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Hexarelin

Tier 1 · Human trials
Also known as Examorelin · EP-23905

Supported by Tier-1 human RCT and pharmacokinetic data on acute GH release, dose-response, cardiac inotropic effects, and HPA-axis stimulation. However, most cardioprotective, anti-fibrotic, renal, and metabolic mechanisms derive from animal or in vitro studies. Several quantitative claims (GH-peak superiority over GHRP-2, desensitization timing, diagnostic specificity, discontinuation after Phase II) rest on single lower-tier sources.

Half-life
~0.92 h
Routes
Intravenous · Subcutaneous · Oral · Intranasal
Goals
gh stimulation · longevity · body composition
Cost / mg
Not recorded

How it works

Hexarelin is a synthetic six-amino-acid peptide that acts as a growth hormone secretagogue. It mimics the natural hormone ghrelin by binding to the growth hormone secretagogue receptor (GHS-R1a) on the pituitary gland, prompting a strong, pulsatile release of growth hormone. It also acts at the hypothalamus to boost GHRH activity and reduce somatostatin's braking effect. Because release stays pulsatile and subject to normal feedback, it tends to avoid continuously supra-physiologic GH levels. Beyond growth hormone, hexarelin engages a separate cardiac receptor (CD36) that produces heart-related effects independent of growth hormone, and it mildly stimulates cortisol, ACTH, and prolactin.

Overview

Overview

Hexarelin (also called Examorelin or EP-23905) is a synthetic hexapeptide growth hormone secretagogue with the sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2 and a molecular weight of approximately 887.04 Da. It was developed in the early 1990s by Romano Deghenghi and colleagues at Europeptides as a structural modification of GHRP-6; the D-2-methyltryptophan substitution confers enhanced metabolic/proteolytic stability along with increased GH-releasing potency and GHS-R1a binding affinity. Compared with the natural ligand ghrelin — which is chemically unstable and rapidly transformed and degraded — hexarelin is described as more stable and functionally more potent.

Growth Hormone Activity

Hexarelin stimulates GH release both in vitro and in vivo by binding and activating GHS-R1a on anterior pituitary somatotrophs, and by acting at the hypothalamus to promote GHRH neuron activity and antagonize somatostatin tone. Its GH-releasing activity is synergistic with GHRH — combined low-dose hexarelin and GHRH produce GH release exceeding either agent alone. The GH effect is not blocked by naloxone but is blunted by glucose, free fatty acids, glucocorticoids, rhGH, and exogenous somatostatin. Because it promotes pulsatile GH release subject to negative feedback, it may avoid persistently supra-therapeutic GH levels. In comparative human studies hexarelin is reported to produce the strongest acute GH peaks of any GHRP, with peak GH roughly 20-30% greater than GHRP-2 (single-source figure).

GH responses are age-dependent: hexarelin is a powerful GH stimulus in pubertal children and adults but weak in prepubertal children and the elderly. In one age-comparison study, GH response to 2 µg/kg IV was 19.0±4.6 µg/l (prepubertal), 67.6±12.7 (pubertal), 60.9±8.0 (young adults), and 22.4±4.9 (elderly). GH responsiveness varies by condition — maintained in hypersecretory states (acromegaly, anorexia nervosa, hyperthyroidism), still reported effective (though sometimes reduced) in obesity, hypothyroidism, idiopathic GH deficiency and short stature, and nearly absent in pituitary stalk disconnection and Cushing's syndrome. Diagnostic specificity for GH deficiency was reported at 62% (1 µg/kg) and 75% (2 µg/kg), no better than GHRH+pyridostigmine or arginine+estrogen (single study). Prolonged GHRP administration increases IGF-1 in animals and humans, and increased height velocity has been reported in short children on chronic treatment.

Cardiovascular Actions

GHS-R is also peripherally distributed, with highest human binding in myocardium/ventricles. A distinct cardiac receptor, CD36 (an 88 kDa scavenger glycoprotein), mediates GH-independent cardioprotective effects — these were absent in CD36-null mice and CD36-deficient rats. In humans, acute IV hexarelin (2 µg/kg) produced a short-lasting positive inotropic effect, raising LVEF from 64.0±1.5% to 70.7±3.0% without changing blood pressure or heart rate, and in 24 coronary artery disease patients it increased LVEF, cardiac index/output, and mean arterial pressure while reducing wedge pressure, whereas rhGH, GHRH, and placebo had no hemodynamic effect. Animal studies report infarct-size reduction of 40-60%, anti-apoptotic and anti-fibrotic effects, reduced LV dysfunction in heart failure models, and attenuation of abdominal aortic aneurysm; these cardioprotective, renal ischemia-reperfusion, PPARγ/CD36 metabolic, and MDM2/p53 mechanisms remain largely preclinical.

Other Effects and Development Status

Hexarelin stimulates the HPA axis (ACTH/cortisol, probably via central AVP mechanisms), mildly increases appetite, and influences sleep. It has been envisaged for short stature, aging, catabolic/wasting states, obesity, and dilated cardiomyopathy, and is cited among promising longevity leads via the GH/IGF axis. It was also screened in silico against SARS-CoV-2 targets. According to a single lower-tier source, clinical development was discontinued after Phase II.

What the research shows

183 findings extracted from the 23 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 43 human trial findings, 24 human study findings, 11 animal findings, 1 in vitro finding and 1 expert opinion finding.

  • human trialAcute administration of hexarelin increases left ventricular ejection fraction in normal subjects and even in patients with severe GH deficiency1

  • human trialIn patients with coronary artery disease undergoing bypass surgery, hexarelin induced a prompt increase in left ventricular ejection fraction after 10 minutes1

  • human trialHexarelin increased cardiac index in coronary artery disease patients during bypass surgery1

  • human trialHexarelin increased cardiac output in coronary artery disease patients during bypass surgery lasting up to 90 minutes1

  • human trialHexarelin induced reduction of wedge pressure in coronary artery disease patients1

  • human trialHexarelin caused increased mean arterial pressure in coronary artery disease patients during bypass surgery1

  • human trialHexarelin caused transient decrease of central venous pressure in coronary artery disease patients1

  • human trialRhGH, GHRH and placebo did not exert any hemodynamic effect in coronary artery disease patients undergoing bypass surgery1

Show 72 more findings

  • human trialThe mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml−1 after 0, 0.5, 1 and 2 μg·kg−1, respectively2

  • human trialThe corresponding Emaxs were 55.1 ng·ml−1 and 3936 ng·min·ml−1, thus indicating that the effect after the 2 μg·kg−1 dose is very close to the maximal response2

  • human trialIntravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations2

  • human trialintravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone3

  • human trialMean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng/ml after 0, 0.5, 1 and 2 micrograms/kg hexarelin respectively3

  • human trialThe corresponding Emax values were 55.1 ng/ml and 3936 ng·min·ml−1, indicating that the effect after the 2 micrograms/kg dose is very close to the maximal response3

  • human trialPlasma growth hormone concentrations increased dose-dependently after injection of hexarelin3

  • human trialMean peak plasma growth hormone concentrations (Cmax) were 3.9 ng/ml after 0 micrograms/kg (placebo)3

  • human trialMean peak plasma growth hormone concentrations (Cmax) were 26.9 ng/ml after 0.5 micrograms/kg hexarelin3

  • human trialMean peak plasma growth hormone concentrations (Cmax) were 52.3 ng/ml after 1 microgram/kg hexarelin3

  • human trialMean peak plasma growth hormone concentrations (Cmax) were 55.0 ng/ml after 2 micrograms/kg hexarelin3

  • human trialThe effect after 2 micrograms/kg dose is very close to the maximal response3

  • human trialHexarelin is a powerful stimulus of GH secretion in pubertal children and in adults4

  • human trialHexarelin is not a powerful stimulus of GH secretion in prepubertal children and in elderly subjects4

  • human trialIn pubertal children, the GH response to Hexarelin was higher than that to ARG + GHRH but this difference did not attain statistical significance4

  • human trialIn young adults, the GH response to Hexarelin was similar to that to ARG + GHRH4

  • human trialIn elderly subjects, the GH response to Hexarelin was higher than that to GHRH alone but lower than that to ARG + GHRH4

  • human trialAge-related variations in the GH response to GHRPs probably limit their reliability for the evaluation of GH releasable pool in prepubertal children and elderly subjects4

  • human trialHexarelin at 1 microg/kg i.v. produced Cmax of 26.8+/-10.5 ng/ml in familial short stature subjects7

  • human trialHexarelin at 1 microg/kg i.v. produced AUC of 1448+/-514 ng/min x ml in familial short stature subjects7

  • human trialHexarelin at 2 microg/kg i.v. produced Cmax of 37.7+/-16 ng/ml in familial short stature subjects7

  • human trialHexarelin at 2 microg/kg i.v. produced AUC of 1979+/-888 ng/min x ml in familial short stature subjects7

  • human trialHexarelin did not show more specificity than GHRH+pyridostigmine and arginine plus estrogen7

  • human trialSpecificity was 62% for hexarelin 1 microg/kg and 75% for hexarelin 2 microg/kg7

  • human trialHexarelin, but not rhGH, significantly increased cortisol levels8

  • human trialAldosterone and catecholamine levels did not change with hexarelin or rhGH administration8

  • human trialHexarelin increased left ventricular ejection fraction (LVEF) from 64.0±1.5% to 70.7±3.0% (p<0.03)8

  • human trialHexarelin did not significantly change mean blood pressure (92.8±4.7 vs 92.4±3.2 mmHg)8

  • human trialHexarelin did not significantly change heart rate (63.1±2.1 vs 67.0±2.9 bpm)8

  • human trialLVEF significantly raised at 15 min, peaked at 30 min and lasted up to 60 min after hexarelin8

  • human trialHexarelin significantly increased ACTH and cortisol release9

  • human trialHexarelin also caused significant GH and PRL release9

  • human trialHexarelin caused an acute small increment in appetite9

  • human trialThe effect of hexarelin on the HPA axis was augmented by the addition of CRH in a dose that on its own produces maximal stimulation9

  • human trialHexarelin effects were not influenced by the addition of desmopressin9

  • human studyGhrelin administration can improve cardiac function in rats and patients with chronic heart failure, indicated by increased left ventricle ejection fraction (LVEF), cardiac output, and exercise capacity5

  • human studyAcute intravenous administration of hexarelin had a short-lasting, positive inotropic effect in seven male volunteers5

  • human studyHexarelin administration increased LVEF (70.7 ± 3.0% vs. 64.0 ± 1.5%, P < 0.03) without affecting mean blood pressure and heart rate5

  • human studyLVEF was significantly increased after 15 min and peaked at 30 min, and the effect lasted for up to 60 min after administration5

  • human studyGHSs might improve growth velocity in children6

  • human studyGHSs might stimulate appetite6

  • human studyGHSs might improve lean mass in wasting states and in obese individuals6

  • human studyGHSs might decrease bone turnover6

  • human studyGHSs might increase fat-free mass6

  • human studyGHSs might improve sleep6

  • human studyGH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration10

  • human studyProlonged administration of GHRPs increases IGF-1 levels both in animals and in humans10

  • human studyThe GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations10

  • human studyGH-releasing activity increases from birth to puberty, persists at a similar level in adulthood and decreases thereafter10

  • human studyBy the sixth decade of life, the activity of GHRPs is reduced but it is still marked and higher than that of GHRH10

  • human studyGHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as in acromegaly, anorexia nervosa and hyperthyroidism10

  • human studyReduced GH responses after GHRP administration have been reported in idiopathic GH deficiency, idiopathic short stature, obesity and hypothyroidism10

  • human studyIn patients with pituitary stalk disconnection or Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent10

  • human studyIn short children an increase in height velocity has been reported during chronic GHRP treatment10

  • human studyHexarelin shows a positive inotropic effect in normal subjects as well as in patients with GH deficiency16

  • human studyThe synthetic growth hormone releasing peptides (GHRPs) GHRP-6 and hexarelin elicit in obese patients GH responses greater than those evoked by GHRH, but still lower than those observed in lean subjects.17

  • human studyThe GH-releasing effect of GHRPs is the same in both sexes, but undergoes age-related variations, increasing from birth to puberty and decreasing in aging19

  • human studyGHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as acromegaly, anorexia nervosa, and hyperthyroidism19

  • human studyIn patients with pituitary stalk disconnection and in Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent19

  • animalIn rodents with acute myocardial infarction, ghrelin administration prevented malignant arrhythmias and reduced mortality in the acute phase, while improving left ventricle dysfunction and attenuating cardiac remodeling in the subacute phase5

  • animalHexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI)12

  • animalPretreatment with Hexarelin exhibits a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis in rats subjected to I/R12

  • animalHexarelin administration decreased infrarenal aorta diameter in a mouse model of elastase-induced abdominal aortic aneurysm13

  • animalHexarelin attenuated abdominal aortic aneurysm development by inhibiting SMC phenotype switch and NF-κB signaling mediated inflammatory response13

  • animalGHRP hexarelin regulates PPARγ downstream actions with benefits on atherosclerosis14

  • animalHexarelin injected into the paraventricular nucleus of the hypothalamus did not increase spontaneous penile erections in male rats15

  • animalHexarelin protects from ischemia-induced myocardial damage in aged and GH deficient rats16

  • animalGH peak response to acute hexarelin initially increased with maximum at 3rd week, then decreased to basal values or less at 6th week18

  • animalGH peak response to acute GHRH initially increased with maximum at 3rd week, then decreased to basal values at 6th week18

  • animalAcute feeding response to hexarelin was abolished at 3rd week and returned to normal at 6th week18

  • in vitroHexarelin reduced cell apoptosis in post-H/R HK-2 cells in vitro12

  • expert opinionHexarelin is protective in cardiovascular diseases such as myocardial infarction and atherosclerosis13

How it works

Based on 14 human trial findings, 6 human study findings, 22 animal findings, 11 in vitro findings, 7 expert opinion findings and 7 theoretical findings.

  • human trialHexarelin is a peptidyl GH secretagogue with neuroendocrine and cardiovascular activities mediated by specific GH secretagogue-receptors1

  • human trialHexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo2

  • human trialHexarelin is a hexapeptide (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo3

  • human trialHexarelin is a hexapeptide (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2)3

  • human trialHexarelin stimulates the release of growth hormone both in vitro and in vivo3

  • human trialHexarelin is a synthetic GH-releasing peptide4

  • human trialGHRPs possess marked, dose-related and reproducible GH-releasing effect even after oral administration4

  • human trialHexarelin is a synthetic hexapeptide with strong GH-stimulating activity7

Show 59 more findings

  • human trialThe acute administration of hexarelin exerts a short-lasting, positive inotropic effect8

  • human trialThe inotropic effect of hexarelin seems GH-independent and might be mediated by specific GHS myocardial receptors8

  • human trialHexarelin stimulates the hypothalamo-pituitary-adrenal (HPA) axis via central mechanisms probably involving CRH or arginine vasopressin (AVP)9

  • human trialThe effect of hexarelin on the HPA axis does not involve CRH, but may occur through the stimulation of AVP release9

  • human trialThe effect of GHSs on the HPA axis involve at least in part the stimulation of AVP release9

  • human trialGH secretagogues act via specific receptors in the hypothalamus and the pituitary gland to release GH9

  • human studyCD36 is a specific cardiac receptor for hexarelin that mediates its cardioprotective effects5

  • human studyGH secretagogues promote pulsatile release of GH that is subject to negative feedback and can prevent supra-therapeutic levels of GH and their sequelae6

  • human studyGHRPs including Hexarelin have potent stimulatory effects on somatotrope secretion in animals and humans10

  • human studyThe GH-releasing activity of GHRPs is synergistic with that of GHRH10

  • human studyGH-releasing activity is not affected by opioid receptor antagonists, such as naloxone10

  • human studyHighest GHRP receptor binding levels in human cardiovascular system were detected in ventricles, followed by atria, aorta, coronaries, carotid, endocardium and vena cava16

  • animalHexarelin's protective effect is achieved through downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and upregulation of the anti-apoptotic protein Bcl-212

  • animalHexarelin significantly suppresses MDM2 and p53 in both in vivo and in vitro experiments of I/R-induced AKI12

  • animalHexarelin improved elastin degradation in hexarelin-treated group compared to control13

  • animalHexarelin rescued smooth muscle cell contractile phenotype with increased α-SMA and decreased MMP213

  • animalHexarelin inhibited inflammatory cell infiltration13

  • animalHexarelin inhibited NLRP3 inflammasome activation and IL-18 production13

  • animalHexarelin suppressed NF-κB signaling pathway which is a key initiator of inflammatory response13

  • animalGHRP hexarelin regulates PPARγ downstream actions with benefits on hepatic cholesterol biosynthesis14

  • animalGHRP hexarelin regulates PPARγ downstream actions with benefits on fat mitochondrial biogenesis14

  • animalEP 60761 and EP 50885, but not hexarelin, increased dose-dependently the number of spontaneous penile erections when injected into the paraventricular nucleus15

  • animalEP 60761-induced penile erection was prevented by oxytocin receptor antagonist given intracerebroventricularly15

  • animalEP 60761-induced penile erection was prevented by NO inhibitor L-NAME given into paraventricular nucleus or intracerebroventricularly15

  • animalEP 60761-induced penile erection was prevented by N-type Ca2+ channel blocker omega-conotoxin-GVIA15

  • animalEP 60761-induced penile erection was prevented by morphine but not by dopamine receptor antagonist or NMDA receptor antagonist15

  • animalEP 60761 and EP 50885 induced penile erection by increasing central oxytocin transmission through activation of NO synthase in oxytocinergic neurons in the paraventricular nucleus15

  • animalHexarelin initially primed the pituitary to acute administration of further hexarelin or GHRH, followed by downregulation of GH response to hexarelin18

  • animalResponse to GHRH was preserved despite hexarelin downregulation18

  • animalDifferent timing of neuroendocrine versus behavioural response to hexarelin suggests existence of different subtypes of central nervous system GH-releasing peptide receptors18

  • animalHexarelin is a hexapeptide growth hormone-releasing peptide (GHRP) that has been shown to be effective at releasing GH in animals and humans19

  • animalThe GH-releasing activity of GHRPs is synergistic with that of GHRH19

  • animalGH-releasing activity of GHRPs is not affected by opioid receptor antagonists19

  • animalGH-releasing activity of GHRPs is blunted by inhibitory influences such as neurotransmitters, glucose, free fatty acids, glucocorticoids, rhGH, and exogenous somatostatin19

  • in vitroHexarelin's cardiac action is mediated in part by GHSR 1a and largely by activation of the CD36 receptor in isolated working hearts5

  • in vitroAlexamorelin is a synthetic peptide and growth hormone secretagogue (GHS) with potential performance-enhancing properties11

  • in vitroGrowth hormone releasing peptides (GHRP) are potent inducers of PPARγ through activation of the scavenger receptor CD3614

  • in vitroGH-releasing peptides exhibit strong, dose-dependent and reproducible GH-releasing activity16

  • in vitroGH-releasing peptides have significant PRL- and ACTH/cortisol-releasing effects16

  • in vitroGHRP receptors are identified in the pituitary gland, hypothalamus and various extra-hypothalamic brain regions16

  • in vitroGHRP receptors are present in peripheral tissues such as heart, adrenal, ovary, testis, lung and skeletal muscle with density significantly higher than in the hypothalamo-pituitary system16

  • in vitroHexarelin showed anti-apoptotic activity in H9c2 myocytes16

  • in vitroGHRPs possess direct GH-independent cardiotropic effects16

  • in vitroGHRPs act via specific receptors present at either the pituitary or the hypothalamic level19

  • in vitroThe GHRP receptor has been cloned and does not show sequence homology with other G-protein-coupled receptors known so far19

  • expert opinionHexarelin is a synthetic growth hormone-releasing peptide that can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin5

  • expert opinionGHSR is peripherally distributed in the heart and blood vessels, suggesting hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects5

  • expert opinionGHRP receptor does not show sequence homology with other G-protein-coupled receptors known so far10

  • expert opinionHexarelin is a synthetic growth hormone-releasing peptide that can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin20

  • expert opinionGHSR is distributed peripherally in the heart and blood vessels, suggesting hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects20

  • expert opinionCD36 is a non-GHSR cardiac receptor for hexarelin that mediates its cardioprotective effects20

  • expert opinionHexarelin mechanisms are relevant to ageing pathways involving growth hormone axis and insulin-like growth factor (GH/IGF)21

  • theoreticalAlexamorelin mimics the natural peptide hormone ghrelin by binding to the GHS type 1a receptor (GHS-R1a) in the pituitary gland, thereby promoting endogenous growth hormone release11

  • theoreticalMolecular docking revealed a strong binding affinity between Hexarelin and MDM212

  • theoreticalHexarelin's anti-apoptosis effect is at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein p5312

  • theoreticalHexarelin is a synthetic growth hormone-releasing peptide13

  • theoreticalThe GHRP-CD36-PPARγ pathway controls various tissue metabolic functions14

  • theoreticalGHRPs probably have a dual site of action on both the pituitary and the hypothalamus, possibly involving regulatory factors in addition to GHRH and somatostatin19

  • theoreticalHexarelin was screened against SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp) and its cofactors (nsp7 and nsp8) in an in silico drug repurposing study of 7922 FDA approved molecules22

Dosing

Based on 4 human trial findings and 1 animal finding.

  • human trialThe calculated ED50 values were 0.50 and 0.64 μg·kg−1 for Cmax and AUC0–180, respectively2

  • human trialThe calculated ED50 values were 0.50 and 0.64 microgram/kg for Cmax and AUC0-180 respectively3

  • human trialED50 values were 0.50 microgram/kg for Cmax and 0.64 microgram/kg for AUC0-1803

  • human trialThe most effective dose of hexarelin was 2 microg/kg i.v.7

  • animal250 microg/kg s.c. twice daily hexarelin administered for 6 weeks in young beagle dogs18

How the body handles it

Based on 7 human trial findings, 1 human study finding, 1 animal finding, 4 in vitro findings and 1 expert opinion finding.

  • human trialPlasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min2

  • human trialThe corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 μg·min·ml−12

  • human trialPlasma growth hormone concentrations increased dose-dependently after intravenous injection of hexarelin, peaking at about 30 min and then decreasing to baseline values within 240 min3

  • human trialAreas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0-180) were 0.135, 1.412, 2.918 and 3.695 micrograms·min·ml−1 after 0, 0.5, 1 and 2 micrograms/kg doses respectively3

  • human trialGrowth hormone peaked at about 30 min after hexarelin injection3

  • human trialGrowth hormone decreased to baseline values within 240 min with a half-life of about 55 min3

  • human trialGH and hexarelin increased circulating GH levels to the same extent (AUC: 1594.6±88.1 vs 1739.3±262.2 μg/l/min for 90 min)8

  • human studyThe effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration10

Show 6 more findings

  • animalThe marked GH-releasing activity of GHRPs is reproducible and dose-related after intravenous, subcutaneous, intranasal, and even oral administration19

  • in vitroN-Acetylation was identified as the primary transformation of alexamorelin, with the highest probability score (98%), and occurring either at the C-terminal Ala or the N-terminal Lys11

  • in vitroOther predicted transformations of alexamorelin included N-oxidation, hydroxylation, amide hydrolysis, oxidative deamination, and phase II N-glucuronidation, with probability scores below 40%11

  • in vitroAfter 3 h of incubation with hepatocytes, only one metabolite (known as examorelin or hexarelin) was detected, resulting from the C-terminal cleavage of the Ala amino acid; this metabolic reaction is mediated by a carboxypeptidase11

  • in vitroThe alexamorelin signal decreased approximately 150-fold after 3 h, indicating significant hepatic metabolism11

  • expert opinionHexarelin is a chemically stable and potent synthetic hexapeptide that can be administered orally5

Safety and side effects

Based on 3 human trial findings and 1 human study finding.

  • human trialPlasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration2

  • human trialThe peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels2

  • human trialHexarelin was well tolerated in all subjects2

  • human studyGHSs are well tolerated, with some concern for increases in blood glucose because of decreases in insulin sensitivity6

What people use it for

Based on 2 human study findings, 1 in vitro finding, 4 expert opinion findings and 2 theoretical findings.

  • human studyHexarelin, as a GHRP, acts as a growth hormone releasing stimulus in obesity.17

  • human studyGHRPs and their analogs have been reported to be effective in idiopathic short stature, in some situations of GH deficiency, in obesity, and in hypothyroidism19

  • in vitroGH-releasing peptides influence food intake and sleep pattern16

  • expert opinionHexarelin is a hexapeptide GHRP that has been synthesized and is available for human studies10

  • expert opinionGHRPs might have a place in the therapy of obesity.17

  • expert opinionHexarelin may be a promising therapeutic agent for some cardiovascular conditions20

  • expert opinionHexarelin is among the most promising leads for longevity21

  • theoreticalExamorelin (hexarelin) is a commercially available GHS secretagogue11

Show 1 more finding

  • theoreticalA potential role in the treatment of short stature, aging, catabolic states, and dilated cardiomyopathy has been envisaged19

Other findings

Based on 4 expert opinion findings.

  • expert opinionWhen compared with ghrelin, hexarelin is chemically more stable and functionally more potent5

  • expert opinionGhrelin is an unstable natural peptide that is transformed and degraded, which limits its clinical use5

  • expert opinionHexarelin is chemically more stable than ghrelin20

  • expert opinionHexarelin is functionally more potent than ghrelin20

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Limited evidence

Most cardioprotective, anti-fibrotic, renal, and metabolic effects come from animal or in vitro studies, not human trials.

Infarct-size reduction, anti-fibrotic effects, abdominal aortic aneurysm attenuation, renal ischemia-reperfusion protection, PPARγ/CD36 metabolic effects, and MDM2/p53 anti-apoptotic mechanisms are all from rodent or cell studies. Human cardiac data are limited to acute LVEF/inotropic effects in small groups (7 volunteers, 24 CAD patients).

Contested

Reported half-life values vary across sources.

Tier-1 human studies report a half-life of about 55 minutes; other sources state 'about one hour' (Hexarelin | Reviews, Clinical Trials, and Safety), 30-60 minutes in animal models (Hexarelin Half-Life and Stability: What Research Shows | Palmetto Peptides), or 30-40 minutes (Hexarelin UK: Complete Research Guide (2026), tier 4). Animal half-lives differ by species (120 min in dogs, ~76 min in rats).

Single source

Claim that hexarelin development was discontinued after Phase II comes from a single lower-tier source.

The statement that clinical development ended after Phase II investigation appears only in Hexarelin: Research Evidence & Safety Profile | PeptideInsight (tier 3 web source) and is not corroborated by other sources.

Single source

Desensitization timing and magnitude of GH-peak superiority over GHRP-2 rely on individual lower-tier sources.

The specific '20-30% greater GH than GHRP-2', '40-120 ng/mL peak', '10-25 fold', and '4-6 week' desensitization figures come primarily from Hexarelin: Strongest GHRP, Desensitization & Heart Research (tier 2 web). The broader concept of partial desensitization is supported by tier-1 Growth hormone-releasing peptides., but the specific quantities are single-source.

Single source

Diagnostic specificity data for hexarelin comes from one study.

Reported specificity of 62% (1 µg/kg) and 75% (2 µg/kg) for GH deficiency diagnosis, and the finding that hexarelin was no more specific than GHRH+pyridostigmine or arginine+estrogen, come only from Hexarelin-induced growth hormone response in short stature. Comparison with growth hormone-releasing hormone plus pyridostigmine and arginine plus estrogen. - Abstract - Europe PMC.

Limited evidence

Some mechanistic signaling claims are labeled theoretical rather than experimentally confirmed for hexarelin.

The phospholipase C/IP3/calcium GH-exocytosis pathway (Hexarelin: Research Evidence & Safety Profile | PeptideInsight) and the GHRP-CD36-PPARγ tissue metabolic pathway (The CD36-PPARγ Pathway in Metabolic Disorders.) are described as theoretical/inferred, and DPP-IV/renal clearance in Hexarelin Half-Life and Stability: What Research Shows | Palmetto Peptides is inferred from analog studies.

Inconsistency

Cortisol (~40%) and prolactin (~80%) increase figures sit next to a statement that acute dosing caused 'only slight incr…

Within one paragraph the profile reports a ~40% cortisol rise and ~80% prolactin rise (Hexarelin: Research Evidence & Safety Profile | PeptideInsight/The Growth Hormone Secretagogue Hexarelin Stimulates the Hypothalamo-Pituitary-Adrenal Axis via Arginine Vasopressin/What is Hexarelin Peptide? - Creative Peptides) and then says acute dosing 'otherwise caused only slight increases in prolactin, cortisol, and ACTH' (Growth hormone-releasing activity of hexarelin in humans | European Journal of Clinical Pharmacology | Springer Nature Link). These are not reconciled and read as contradictory;

What you may have heard

The claim that DPP-IV drives hexarelin's rapid breakdown is inferred from related peptides, not measured for hexarelin itself.

Hexarelin's short plasma half-life (roughly 30–60 minutes in rodent models) is attributed to rapid enzymatic degradation, with cleavage by dipeptidyl peptidase IV (DPP-IV) and other plasma peptidases named as the route. However, the description in Hexarelin Half-Life and Stability: What Research Shows explicitly states that this primary clearance route is 'inferred from analog studies' rather than established by direct measurement of hexarelin, so the specific role of DPP-IV in its degradation remains an extrapolation.

What you may have heard

The oral route is called "marked" and dose-related, yet every dose actually reported is intravenous.

Reviews of GH-releasing peptides describe the GH-releasing activity of these compounds, including hexarelin, as "marked, dose-related and reproducible" after oral administration as well as by the intravenous, subcutaneous and intranasal routes. But the only human dosing that is actually quantified is intravenous: the maximal effective dose used in testing is 2 µg/kg i.v. (reported as 1–2 µg/kg i.v. in the early clinical work by Ghigo and colleagues). No oral dose, bioavailability figure, or direct oral-versus-injection comparison is given, so how the oral route's practical potency compares with injection cannot be judged from this evidence.

Other

The ~55 min 'half-life' may conflate the GH-response time course with the pharmacokinetic half-life of the hexarelin pep…

Claim 11 derives '55 minutes' in the context of plasma GH peaking at 30 min and returning to baseline by 240 min — that is a GH secretory time course, not necessarily peptide plasma half-life. The animal figures (dogs 120 min, rats 76 min) are true peptide PK. Presenting a single 0.92 h value as the peptide half-life should be checked against whether Growth hormone-releasing activity of hexarelin in humans. .../Growth hormone-releasing activity of hexarelin in humans. A dose-response study - PubMed measured hexarelin plasma concentrations or GH kinetics.

What you may have heard

The study concludes the adrenal effect works through vasopressin rather than CRH, yet its own data run the other way.

In 'The Growth Hormone Secretagogue Hexarelin Stimulates the Hypothalamo-Pituitary-Adrenal Axis via Arginine Vasopressin', hexarelin raised ACTH and cortisol, and the authors conclude that this effect 'does not involve CRH, but may occur through the stimulation of AVP release.' The experimental results sit awkwardly with that conclusion: the response was significantly augmented by adding CRH, while adding desmopressin — an AVP analog — did not change it. So the mechanism the study names (AVP) is the one whose analog had no effect, and the mediator it excludes (CRH) is the one that amplified the response.

Using it with other compounds

Check a stack
  • MK-677Same mechanism

    Worth caution

    MK-677 is an oral ghrelin-mimetic that hits the same GHS-R1a receptor hexarelin does. Combining them is redundant — both compete for and desensitize the same receptor — and MK-677's long half-life keeps that receptor occupied around the clock, which can blunt the pulse a short-acting injectable like hexarelin is trying to create. Pick one GHS-R1a agonist rather than layering two.

    Tier 2Supported by animal / early studies

    Shares GH axis · IGF1 signaling

  • SS-31Complementary

    Worth caution

    Both have cardioprotective, anti-apoptotic profiles against ischemia-reperfusion injury but by entirely different mechanisms: hexarelin via CD36/GH-independent inotropy and inflammasome suppression, SS-31 by stabilizing mitochondrial cardiolipin and reducing mitochondrial ROS. Convergence on cardiac protection makes them mechanistically complementary in research settings.

    Tier 4Theoretical — not established
  • IpamorelinSame mechanism

    Worth caution

    Both hexarelin and ipamorelin are growth hormone secretagogues that switch on the exact same pituitary receptor (GHS-R1a) to trigger a GH pulse, so stacking them is largely redundant rather than additive — you're pushing the same button twice. The key difference is selectivity: hexarelin also raises ACTH, cortisol and prolactin and blunts (desensitizes) with continued use, whereas ipamorelin gives a cleaner GH pulse without those extra hormones. For most goals you'd choose one, and ipamorelin is the cleaner GHS-R1a option.

    Tier 2Supported by animal / early studies

    Timing If both are on hand, use one per session rather than doubling up on the same receptor.

    Shares GH axis

  • SermorelinSame downstream effect

    May be complementary

    Sermorelin is a GHRH-receptor agonist and hexarelin is a GHS-R1a agonist — two different receptors that feed the same GH secretory pathway. Pairing a GHRH analog with a ghrelin-mimetic secretagogue is a well-established synergistic strategy: the GHRH signal and the secretagogue signal reinforce each other for a bigger pulse than either produces alone.

    Tier 2Supported by animal / early studies

    Timing Best co-administered on an empty stomach, often at night to align with natural GH pulses.

    Shares GH axis · IGF1 signaling

  • TB-500Complementary

    Worth caution

    Both show cardiac-repair and anti-inflammatory signals through different routes: hexarelin via CD36/PI3K-Akt cardioprotection and NLRP3/NF-κB suppression, TB-500 via actin/cytoskeletal remodeling, angiogenesis and NF-κB suppression. They target the same repair and inflammation-resolution goals through non-overlapping mechanisms, making them a plausible complementary pair for tissue recovery.

    Tier 4Theoretical — not established

    Shares anti inflammatory · NF kB modulation · mTOR PI3K

  • HumaninComplementary

    Worth caution

    Both peptides report cardioprotection against ischemia-reperfusion injury and anti-apoptotic effects, but by different means: hexarelin through CD36/PI3K-Akt and (theoretical) MDM2 anti-apoptotic docking, humanin as a mitochondrial 'mitokine' acting via gp130/STAT3 and PI3K/Akt survival signaling. Overlapping IGF-1 and PI3K/Akt survival pathways make them mechanistically complementary for cytoprotective goals.

    Tier 4Theoretical — not established

    Shares IGF1 signaling · anti inflammatory · mTOR PI3K

  • KlothoComplementary

    Worth caution

    Both have anti-fibrotic and anti-inflammatory profiles that converge on TGF-β and NLRP3/NF-κB suppression via different upstream biology — hexarelin through GHS-R/CD36 signaling and klotho through FGF23/TGF-β and Nrf2 pathways. This makes them a plausible complementary pair for anti-fibrotic and inflammation-dampening aims, though evidence for co-use is only theoretical.

    Tier 4Theoretical — not established

    Shares anti inflammatory · NF kB modulation · IGF1 signaling

  • TesamorelinSame downstream effect

    May be complementary

    Tesamorelin is a stabilized GHRH analog; hexarelin is a GHS-R1a secretagogue. They act on distinct receptors that both drive pituitary GH release, so combined they can produce a larger, more physiologic GH/IGF-1 response — with tesamorelin adding a documented visceral-fat-lowering effect. Monitor IGF-1 since two upstream drivers stacking can push it higher than intended.

    Tier 2Supported by animal / early studies

    Timing Co-inject on an empty stomach; keep IGF-1 in a sensible range with periodic monitoring.

    Shares GH axis · IGF1 signaling · lipolysis

  • BPC-157Complementary

    Worth caution

    Hexarelin shows GH-independent cardioprotective and anti-fibrotic effects (NLRP3/NF-κB and TGF-β suppression, PI3K/Akt survival signaling), while BPC-157 drives angiogenesis and tissue repair via VEGFR2/eNOS and overlapping PI3K/Akt–ERK pathways. Different upstream targets converging on tissue repair and cytoprotection make them potentially complementary for recovery contexts.

    Tier 4Theoretical — not established
    What the research doesn't establish
    Although both peptides converge on PI3K/Akt and ERK1/2 signaling, this shared downstream overlap does not demonstrate that their distinct upstream actions coordinate. Hexarelin acts through GHS-R1a with inflammasome/NF- cB and TGF- cB suppression, while BPC-157 acts through VEGFR2/eNOS and integrin-ECM remodeling; no evidence shows these separate mechanisms work together or fill complementary roles in any defined recovery setting.
  • CJC-1295Complementary

    Worth caution

    Hexarelin is a ghrelin-receptor (GHS-R1a) agonist, a different upstream mechanism from CJC-1295's GHRH receptor. The two converge on greater GH secretion, so combining amplitude (GHRH) with a secretagogue can be additive. Note hexarelin also stimulates ACTH/cortisol and prolactin and can desensitize its receptor over time, so it's less selective than ipamorelin.

    Tier 3Largely anecdotal — commonly discussed

    Timing Dose on an empty stomach; watch for cortisol/prolactin effects with repeated hexarelin use.

    Shares GH axis · IGF1 signaling

  • Follistatin-344Complementary

    May be complementary

    Hexarelin raises IGF-1 and, notably, suppresses TGF-beta driven fibrosis — overlapping with Follistatin's own anti-fibrotic, muscle-sparing action. One works through GH/IGF-1, the other through myostatin/activin blockade, so they converge on healthier, larger muscle through different routes.

    Tier 4Theoretical — not established

    Shares IGF1 signaling · mTOR PI3K · anti inflammatory

Safety and side effects

Tolerability

Growth hormone secretagogues, including hexarelin, are generally described as well tolerated, and in dose-response human studies hexarelin was well tolerated in all subjects. Acute dosing left plasma glucose, LH, FSH, TSH, and IGF-1 unaffected.

Hormonal Effects

Unlike more selective secretagogues such as ipamorelin, hexarelin elevates cortisol, ACTH, and prolactin at GH-releasing doses. Reported figures include an approximately 40% maximal cortisol increase at 0.5 µg/kg IV and about 80% prolactin increase at standard doses; acute dosing otherwise caused only slight increases in prolactin, cortisol, and ACTH. It significantly stimulates the HPA axis, an effect augmented by CRH but not desmopressin. A small acute increase in appetite has been observed.

Desensitization

Hexarelin causes desensitization/tachyphylaxis with continuous or repeated dosing, with diminished GH responses reported after 4-6 weeks of continuous administration (single-source timing). Desensitization is partial — greater during continuous infusion, less during intermittent administration. In beagle dogs given 250 µg/kg SC twice daily for 6 weeks, the acute GH peak first increased (maximum at week 3) then declined to basal or lower by week 6, reflecting initial pituitary priming followed by downregulation, while the response to GHRH was preserved.

Metabolic Considerations

As with GH secretagogues generally, there is some concern for increases in blood glucose due to decreased insulin sensitivity.

Note: Most cardiovascular, renal, and metabolic benefits derive from animal or in vitro work; human data are limited to acute effects in small groups. Reported quantitative safety figures (cortisol/prolactin magnitudes, desensitization timing) rest on individual lower-tier sources.

Reconstitution and handling

Storage and Stability

No dose has been established for this compound. No regulatory label exists for it, so the figures below are what sources report — not guidance.

Hexarelin is chemically stable relative to ghrelin, owing to its D-2-methyltryptophan substitution which enhances proteolytic stability. Lyophilized hexarelin stored at appropriate temperatures can remain intact for extended periods, whereas reconstituted solutions require careful cold-chain management to preserve activity. In plasma it undergoes rapid enzymatic degradation (including inferred DPP-IV cleavage and other peptidases) plus renal clearance, and lacks protective modifications such as PEGylation.

Administration Routes

Hexarelin shows marked, dose-related, and reproducible GH-releasing activity across multiple routes — intravenous, subcutaneous, oral, and intranasal. It is sufficiently chemically stable to be administered orally. Subcutaneous bioavailability was 64% in rats.

Dosing in Research

The most effective and standard dose in human studies is 2 µg/kg intravenous. In a dose-response study of 12 adult males, mean peak plasma GH (Cmax) was 3.9, 26.9, 52.3, and 55.0 ng/ml at 0 (placebo), 0.5, 1, and 2 µg/kg, with AUC0-180 of 0.135, 1.412, 2.918, and 3.695 µg·min·ml⁻¹ respectively. ED50 values were 0.50 µg/kg (Cmax) and 0.64 µg/kg (AUC), with Emax of 55.1 ng/ml and 3936 ng·min·ml⁻¹ — indicating the 2 µg/kg dose is near the maximal response. After IV injection, plasma GH peaks at ~30 min and returns to baseline within 240 min. Subcutaneous administration has produced peak GH of 40-120 ng/mL at 15-45 min (10-25 fold above baseline; single-source figures).

This information summarizes research findings and is not dosing guidance.

Sources

Ordered by evidence quality — the strongest first.

  1. Effects of acute hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery(opens in a new tab)
    Tier 1Web · sciencedirect.com
  2. Growth hormone-releasing activity of hexarelin in humans | European Journal of Clinical Pharmacology | Springer Nature Link(opens in a new tab)
    Tier 1Web · link.springer.com
  3. Growth hormone-releasing activity of hexarelin in humans. ...(opens in a new tab)
    Tier 1Web · researchgate.net
  4. Hexarelin, a synthetic GH-releasing peptide, is a powerful stimulus of GH secretion in pubertal children and in adults but not in prepubertal children and in elderly subjects(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov
  5. The cardiovascular action of hexarelin - PMC - NIH(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  6. The Safety and Efficacy of Growth Hormone Secretagogues.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  7. Hexarelin-induced growth hormone response in short stature. Comparison with growth hormone-releasing hormone plus pyridostigmine and arginine plus estrogen. - Abstract - Europe PMC(opens in a new tab)
    Tier 1Web · europepmc.org · 1999
  8. (PDF) Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans(opens in a new tab)
    Tier 1Web · academia.edu · 1999
  9. The Growth Hormone Secretagogue Hexarelin Stimulates the Hypothalamo-Pituitary-Adrenal Axis via Arginine Vasopressin(opens in a new tab)
    Tier 1Web · academia.edu · 1999
  10. Growth hormone-releasing peptides.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 1997
  11. Identification of alexamorelin consumption biomarkers using human hepatocyte incubations and high-resolution mass spectrometry.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  12. Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  13. Hexarelin attenuates abdominal aortic aneurysm formation by inhibiting SMC phenotype switch and inflammasome activation.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  14. The CD36-PPARγ Pathway in Metabolic Disorders.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  15. EP 60761 and EP 50885, two hexarelin analogues, induce penile erection in rats.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2000
  16. Growth hormone-releasing peptides and the cardiovascular system.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2000
  17. Growth hormone in obesity.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 1999
  18. Six-week treatment with hexarelin in young dogs: evaluation of the GH responsiveness to acute hexarelin or GHRH administration, and of the orexigenic effect of hexarelin.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 1999
  19. Growth hormone-releasing peptides and their analogs.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 1998
  20. The cardiovascular action of hexarelin.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2014
  21. We are ageing.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2014
  22. SARS-CoV-2 RNA Dependent RNA polymerase (RdRp) - A drug repurposing study.(opens in a new tab)
    Tier 4PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  23. Gateways to clinical trials.(opens in a new tab)
    Tier 4PubMed · pubmed.ncbi.nlm.nih.gov · 2002

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