GHRP-2

Overview

GHRP-2 (generic name pralmorelin; development codes KP-102 and GPA-748) is a synthetic hexapeptide that acts as an agonist of the ghrelin / growth-hormone-secretagogue receptor (GHS-R1a). It belongs to the family of growth-hormone-releasing peptides (GHRPs) that also includes GHRP-6 and hexarelin. Like the endogenous hormone ghrelin, GHRP-2 binds GHS-R1a and triggers a strong, transient pulse of growth hormone (GH) release from the pituitary.

GHRP-2 is notable as essentially the only GHRP to have obtained any regulatory approval: in Japan it is marketed by Kaken Pharmaceutical as pralmorelin (brand name "GHRP Kaken 100"), a single-dose diagnostic agent used to provoke GH release when assessing growth hormone deficiency. It is not approved as a therapeutic drug in the United States, the European Union, or other major markets, and it is not approved anywhere for anti-aging, body-composition, or performance uses.

A defining contrast with the more selective ipamorelin is that GHRP-2 is not GH-selective: in human studies it also modestly raises ACTH, cortisol, and prolactin, and it reliably increases appetite and food intake.

Chemistry and structure

GHRP-2 is a small, fully synthetic peptide built partly from D-configured and non-natural amino acids, which contribute to receptor activity and metabolic stability relative to naturally occurring peptides.

The sequence includes D-2-Nal (D-2-naphthylalanine), D-Phe (D-phenylalanine), and D-Ala (D-alanine). These residues distinguish GHRP-2 from endogenous ghrelin, which is a 28-residue peptide that carries an essential octanoyl (acyl) modification. GHRP-2 requires no acylation to activate the receptor. The drug substance used in the Japanese diagnostic product is the dihydrochloride salt, which has a higher formula weight than the free base.

Mechanism of action

GHRP-2 binds and activates GHS-R1a, the receptor for endogenous ghrelin, which is expressed in the anterior pituitary and the hypothalamus. Activation drives the release of stored GH from pituitary somatotrophs, producing a discrete GH pulse rather than a sustained elevation. In animal models (KP-102 / GHRP-2), its GH-releasing activity acted at both hypothalamic and pituitary sites and was more potent than exogenously injected growth-hormone-releasing hormone (GHRH).

This mechanism is distinct from that of GHRH analogs such as CJC-1295 and tesamorelin, which act on the separate GHRH receptor. Because the two receptor pathways are complementary, ghrelin-receptor agonists and GHRH analogs are frequently discussed together in research on the GH/IGF-1 axis.

A key pharmacological point is that GHRP-2 is not selective for GH. Beyond GH release, GHS-R1a activation and downstream signaling also engage:

• the HPA axis, producing modest, transient rises in ACTH and cortisol; and
• prolactin secretion (a slight increase); and
• appetite, consistent with ghrelin's role in stimulating hunger and food intake.

Animal work (Hirotani et al., 2005) suggested the ACTH-releasing activity of GHRP-2 in rats is mediated mainly through release of corticotropin-releasing factor (CRF), while human data in pituitary-disorder patients (Kimura et al., 2010) provided evidence that GHRP-2 can also stimulate ACTH more directly.

Research and evidence

It is useful to separate animal/pharmacology data from the human clinical evidence.

Animal and in-vitro evidence

• Potency and characterization (Doi et al., 2004). Pharmacological characterization of KP-102 (GHRP-2) showed potent GH release acting at both hypothalamic and pituitary sites, more potent than exogenous GHRH in conscious rats.
• HPA-axis mechanism (Hirotani et al., 2005). In rats, the ACTH-releasing activity of KP-102 (GHRP-2) appeared to be mediated mainly by release of CRF, consistent with hypothalamic involvement in its cortisol-related effects.

Human evidence

• Hormone profile in man (Arvat et al., 1997). In healthy young adults, intravenous GHRP-2 produced a GH response stronger than maximal-dose GHRH, while also producing modest increases in prolactin, ACTH, and cortisol. The prolactin effect was lower than that of TRH, and the ACTH/cortisol effect was comparable to that of human CRH.
• Appetite (Laferrère et al., 2005). In a randomized, double-blind crossover study, seven lean healthy men ate roughly 36% more at an ad libitum meal after GHRP-2 infusion than after saline, confirming a ghrelin-like appetite-stimulating effect in humans.
• Diagnostic use. GHRP-2 is used as a provocative stimulus for GH secretion. In Japan it is approved (as pralmorelin) for GH-deficiency testing; published cutoffs have been used to distinguish GH-sufficient from GH-deficient individuals, and the test avoids the hypoglycemia of the insulin tolerance test.

There are no large, long-term, controlled human trials supporting GHRP-2 as a therapy for anti-aging, body composition, athletic performance, or other popularly marketed uses; its established human role is as a diagnostic GH stimulus.

Safety and risks

Human exposure data come largely from single-dose diagnostic use and small pharmacodynamic studies. In those settings, single diagnostic doses have generally been described as tolerated. However, GHRP-2's broader hormonal activity raises specific considerations:

• Cortisol and ACTH. GHRP-2 modestly and transiently raises ACTH and cortisol, engaging the stress-hormone (HPA) axis. This contrasts with the selectivity reported for ipamorelin, which spares ACTH/cortisol in studies. Repeated or chronic stimulation of this axis is not well characterized.
• Prolactin. A slight increase in prolactin has been reported in human studies.
• Appetite and food intake. GHRP-2 reliably increases hunger and caloric intake in humans, which is relevant to any chronic use.
• GH/IGF-1 axis. As a GH secretagogue, class-level concerns associated with raising GH/IGF-1 signaling (for example, effects on glucose handling, insulin sensitivity, fluid retention, or the theoretical unmasking of occult conditions) are relevant considerations.
• Long-term safety. Published human data center on single-dose or short-term use. Long-term safety of repeated GHRP-2 administration in humans is not established.
• Product quality. Material sold as "GHRP-2" in the research-chemical market is not subject to pharmaceutical quality control; purity, identity, and sterility cannot be assumed.

This section is descriptive, not a safety endorsement, and no dosing guidance is provided.

Regulatory status

• Japan. Pralmorelin (GHRP-2) is approved as a diagnostic agent for assessing growth hormone deficiency, marketed by Kaken Pharmaceutical (brand "GHRP Kaken 100"). This is a diagnostic indication (provoking a GH response for testing), not a therapeutic approval.
• United States. Not FDA-approved for any indication, therapeutic or diagnostic. Distributed as a research chemical and commonly labeled "not for human consumption."
• European Union. Not EMA-approved for any indication.
• General. The Japanese diagnostic approval does not translate into therapeutic approval elsewhere; outside that specific diagnostic context there is no recognized human-therapeutic channel for GHRP-2 in most jurisdictions.

How it compares

GHRP-2 is one of several agents that raise GH through related but distinct mechanisms. The comparison below is factual and not a recommendation.

The principal point of contrast: GHRP-2 and ipamorelin act at the same receptor, but GHRP-2 is the less selective of the two, additionally engaging the cortisol/prolactin and appetite pathways, whereas ipamorelin was characterized specifically for sparing those. GHRH analogs such as CJC-1295 and tesamorelin act on a different receptor entirely.

Legal status

• Anti-doping (sport). GHRP-2 is prohibited at all times (in and out of competition) under the World Anti-Doping Agency (WADA) Prohibited List, within Section S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics), which explicitly covers growth hormone secretagogues and ghrelin-receptor agonists/mimetics. Athletes in WADA-governed sport must not use it.
• United States. Not FDA-approved; sold as a research chemical.
• General. Regulatory and legal status varies by country. Japan's diagnostic approval is an exception specific to that use; it does not create a legitimate therapeutic channel elsewhere.

Common misconceptions