, MF-6003, His-D-2-Me-Trp-Ala-Trp-D-Phe-Lys-NH2
Hexarelin, generically examorelin, is GHRP-6 with a single methyl group added, a change that makes it more potent and more metabolically stable. It is pharmacologically the most interesting compound in this class because it acts at two receptors, not one: the ghrelin receptor for growth hormone release, and the scavenger receptor CD36 on cardiomyocytes for a direct cardiac effect independent of growth hormone. It has never been approved anywhere, and the human studies are small, mostly acute, and include one distinctly unhelpful finding about repeated use.
Mechanism
Hexarelin is a hexapeptide agonist at the growth hormone secretagogue receptor 1a, differing from GHRP-6 only by methylation of the D-tryptophan at position two. That methyl group increases both potency and resistance to enzymatic degradation. Through GHS-R1a it acts at the pituitary somatotroph (Gq coupling, phospholipase C, calcium mobilisation, growth hormone exocytosis) and at the hypothalamic arcuate nucleus, where it suppresses somatostatin tone and amplifies endogenous GHRH release. Like GHRP-2 and GHRP-6, and unlike ipamorelin, it is not selective: it raises ACTH, cortisol and prolactin alongside growth hormone.
What distinguishes hexarelin is a second, entirely separate receptor. Bodart and colleagues purified the cardiac binding protein for hexarelin and found it was CD36, a multifunctional scavenger receptor expressed on cardiomyocytes and microvascular endothelial cells, not GHS-R1a at all. In perfused hearts, hexarelin raised coronary perfusion pressure dose-dependently, and this effect was absent in hearts from CD36-null mice and from spontaneously hypertensive rats that are genetically CD36-deficient. This gives hexarelin a direct cardiac action that does not depend on growth hormone release, and it is the reason hexarelin occupies a distinct place in cardiovascular research rather than being simply a stronger GHRP-6. In humans, acute intravenous hexarelin produced a short-lasting positive inotropic effect in both growth hormone-deficient patients and healthy controls, without changes in catecholamines, mean blood pressure or heart rate, a pattern consistent with a direct myocardial receptor action rather than a systemic haemodynamic or growth-hormone-mediated one.
What the research shows
The acute human pharmacology is solid, if small in scale. Imbimbo and colleagues ran a double-blind, placebo-controlled rising-dose study in twelve adult male volunteers and showed dose-dependent growth hormone release (peak concentrations of 3.9, 26.9, 52.3 and 55.0 ng/mL at 0, 0.5, 1 and 2 micrograms per kilogram), peaking at about 30 minutes and resolving within four hours. Bisi and colleagues used equilibrium radionuclide angiocardiography in seven men with growth hormone deficiency and nine controls: hexarelin raised left ventricular ejection fraction significantly in both groups without altering catecholamines or blood pressure, which the authors interpreted as a short-lasting, probably growth-hormone-independent inotropic effect. A separate study by the same group compared hexarelin with recombinant growth hormone in seven male volunteers and found the same pattern: ejection fraction rose from 64.0 to 70.7 per cent with hexarelin but not with growth hormone, and hexarelin, unlike growth hormone, significantly raised cortisol.
The finding that most complicates hexarelin's case is Rahim and colleagues' 16-week study. Healthy subjects received hexarelin 1.5 micrograms per kilogram subcutaneously twice daily, and the growth hormone response fell substantially over the treatment period. Mean area under the growth hormone curve dropped from 19.1 micrograms per litre per hour at baseline to 13.1 at one week and 10.5 by week 16, recovering to 19.4 four weeks after stopping. Just as importantly, IGF-1, the IGF binding proteins, body composition and bone mineral density did not change over the 20-week period at all. So the one repeated-dosing study in humans shows both that the pituitary desensitises to sustained hexarelin exposure and that nothing downstream moved. This is the single most important piece of information about hexarelin for anyone extrapolating from single-dose studies, and it is rarely mentioned in material promoting the compound.
What does not exist is any trial of clinical outcome. No randomised controlled trial has tested hexarelin for cardiac function in heart disease, for body composition, for muscle, or for anything else measured as an endpoint that matters to a patient. The CD36 story is genuinely novel pharmacology, and it has sat at the mechanistic stage for over twenty years without a clinical programme behind it.
Evidence assessment
Limited evidence
Human data consist of acute pharmacology and cardiac imaging studies of seven to sixteen participants plus one 16-week study in which the growth hormone response roughly halved and IGF-1, body composition and bone density did not change at all; no randomised trial of any clinical outcome has been conducted.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Growth hormone-releasing activity of hexarelin in humans. A dose-response study Limited evidence
Plasma growth hormone rose dose-dependently (peaks of 3.9, 26.9, 52.3 and 55.0 ng/mL at 0, 0.5, 1 and 2 micrograms/kg), peaking at about 30 minutes and returning to baseline within 240 minutes.
Growth hormone status during long-term hexarelin therapy Limited evidence
Mean area under the GH curve fell from 19.1 micrograms/L/hour at baseline to 13.1 at week 1 and 10.5 at week 16, recovering to 19.4 at week 20; IGF-1, IGF binding proteins, body composition and bone mineral density did not change significantly over the 20 weeks.
Cardiac effects of hexarelin in hypopituitary adults Limited evidence
Left ventricular ejection fraction rose significantly in both groups without changes in catecholamines or blood pressure, indicating a short-lasting and probably growth-hormone-independent inotropic effect.
CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart Preclinical only
The cardiac binding protein for hexarelin was identified as CD36, not GHS-R1a; hexarelin raised coronary perfusion pressure dose-dependently, an effect absent in CD36-deficient hearts.
Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans Limited evidence
Hexarelin raised left ventricular ejection fraction from 64.0 to 70.7 per cent, peaking at 30 minutes and lasting up to 60 minutes, while recombinant growth hormone did not; hexarelin, but not growth hormone, significantly increased cortisol, and aldosterone and catecholamines were unchanged by either.
Safety
Single doses were well tolerated across the acute human studies, with no significant changes in blood pressure, heart rate or catecholamines reported. The 16-week study is the only meaningful repeated-dosing data in humans and it produced two findings worth taking seriously: the growth hormone response attenuated by roughly half over the treatment period, and IGF-1, the IGF binding proteins, body composition and bone mineral density were unchanged throughout, which is to say the biomarker cascade that is supposed to deliver any benefit did not move. Hexarelin also raises cortisol acutely, demonstrated directly in the comparison against recombinant growth hormone, and the consequences of sustained adrenal axis stimulation have not been characterised. Its direct action at cardiac CD36 receptors is a genuine pharmacological effect that cuts both ways: it is the basis of research interest in cardioprotection, and it also means hexarelin has cardiac activity that no other compound in this class shares and that has never been assessed for safety in people with heart disease. Class concerns (glucose intolerance, fluid retention, arthralgia, and neoplasia risk from sustained IGF-1 elevation) remain untested. Unregulated hexarelin has no verified identity, purity, sterility or endotoxin testing.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation. Supply for human use is unlawful under the Human Medicines Regulations 2012. Lawful only as a laboratory research chemical; providing dosing or administration instructions is treated by the MHRA as marketing an unlicensed medicine. |
| United States | Not approved by the FDA for any indication. Clinical development was not carried through to registration. It is not on Category 1 of the FDA's interim 503A bulk drug substances list and cannot lawfully be compounded for human use. Sold online as 'for research use only', a phrase indicating no regulatory review of identity, purity or safety and serving principally to permit the sale of an unapproved drug to consumers. |
| WADA (sport) | Prohibited at all times under section S2.2.4 of the WADA Prohibited List, which names examorelin (hexarelin) explicitly among prohibited growth hormone-releasing peptides. |
Questions
Chemically the difference is a single methyl group on the tryptophan at position two, which makes hexarelin more potent and more resistant to degradation. Pharmacologically the difference is larger than that implies: hexarelin also binds CD36, a scavenger receptor on cardiomyocytes, giving it a direct cardiac action that does not depend on growth hormone at all.
The growth hormone response does diminish. In the only repeated-dosing study in humans, twice-daily hexarelin over 16 weeks roughly halved the growth hormone response, from a mean area under the curve of 19.1 to 10.5 micrograms per litre per hour, recovering four weeks after stopping. The same study found no change in IGF-1, body composition or bone mineral density over 20 weeks, so not only did the response fade, nothing downstream of it moved in the first place.
Hexarelin has a real and unusual cardiac pharmacology, acting directly on CD36 receptors on heart muscle, and acute dosing raised ejection fraction in small imaging studies of seven to sixteen men. But no randomised trial has ever tested hexarelin for a cardiac outcome in people with heart disease. The mechanism has been known since 2002 and has not been taken into a clinical programme.
No. Hexarelin has never received marketing approval in any country for any indication. It is prohibited at all times in sport under the WADA list, and cannot lawfully be supplied for human use in the US or UK.