GHRP-2 — identity, handling and published literature

GHRP-2, also known as pralmorelin, is a synthetic six-residue growth hormone secretagogue peptide, supplied for laboratory use as a sterile lyophilised powder for reconstitution.

Presentation and physical properties

GHRP-2 is a synthetic hexapeptide amide incorporating three non-proteinogenic features: two D-configuration alanine and phenylalanine residues, a D-2-naphthylalanine residue at position two, and a C-terminal carboxamide in place of a free carboxylic acid. It is not a fragment or analogue of any human protein; it is a wholly synthetic sequence arrived at through structure–activity work on the growth hormone-releasing peptide series, of which GHRP-6 was the first member studied.

The material is normally presented as a white to off-white lyophilised cake or powder, most commonly as the acetate salt. The molecular formula and mass recorded below are those of the free base; an acetate or trifluoroacetate counter-ion adds to the mass of the supplied solid, so a vial’s nominal peptide content and its gross weight are not the same figure. Peptide content is conventionally established by amino acid analysis or by a nitrogen determination rather than inferred from the weight of the cake.

The peptide is freely soluble in water and in aqueous bacteriostatic diluents. The three aromatic residues — naphthylalanine, tryptophan and phenylalanine — give the molecule appreciable ultraviolet absorbance near 280 nm, which is the basis of routine chromatographic quantification. Lyophilised cakes of this size are markedly hygroscopic and pick up atmospheric moisture rapidly once a vial is opened to room air.

Reconstitution arithmetic

Reconstitution is a dilution calculation and nothing more. The concentration of a reconstituted vial is the peptide mass in the vial divided by the volume of diluent added:

concentration (mg/mL) = vial content (mg) ÷ diluent volume (mL)

The mass of the lyophilised solid does not change when diluent is added. Adding more diluent does not add or remove peptide; it only distributes the same mass through a larger volume, so the concentration falls in exact inverse proportion to the volume. The tables below work that arithmetic through for two vial sizes commonly encountered in the literature and in laboratory supply. The final column expresses the same figure per 0.01 mL, because 0.01 mL is one graduation on a U-100 syringe barrel — that is a statement about the graduations on a piece of glassware, not a recommendation of any amount.

5 mg vial

10 mg vial

Two arithmetic points are worth stating explicitly. First, the figures above assume the stated vial content is peptide mass rather than gross salt mass; where a certificate reports peptide content as a percentage of gross weight, that percentage must be applied before the division. Second, the displaced volume of the lyophilised solid itself is small at these masses but is not zero, so a vial reconstituted to a marked volume and a vial reconstituted with a measured volume of diluent are not identical preparations. For analytical work the difference is resolved by preparing to a final volume in a volumetric vessel rather than by adding a measured volume to the vial.

This section gives concentration only. It does not state, imply or support any quantity of this substance for administration to any organism.

Storage and stability

As supplied, the lyophilised solid is the stable form. General practice for synthetic peptides of this class is storage of the sealed lyophilised vial at −20 °C or below, protected from light and from moisture, with desiccation maintained. Short periods at 2–8 °C and brief excursions to ambient temperature during shipping are ordinarily tolerated by the dry solid; it is the reconstituted solution that is the fragile state.

Once in solution the peptide is subject to the ordinary degradation routes of a tryptophan-containing sequence: oxidation of the indole side chain, which is accelerated by light and by dissolved oxygen, and slow hydrolytic cleavage. Refrigeration at 2–8 °C, exclusion of light, and avoidance of repeated freeze–thaw cycling are the standard mitigations. Where a solution must be held beyond short-term refrigeration, aliquoting into single-use portions before freezing avoids the cumulative damage that repeated cycling causes.

The D-amino acid substitutions and the C-terminal amide were introduced into this series specifically to resist enzymatic degradation, and they do confer resistance to the exopeptidases that would rapidly clear an all-L sequence. They confer no protection against oxidation or against non-enzymatic hydrolysis, and they are therefore not a reason to relax handling of the reconstituted material.

Bacteriostatic diluents containing benzyl alcohol permit multiple withdrawals from a single vial over a limited period; sterile water without a preservative does not, and a vial reconstituted with unpreserved water should be treated as single-use. The choice of diluent is a microbiological question rather than a chemical one — neither diluent alters the arithmetic in the preceding section.

Analytical identity

Identity of a GHRP-2 preparation rests on three independent determinations, and a certificate reporting only one of them establishes correspondingly less.

Chromatographic purity is conventionally established by reversed-phase HPLC with ultraviolet detection, exploiting the strong absorbance of the naphthylalanine and tryptophan residues near 280 nm and the general peptide-bond absorbance near 214 nm. A purity figure from RP-HPLC is a statement about the proportion of ultraviolet-absorbing material eluting in the main peak; it says nothing about non-absorbing contaminants such as residual salts, counter-ions or water, which is why peptide content is a separate determination from chromatographic purity.

Mass determination by electrospray ionisation mass spectrometry confirms the molecular mass against the expected 818.0 for the free base. Because the molecule carries a lysine side chain and a free N-terminal amine, both singly and multiply protonated species are ordinarily observed.

Sequence confirmation requires tandem mass spectrometry. This matters more for GHRP-2 than for a typical peptide, because mass alone cannot distinguish the correct sequence from a rearrangement of the same residues, and cannot distinguish D- from L-configuration at any position at all. Stereochemical verification requires chiral amino acid analysis after hydrolysis, which is not part of a routine certificate.

The published analytical literature bears directly on this. Okano and colleagues developed a solid-phase extraction and liquid chromatography–tandem mass spectrometry method for pralmorelin and an identified metabolite in human urine, using a stable-isotope-labelled GHRP-2 internal standard, reporting recoveries of 84–101% and intra- and inter-day precisions of 1.6–3.8% and 1.9–4.3% respectively [8]. Separately, Popławska and Błażewicz analysed a seized injection vial by liquid chromatography and high-resolution tandem mass spectrometry and identified its contents not as GHRP-2 but as a previously unreported heptapeptide of molecular mass 874.02 Da — a glycine analogue of GHRP-2 [12]. That finding is the clearest published demonstration that material presented as GHRP-2 in an unregulated supply chain may be a structurally distinct compound with no literature of its own, and it is the reason sequence confirmation rather than mass alone is the relevant test.

What the published literature investigated

In vitro and receptor pharmacology

GHRP-2 is characterised in the literature as an agonist at the growth hormone secretagogue receptor GHS-R1a, the receptor subsequently identified as the endogenous target of ghrelin. Work in cultured rat anterior pituitary cells formed part of the pharmacological characterisation reported by Doi and colleagues [6]. The receptor pharmacology of the growth hormone-releasing peptide series, including the position of GHRP-2 within it, is reviewed by Ghigo and colleagues [1].

Animal studies

Doi and colleagues reported a multi-model pharmacological characterisation of KP-102, the development designation for GHRP-2, in conscious and pentobarbital-anaesthetised rats, hypophysectomised rats, median eminence-lesioned rats, conscious dogs and cultured rat anterior pituitary cells [6]. The authors reported that growth hormone-releasing activity in conscious animals exceeded that of exogenously injected growth hormone-releasing hormone, that the response showed reduced sensitivity to suppression by endogenous somatostatin relative to GHRH, and that activity was retained in conscious dogs where GHRH was reported ineffective. The same report described stimulation of ACTH and corticosterone secretion but not prolactin, and reported growth acceleration and modest body weight gain over three weeks of administration in normal and monosodium glutamate-treated rats.

Human trials

The human literature on GHRP-2 is unusually substantial for a compound in this category, and it divides into two distinct bodies of work.

The first is a set of early administration studies. Pihoker and colleagues conducted a phase I pharmacokinetic and pharmacodynamic study in ten prepubertal children of mean age 7.7 years, reporting characterisation of pharmacokinetic parameters following a single intravenous administration [3]. The same group reported an intranasal study in fifteen children of short stature, reporting an increase in growth velocity from 3.7 ± 0.2 cm/year to 6.1 ± 0.3 cm/year at six months, a significant rise in growth hormone-binding protein concentrations, and no meaningful change in IGF-1 [2]. Bowers and Granda-Ayala reported acute and chronic studies in ten older men and women with decreased growth hormone secretion and low serum IGF-1, and reported that a thirty-day continuous subcutaneous infusion of GHRP-2 was associated with restoration of pulsatile growth hormone secretion and elevated serum IGF-1 sustained across the study period [4].

Laferrère and colleagues conducted a crossover study in seven lean healthy men, comparing subcutaneous GHRP-2 infusion against saline over 270 minutes followed by a buffet meal, and reported that participants consumed 35.9 ± 10.9% more when infused with GHRP-2 than with saline, with the increase observed in every participant [7]. The authors framed the finding as establishing GHRP-2 as a research tool for studying appetite regulation in humans.

The second and much larger body of work concerns GHRP-2 as a diagnostic stimulation agent, and it exists because GHRP-2 holds a national marketing authorisation in Japan for exactly that purpose. Kinoshita and colleagues compared the arginine and GHRP-2 tests against the insulin tolerance test in 71 pre-operative adult patients with pituitary tumours, reporting sensitivities of 93.8% and 81.3% and specificities of 85.5% and 94.5% for the arginine and GHRP-2 tests respectively in identifying severe growth hormone deficiency [9]. Arimura and colleagues evaluated 47 patients using the insulin tolerance test, CRH stimulation test and GHRP-2 test, reporting 88.9% specificity and 89.7% sensitivity for secondary hypoadrenalism at a cortisol cut-off of 11.6 µg/dL, and concluded the test had diagnostic value comparable to CRH stimulation but inferior to the insulin tolerance test for assessing the hypothalamic-pituitary-adrenal axis [10]. Suzuki and colleagues reported on 36 patients with hypothalamic-pituitary disorders, describing 83% sensitivity and 88% specificity for screening pituitary adrenal insufficiency from the ACTH response [13]. Teramoto and colleagues retrospectively analysed 65 patients aged 65 or over with non-functioning pituitary neuroendocrine tumours, identifying an optimal growth hormone cut-off of 8.08 ng/mL for predicting adrenocortical function [14]. Onuki and colleagues retrospectively examined 23 post-pubertal adolescents tested between 2010 and 2023, reporting median growth hormone peaks of 88.9 and 90.1 ng/mL in idiopathic growth hormone deficiency and short stature groups against 3.4 ng/mL in an organic or genetic deficiency group, and suggested existing diagnostic criteria may require adjustment for adolescents [15].

Reviews

Ghigo and colleagues reviewed the growth hormone-releasing peptide class including mechanism, receptor characteristics, routes and clinical investigation [1]. A 2004 development profile in Drugs R&D summarised the regulatory and commercial history of pralmorelin, including the discontinuation of United States development and the planned Japanese diagnostic approval [5]. Sigalos and Pastuszak reviewed the growth hormone secretagogue class more broadly, covering growth hormone-releasing peptides and the orally available small molecule ibutamoren mesylate [11].

Evidence gaps and limitations

Human trials of GHRP-2 itself exist, and that is a genuine distinction from most compounds in this category. What follows are the limits of that literature, stated without softening.

The administration studies are very small. The phase I study enrolled ten children [3]; the intranasal study fifteen [2]; the chronic infusion study ten [4]; the food intake study seven [7]. None of these is powered to detect anything but a large effect, and none carries a safety database of a size that would support conclusions about uncommon adverse events.

The large Japanese literature is not evidence of what GHRP-2 does over time. Those studies administer a single stimulation dose to provoke a measurable pituitary response, and they measure the diagnostic performance of that provocation — its sensitivity and specificity against a reference test. They are studies of a diagnostic procedure, and they tell one nothing about repeated administration, about duration of exposure beyond minutes to hours, or about any outcome other than the assay reading. Counting them as a long human safety record would be a category error.

The longest human exposure identified in this literature is the thirty-day continuous infusion reported by Bowers and Granda-Ayala in ten subjects [4]. There is no published long-term controlled trial. The intranasal paediatric study followed participants for six to twenty-four months but was uncontrolled and enrolled fifteen children [2].

Development for a therapeutic indication was not completed. The 2004 development profile records that United States development with Wyeth was discontinued, and that Japanese activity proceeded towards a diagnostic approval rather than a treatment authorisation [5]. The compound therefore has no phase III efficacy programme in any indication anywhere, and the only regulatory approval it holds is for single-dose diagnostic use.

Two pharmacological findings in the animal literature are relevant limitations rather than incidental observations: Doi and colleagues reported stimulation of ACTH and corticosterone alongside growth hormone [6], and the human diagnostic literature is built substantially on that same ACTH and cortisol response [10][13]. GHRP-2 is not selective for growth hormone release, and the diagnostic literature is direct evidence of that in humans.

Finally, the identity of unregulated material cannot be assumed. A seized vial presented as a growth hormone-releasing peptide was found on analysis to contain a glycine analogue of GHRP-2 rather than GHRP-2 [12]. No published literature of any kind describes that analogue’s properties.

Regulatory and standards position

United Kingdom. GHRP-2 holds no marketing authorisation from the MHRA. It is not a controlled drug: it does not appear in any Schedule of the Misuse of Drugs Act 1971 or the Misuse of Drugs Regulations 2001, which distinguishes it from somatropin, a Class C controlled drug. Its supply is nonetheless constrained by the Human Medicines Regulations 2012. Under MHRA Guidance Note 8 and the doctrine of a medicinal product by presentation, it is a claim rather than a molecule that brings a substance within the definition of a medicinal product — so a preparation offered with any statement about treating, preventing or affecting a physiological condition may be a medicinal product by presentation irrespective of how the vial is labelled.

European Union. No centralised marketing authorisation exists from the European Medicines Agency, and the substance is not authorised as a medicinal product in the EU.

United States. GHRP-2 is not an FDA-approved drug and holds no marketing authorisation for any indication. Development in the United States was discontinued [5].

Japan. This is the exception, and it is the single most consequential regulatory fact about this compound. Pralmorelin hydrochloride was approved by the Pharmaceuticals and Medical Devices Agency in October 2004 and is marketed by Kaken Pharmaceutical as a single-dose intravenous diagnostic agent for the assessment of growth hormone secretory capacity in adults and in children over four years of age. This is the only national marketing authorisation held by any member of the growth hormone-releasing peptide series, and it is a diagnostic authorisation, not a treatment authorisation. The extensive Japanese clinical literature summarised above exists because of it.

Anti-doping. GHRP-2 is prohibited under the World Anti-Doping Agency Prohibited List at section S2.2.4, Growth Hormone Releasing Factors, where it is named explicitly as “GHRP-2 (pralmorelin)” among the growth hormone-releasing peptides. The prohibition applies at all times — both in-competition and out-of-competition. It sits alongside the other named GHRPs (alexamorelin, examorelin/hexarelin, GHRP-1, GHRP-3, GHRP-4, GHRP-5 and GHRP-6) and the secretagogues and ghrelin mimetics in the same subsection, including anamorelin, ibutamoren, ipamorelin, macimorelin and tabimorelin. Its approved status in Japan confers no exemption from that prohibition. Validated detection is established: a published LC-MS/MS method identifies unchanged pralmorelin and a specific metabolite in urine following administration [8].

Documented enforcement and market adulteration. A GHRP-2 preparation seized as an injection vial was analysed and reported to contain a glycine analogue of GHRP-2 rather than the labelled substance, the authors noting that such a modification “may indicate a new approach to circumvent a detection of doping practices” [12]. This is a published, peer-reviewed record of an unregulated GHRP-2 product proving on analysis not to be GHRP-2.

Laboratory handling and safety

GHRP-2 is a research chemical and should be handled under the general controls applied to biologically active synthetic peptides of unknown occupational hazard. No occupational exposure limit has been established for it, and the absence of a limit should be read as an absence of data rather than as evidence of safety.

The lyophilised solid is a fine powder capable of becoming airborne when a vial is opened or a stopper disturbed. Weighing and transfer of the dry solid are appropriately performed in a containment enclosure or, at minimum, with local exhaust ventilation. Nitrile gloves, safety spectacles and a laboratory coat are the ordinary minimum for handling either the solid or reconstituted solutions.

Vials should be brought to ambient temperature before opening. Opening a vial straight from −20 °C draws moist air onto a cold hygroscopic cake, and the condensation that results both degrades the material and makes the recorded mass unreliable. Diluent should be introduced down the vial wall rather than directed into the cake, and dissolution allowed to proceed by gentle swirling or standing; vigorous agitation of peptide solutions promotes interfacial denaturation and foaming, and foaming itself causes loss of material to the vial walls.

Reconstituted solutions, contaminated consumables and unused material should be disposed of as chemical waste in accordance with local arrangements, not to drain. Where sharps are used in the course of transfer or analysis, they are handled and disposed of under standard sharps protocol. Institutional risk assessment and COSHH assessment should be completed before first use.

Nothing in this section constitutes guidance on administering this substance to any human or animal subject. It concerns handling the material as a laboratory chemical.

References

1. Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. European Journal of Endocrinology. 1997;136(5):445–60. Review. PMID 9186261
2. Pihoker C, Badger TM, Reynolds GA, Bowers CY. Treatment effects of intranasal growth hormone releasing peptide-2 in children with short stature. Journal of Endocrinology. 1997;155(1):79–86. Human trial. PMID 9390009
3. Pihoker C, Kearns GL, French D, Bowers CY. Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a phase I study in children. Journal of Clinical Endocrinology and Metabolism. 1998;83(4):1168–72. Human trial. PMID 9543135
4. Bowers CY, Granda-Ayala R. Growth hormone/insulin-like growth factor-1 response to acute and chronic growth hormone-releasing peptide-2, growth hormone-releasing hormone 1-44NH2 and in combination in older men and women with decreased growth hormone secretion. Endocrine. 2001;14(1):79–86. Human trial. PMID 11322505
5. Pralmorelin: GHRP 2, GPA 748, growth hormone-releasing peptide 2, KP-102 D, KP-102 LN, KP-102D, KP-102LN. Drugs in R&D. 2004;5(4):236–9. Review (no authors listed). PMID 15230633
6. Doi N, Hirotani C, Ukai K, Shimada O, Okuno T, Kurasaki S, Kiyofuji T, Ikegami R, Futamata M, Nakagawa T, Ase K, Chihara K. Pharmacological characteristics of KP-102 (GHRP-2), a potent growth hormone-releasing peptide. Arzneimittelforschung. 2004;54(12):857–67. Rodent, canine and in vitro. PMID 15646370
7. Laferrère B, Abraham C, Russell CD, Bowers CY. Growth hormone releasing peptide-2 (GHRP-2), like ghrelin, increases food intake in healthy men. Journal of Clinical Endocrinology and Metabolism. 2005;90(2):611–4. Human trial. PMID 15699539
8. Okano M, Sato M, Ikekita A, Kageyama S. Determination of growth hormone secretagogue pralmorelin (GHRP-2) and its metabolite in human urine by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Communications in Mass Spectrometry. 2010;24(14):2046–56. Human, analytical method development. PMID 20552695
9. Kinoshita Y, Tominaga A, Usui S, Arita K, Sakoguchi T, Sugiyama K, Kurisu K. The arginine and GHRP-2 tests as alternatives to the insulin tolerance test for the diagnosis of adult GH deficiency in Japanese patients: a comparison. Endocrine Journal. 2013;60(1):97–105. Human trial. PMID 23079545
10. Arimura H, Hashiguchi H, Yamamoto K, Shinnakasu A, Arimura A, Kikuchi A, Deguchi T, Habu M, Fujio S, Arita K, Nishio Y. Investigation of the clinical significance of the growth hormone-releasing peptide-2 test for the diagnosis of secondary adrenal failure. Endocrine Journal. 2016;63(6):533–44. Human trial. PMID 27020037
11. Sigalos JT, Pastuszak AW. The safety and efficacy of growth hormone secretagogues. Sexual Medicine Reviews. 2018;6(1):45–53. Review. PMID 28400207
12. Popławska M, Błażewicz A. Identification of a novel growth hormone releasing peptide (a glycine analogue of GHRP-2) in a seized injection vial. Drug Testing and Analysis. 2019;11(1):162–7. Analytical, seized material. PMID 30051972
13. Suzuki S, Ruike Y, Ishiwata K, Naito K, Igarashi K, Ishida A, Fujimoto M, Koide H, Horiguchi K, Tatsuno I, Yokote K. Clinical usefulness of the growth hormone-releasing peptide-2 test for hypothalamic-pituitary disorder. Journal of the Endocrine Society. 2022;6(8):bvac088. Human trial. PMID 35795807
14. Teramoto S, Tahara S, Hattori Y, Kondo A, Morita A. Assessment of anterior pituitary reserve capacity based on growth hormone response to growth hormone-releasing peptide-2 test in the elderly. Growth Hormone & IGF Research. 2023;71:101545. Human trial. PMID 37295337
15. Onuki T, Tadokoro H, Sawano K, Shibata N, Nyuzuki H, Ogawa Y, Okada M, Sone H, Nagasaki K. Robust growth hormone responses to GH-releasing peptide 2 in adolescents. Journal of Pediatric Endocrinology and Metabolism. 2024;37(8):730–3. Human trial. PMID 38958228

Research use only

GHRP-2 is supplied and described here strictly as a chemical reference substance for laboratory research. It is not a medicine, not a dietary supplement, not a cosmetic and not a food. It holds no marketing authorisation in the United Kingdom, the European Union or the United States, and it is not authorised for human or veterinary use in any of those territories. Its sole national approval, in Japan, is a single-dose diagnostic authorisation held by a licensed pharmaceutical manufacturer and does not extend to material supplied for research.

Nothing in this entry is a recommendation to administer this substance to any human or animal subject, and nothing here states or implies that it treats, prevents or affects any disease or condition. Reports of findings above are statements about what particular published studies recorded; they are not claims about what the compound does. Research involving this substance is the responsibility of the investigator and should proceed only under appropriate institutional review, risk assessment and regulatory approval.

GHRP-2 is prohibited at all times in sport under section S2.2.4 of the World Anti-Doping Agency Prohibited List, and validated urinary detection methods are published.