A synthetic six-amino-acid peptide built from GHRP-6 by adding a methyl group — making it the most potent of the classic growth-hormone-releasing peptides, and more resistant to breakdown. It triggers a strong growth-hormone pulse but also raises stress hormones (cortisol, ACTH) and prolactin more than its cousins. It is not an approved medicine. It never completed development and was never marketed; it is prohibited in sport at all times under WADA category S2.
Potent synthetic GHRP-class ghrelin/GHSR-1a agonist, derived from GHRP-6 by a 2-methyl-Trp substitution that increases potency and proteolytic stability. It produces a robust acute GH pulse but with the most pronounced HPA-axis (ACTH/cortisol) and prolactin co-stimulation of the classic GHRPs. In healthy men, IV hexarelin produced dose-dependent GH release peaking ~30 min, with a GH-response half-life ~55 min. Chronic dosing shows partial, reversible desensitization. Developed by Mediolanum and taken into Phase II for GHD and heart failure, but never marketed.
Hexarelin / examorelin — His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH₂ (C₄₇H₅₈N₁₂O₆, MW ≈ 887.0 Da, CAS 140703-51-1, PubChem CID 6918297, UNII 09QF37C617) — a GHRP-6-derived hexapeptide, centrally penetrant and orally active. A potent, highly selective ghrelin/GHS-receptor agonist. Its standout feature is a second, GH-independent pharmacology: CD36 was identified as the cardiac binding protein mediating hexarelin's cardiovascular action, the basis of an extensive cardioprotection research program separable from GH release.
Hexarelin is the heavyweight of the classic GHRPs — a GHRP-6 derivative engineered for greater potency and stability. It generates the strongest GH pulse of the hexapeptide secretagogues, but at the cost of the most prominent cortisol/ACTH and prolactin spillover, and with documented desensitization on repeated use. Its most distinctive identity is its CD36-mediated cardiovascular biology, which gave it a second research life and a drug-design legacy (EP80317) independent of growth hormone.
Hexarelin mimics ghrelin at the GHSR-1a receptor to release GH, but its potency comes with broader neuroendocrine reach: it co-stimulates the ACTH/cortisol and prolactin axes more than its GHRP siblings. Its defining property is a second receptor, CD36, expressed in heart muscle and microvessels, which mediates a GH-independent cardioprotective pharmacology that drew it into Phase II heart-failure development and seeded the EP80317 drug lineage.
| Driver | Receptor / pathway | Net effect | Evidence |
|---|---|---|---|
| GH secretion | GHSR-1a · Gq/11–PLC–Ca²⁺ | Potent acute GH pulse | Human IV dose-response |
| HPA axis | Central CRH/AVP-linked | ACTH / cortisol ↑ | Human HPA study |
| Prolactin | Lactotroph / neuroendocrine | PRL ↑ | Disease-state study |
| Cardioprotection | CD36 · PI3K/Akt | Anti-apoptotic, anti-fibrotic (preclinical) | CD36 identification |
| Metabolic | GH + non-GH lipid pathways | ↑ glucose/lipid handling (animal) | MKR mice |
| Desensitization | Receptor downregulation | Partial, reversible GH attenuation | Chronic dosing |
| Parameter | Value | Note |
|---|---|---|
| GH-response half-life | ~55 min | IV dose-response study |
| Elimination half-life (PK) | ~75.9 ± 9.3 min | Disposition study |
| Clearance | ~7.6 ± 0.7 mL/min/kg | Vss ~744 ± 81 mL/kg |
| SC bioavailability | ~64% (PK) · ~77% (route study) | High vs intranasal/oral |
| Intranasal bioavailability | ~4.8% | Route comparison |
| Oral bioavailability | ~0.3% | Very low / variable |
| GH Tmax | ~30 min after IV bolus | Returns to baseline over hours |
| Effect | Model / finding | Mechanism | Grade |
|---|---|---|---|
| Receptor identification | CD36 = 84 kDa cardiac binding protein; abolished in CD36-KO | CD36 ectodomain | P |
| Anti-apoptotic | ↓ caspase-3/Bax, ↑ Bcl-2 in cardiomyocytes | PI3K/Akt survival | P |
| Ischemia/reperfusion | ↑ systolic function via IL-1 signaling | Cardiac GHSR-1a | C |
| Heart failure | PTEN modulation attenuates CAL-induced HF | PI3K/Akt/mTOR | C |
| Anti-atherosclerotic | EP80317 (GH-free) reduces atherosclerosis | CD36 · cholesterol efflux | P |
Hexarelin has no FDA-approved therapeutic dosing label. The models below are research-protocol scaffolds built around its best-characterized human data: the IV dose-response (0.5–2 µg/kg) and the striking route-bioavailability differences (SC ≫ intranasal ≫ oral). Because hexarelin co-stimulates ACTH/cortisol and prolactin and shows desensitization on repeated use, the page's true centerpiece is the route + HPA/prolactin monitoring model, not a wellness dose.
0.25–0.5 µg/kg once-daily-equivalent exposure model.0.25 → 0.5 → 1.0 µg/kg; do not assume benefit above the acute GH-stimulation ceiling around 1–2 µg/kg IV.2 mg vial + 2 mL BAC = 1,000 µg/mL; 100 µg = 0.10 mL = 10 U on a U-100 syringe (see calculator).| Band | µg/kg/exposure | 70 kg equiv | Rationale |
|---|---|---|---|
| Low | 0.25–0.5 µg/kg | 17.5–35 µg | At/below lowest studied IV challenge dose |
| Standard research challenge | 0.5–1.0 µg/kg | 35–70 µg | Clear GH response in this range |
| High research challenge | 1.0–2.0 µg/kg | 70–140 µg | Upper IV range; Cmax plateaus 1–2 µg/kg |
| Avoid / not modeled | >2.0 µg/kg | >140 µg | No therapeutic justification; ↑ endocrine adverse risk |
| Body weight | Low 0.25 µg/kg | Standard 0.5 µg/kg | Std-high 1.0 µg/kg | High 2.0 µg/kg |
|---|---|---|---|---|
| 55 kg | 13.75 µg | 27.5 µg | 55 µg | 110 µg |
| 65 kg | 16.25 µg | 32.5 µg | 65 µg | 130 µg |
| 75 kg | 18.75 µg | 37.5 µg | 75 µg | 150 µg |
| 85 kg | 21.25 µg | 42.5 µg | 85 µg | 170 µg |
| 95 kg | 23.75 µg | 47.5 µg | 95 µg | 190 µg |
| 105 kg | 26.25 µg | 52.5 µg | 105 µg | 210 µg |
| Trigger | Action | Rationale |
|---|---|---|
| IGF-1 above age-adjusted range | Hold or de-escalate | GH-axis overactivation concern |
| Edema, paresthesia, headache, BP rise | De-escalate or hold | GH/IGF-1 fluid-retention signal |
| Fasting glucose / A1c worsens | Hold and reassess | GH signaling can worsen insulin sensitivity |
| Prolactin elevation or symptoms | Hold and evaluate | Hexarelin stimulates PRL release |
| AM cortisol symptoms / HPA abnormality | Hold and evaluate | ACTH/cortisol co-release documented |
| Sleep apnea worsens | Stop / hold | GH/IGF-1 fluid effects may worsen airway |
| Active malignancy / unexplained mass | Hard stop | Growth-axis stimulation constraint |
| WADA-tested athlete | Hard stop | Prohibited at all times |
| No endpoint after adequate exposure | Stop, do not escalate indefinitely | Acute response ≠ unlimited escalation |
| Marker | Purpose | Validated? |
|---|---|---|
| IGF-1 | Downstream GH-axis exposure | No — context only |
| Fasting glucose / A1c | Metabolic safety | No |
| Fasting insulin / HOMA-IR | Research metabolic response | No |
| Prolactin | PRL co-release risk | Mechanistic, not protocol-validated (PRL) |
| AM cortisol / ACTH | HPA-axis signal | Mechanistic (ACTH/cortisol) |
| BP / resting HR | Fluid / cardiovascular safety | No |
| Sleep-apnea symptoms | GH-axis safety | No |
| GH stimulation labs | Endocrine response | Yes — challenge-testing context only |
0.5 µg/kg IV bolus, based on the human rising-dose study. Imbimbo 19940.5 → 1.0 → 2.0 µg/kg IV; GH response plateaued between 1 and 2 µg/kg in the Cmax data.2 mg / 2 mL = 1,000 µg/mL; 70 kg × 1 µg/kg = 70 µg = 0.07 mL.| IV dose | Mean GH Cmax | Interpretation |
|---|---|---|
| 0 (placebo) | 3.9 ng/mL | Baseline |
| 0.5 µg/kg | 26.9 ng/mL | Clear response |
| 1.0 µg/kg | 52.3 ng/mL | Strong response |
| 2.0 µg/kg | 55.0 ng/mL | Plateau vs 1 µg/kg |
| Pattern | Interpretation | Evidence |
|---|---|---|
| Robust GH peak | Intact somatotroph reserve | Preserved in idiopathic GHD |
| Reduced / absent peak | Hypothalamic-pituitary disease / stalk defect | Loche 1995 |
| Comparative testing | vs GHRH+pyridostigmine, arginine+estrogen | Guzzaloni 1999 |
5–10 µg/kg exposure model, because intranasal bioavailability was ~4.8%.5 → 10 → 20 µg/kg; pediatric long-term studies used higher repeat-dose intranasal models — do not generalize to adults without oversight. Rahim 1998| Finding | Detail | Grade |
|---|---|---|
| GH release | Intranasal hexarelin stimulated GH in pediatric/short-stature models | B |
| Bioavailability | ~4.8% — far below SC | B |
| Desensitization | Partial reversible attenuation with chronic use | B |
| Route | Biological bioavailability | Practical role |
|---|---|---|
| IV | 100% (reference) | Challenge / diagnostic |
| SC | ~64–77% | Primary research route |
| Intranasal | ~4.8% | Historical, variable |
| Oral | ~0.3% | Minimal systemic exposure |
| Point | Detail |
|---|---|
| Evidence | No located formal human IM PK/PD study |
| Assumption risk | IM ≠ SC kinetics by default |
| Default | SC is the modeled injectable route |
Educational/research math only. Hexarelin is not FDA-approved and protocol dosing is speculative. The GH response plateaus around 1–2 µg/kg, so higher doses add endocrine risk without added GH. Verify peptide purity, sterility, and storage; only use product from a licensed source.
Hexarelin is unapproved and no controlled combination trials exist. The pairings below reflect mechanistic complementarity and practice patterns, not validated protocols. Because hexarelin is the most potent classic GHRP with the strongest ACTH/cortisol and prolactin spillover, any combination magnifies endocrine risk and offers little benefit above its GH plateau. Combination use of investigational compounds requires physician oversight; hexarelin is WADA-prohibited for athletes.
| Component | Arm | Evidence |
|---|---|---|
| Hexarelin | GHSR-1a · Gq/PLC | B (GH arm) |
| Sermorelin / CJC-1295 | GHRH-R · Gs–cAMP | B/D (combo) |
| Agent | Selectivity | Role |
|---|---|---|
| Hexarelin | Potent, high spillover | Strongest GH |
| Ipamorelin | GH-selective | Cleaner alternative |
| Element | Detail | Grade |
|---|---|---|
| CD36 binding | 84 kDa cardiac protein; PI3K/Akt survival | P |
| Drug lineage | EP80317 (GH-free, anti-atherosclerotic) | P |
| Finding | Model | Grade |
|---|---|---|
| ↑ glucose/insulin tolerance | MKR mice | C |
| ↓ plasma/liver triglycerides | MKR mice | C |
| Marker | Purpose | Grade |
|---|---|---|
| IGF-1 / glucose | GH-axis & metabolic guard | D |
| Cortisol / prolactin | Spillover surveillance | D |
| Condition | Status |
|---|---|
| Active malignancy / GH excess | Absolute avoid |
| Uncontrolled diabetes | Avoid |
| WADA-tested athlete | Prohibited |
Hexarelin's safety signal is dominated by its broad endocrine reach: a potent GH/IGF-1 pulse, the most pronounced ACTH/cortisol and prolactin co-stimulation of the classic GHRPs, documented desensitization on repeated dosing, and the general GH-axis adverse pattern (edema, glucose effects, sleep-apnea aggravation). Long-term human safety is unstudied, and it is WADA-prohibited.
IGF-1, fasting glucose, HbA1c, fasting insulin (HOMA-IR), prolactin, AM cortisol/ACTH if risk, BP/HR, weight. Sleep-apnea screen. Pregnancy test if reproductive potential. Pituitary imaging if a mass is suspected. Document WADA status for athletes.
IGF-1 at baseline, 4–6 weeks, then cycle review (hold if above age-adjusted range); fasting glucose/A1c at cycle review; BP/edema weekly; prolactin and AM cortisol if symptomatic; sleep-apnea symptoms ongoing. None of these thresholds is validated specifically for hexarelin.
Hard-stop on pregnancy, active malignancy/unexplained mass, acromegaly/GH excess, or WADA-tested status. De-escalate on IGF-1 above range, new edema/carpal-tunnel, worsening glucose, prolactin or cortisol symptoms, or worsening sleep apnea. No measurable endpoint after adequate exposure is a reason to stop, not escalate.
| Condition | Concern | Severity · grade |
|---|---|---|
| Active malignancy / unexplained mass | Growth-axis stimulation concern | High |
| Acromegaly / elevated IGF-1 | May worsen GH/IGF-1 excess | High |
| Pituitary adenoma / endocrine tumor | Can alter GH/ACTH/PRL signaling | High |
| Cushing's syndrome / adrenal disease | HPA-axis stimulation risk | High |
| Hyperprolactinemia | PRL co-release may worsen issue | Moderate–High |
| Uncontrolled diabetes | GH-axis can worsen glucose handling | High |
| Severe untreated sleep apnea | GH/edema/fluid effects may worsen symptoms | Moderate–High |
| Pregnancy / lactation | No adequate safety data | High |
| Pediatric non-research use | Growth/endocrine-axis risk; specialist context only | High |
| WADA-tested athlete | Prohibited at all times | High |
| Severe insulin resistance / metabolic syndrome | Potential glycemic worsening | Caution |
| Known peptide hypersensitivity | Immunogenicity concern | Monitor |
| Non-sterile / unverified product | Compounding / endotoxin risk | Avoid |
| Concurrent corticosteroids | Compounded HPA-axis effects | Monitor |
| Proliferative diabetic retinopathy | Growth-factor concern | High |
| Carpal-tunnel / neuropathy history | GH/IGF-1 fluid-tissue effects | Monitor |
Hexarelin has moderate-quality human evidence for acute endocrine stimulation — especially GH release, with measurable ACTH/cortisol and prolactin co-effects — and a substantial preclinical cardiovascular program. It has weak-to-moderate evidence for repeated-use endocrine models and preclinical-only evidence for cardiometabolic, cardiovascular, renal, and tissue-protection claims. Missing: modern, adequately powered, indication-specific RCTs with validated dosing and clinical outcomes.
Double-blind, placebo-controlled rising-dose study in 12 healthy men: IV 0.5/1/2 µg/kg produced dose-dependent GH increases (mean Cmax 26.9/52.3/55.0 ng/mL), peaking ~30 min, with a GH-response half-life ~55 min. The foundational human PD characterization.
Compared GH-releasing activity across four routes in man, establishing the dramatic bioavailability hierarchy: SC high (~64–77%) versus intranasal (~4.8%) and oral (~0.3%) — the basis for SC being the practical research route.
Formal PK study reporting elimination half-life ~75.9 ± 9.3 min, clearance ~7.6 ± 0.7 mL/min/kg, Vss ~744 ± 81 mL/kg, SC bioavailability ~64%, and no accumulation across the studied dose range.
In 15 healthy young men, hexarelin stimulated the hypothalamic-pituitary-adrenal axis (ACTH/cortisol), compared against CRH and desmopressin — establishing the adrenal-axis spillover that distinguishes hexarelin's risk profile.
Characterized hexarelin's ACTH/cortisol secretion relative to CRH and vasopressin, showing a distinct GHRP-mediated central pathway for HPA-axis activation rather than simple CRH mimicry.
Documented age-related variation in the GH, prolactin, ACTH, and cortisol responses to hexarelin in normal subjects — confirming the multi-hormone, non-selective endocrine signature of the peptide.
In patients with active acromegaly or pathological hyperprolactinaemia, hexarelin produced PRL and GH responses that differed by disease state — informing how the peptide behaves when pituitary regulation is already disordered.
Long-term hexarelin therapy showed partial, reversible attenuation of the GH response over time (desensitization), with growth/IGF-1 signals reported — the key evidence that chronic GHRP dosing downregulates responsiveness.
Demonstrated GH-releasing activity by intranasal administration of hexarelin in pediatric/short-stature contexts, compared with IV — one of the route studies establishing intranasal activity at much lower potency than injection.
In 27 short-stature subjects, compared the hexarelin-induced GH response (IV 1 and 2 µg/kg) against GHRH+pyridostigmine and arginine+estrogen — positioning hexarelin among standard provocative GH tests.
GH response to hexarelin was preserved in idiopathic GH deficiency but reduced or absent in hypothalamic disease and stalk defects — supporting its use as a probe that distinguishes pituitary from hypothalamic pathology.
Identified CD36 (an 84 kDa cardiac glycoprotein in cardiomyocytes and microvascular endothelium) as the binding protein mediating hexarelin's cardiovascular action; the coronary response was abolished in CD36-knockout hearts — proof of a GH-independent cardiac mechanism.
Synthesis of preclinical cardioprotection across fibrosis, ischemic heart disease, cardiac dysfunction, and atherosclerosis models, framing hexarelin's GH-independent CD36/GHSR cardiovascular pharmacology.
In non-obese insulin-resistant MKR mice, hexarelin improved glucose/insulin intolerance and reduced plasma and liver triglycerides — preclinical metabolic signal, not validated human therapy.
Investigated hexarelin's anti-apoptotic, tissue-protective pathways in an ischemic acute-kidney-injury model — extending the CD36/GHSR cytoprotection hypothesis beyond the heart, at a preclinical level.
Reported the acute cardiovascular and hormonal effects of GH and hexarelin in humans — early human evidence that hexarelin has direct cardiovascular activity alongside its GH-releasing action, foreshadowing the CD36 mechanism.
In neonatal rat cardiomyocytes, hexarelin markedly reduced angiotensin-II-induced apoptosis and DNA fragmentation, inhibiting caspase-3 and Bax while upregulating Bcl-2 and GHS-R — a cellular basis for its anti-remodeling cardioprotection.
In an in-vivo rat I/R model, SC hexarelin (100 µg/kg/day) improved systolic function and cardiomyocyte survival, modulating IL-1β/IL-1Ra through cardiac GHSR-1a — effects slightly superior to equimolar ghrelin and blocked by a GHSR antagonist.
The hexarelin-derived azapeptide EP80317, which lacks GH-releasing activity, reduced atherosclerosis in apoE-knockout mice via CD36 — cutting modified-LDL uptake and upregulating cholesterol-efflux genes — proving the cardiovascular biology is CD36-mediated and GH-independent.
Hexarelin is the potency leader of the classic GHRPs and the one with the deepest cardiovascular research, but also the broadest off-target endocrine spillover. GHRP-2 gives high peak GH with a diagnostic history; GHRP-6 has the strongest appetite; ipamorelin is the GH-selective "clean" option; the GHRH analogs (sermorelin, CJC-1295) work through the complementary receptor arm.
| Agent | Mechanism class | Primary position | Routes | Human evidence | Status |
|---|---|---|---|---|---|
| Hexarelin | GHSR-1a agonist + CD36 | Most potent classic GHRP; CD36 cardiac research | IV · SC · IN · oral | Human endocrine challenge + preclinical cardio | Not FDA-approved; WADA-banned |
| GHRP-2 / Pralmorelin | GHSR-1a agonist | High peak GH; Japan diagnostic | IV · nasal · SC | Human PD + Japan diagnostic | Japan diagnostic; not FDA; WADA-banned |
| GHRP-6 | GHSR-1a agonist + CD36 | Strongest appetite; original GHRP | IV · oral · SC | Human acute endocrine + PK | Not FDA; FDA 503B Cat 2; WADA-banned |
| Ipamorelin | GHSR-1a agonist (selective) | GH-selective; minimal ACTH/PRL/appetite | SC | Human/animal PD | Not FDA; FDA 503B Cat 2; WADA-banned |
| MK-677 / Ibutamoren | Oral non-peptide GHSR-1a agonist | Oral, long-acting; sustained IGF-1 | Oral | Human trials (incl. long-term) | Not FDA-approved; WADA-banned |
| Sermorelin | GHRH-receptor agonist | Physiologic GH; Dx/pediatric pedigree | SC · IV (Dx) | Human pharmacology + pediatric trials | Was FDA-approved (Geref); compounded |
| CJC-1295 | GHRH analog | Longer-acting GHRH stimulation | SC | PK studies | Not FDA-approved; WADA-banned |
Evidence grades reflect the strength of support for the specific claim cited, not the prestige of the journal. Hexarelin's human IV dose-response, route-comparison, HPA-axis, and PK studies are its firmest evidence; the CD36 identification and cardiovascular reviews support specific mechanism and tissue-protection claims at a preclinical level.