GHRP-6 and GHRP-2 are real pharmacology with a real legacy. GHRP-6 predicted a receptor in 1984, the receptor predicted a hormone, and that hormone, ghrelin, produced approved drugs for GH-deficiency testing and cancer cachexia. The GHRPs themselves raise prolactin, ACTH and cortisol as well as GH, and FDA lists both among bulk substances that may present safety risks in compounding.
Key points
- GHRP-6 was described in 1984 as a hexapeptide that releases GH specifically and in a dose-related way, before its receptor was known [1].
- Merck cloned the secretagogue receptor (GHS-R) in 1996 and concluded that these compounds mimicked an as-yet-undiscovered hormone [3].
- In 1999 that hormone was identified: ghrelin, a 28-amino-acid gastric peptide that was associated with increased food intake in humans [4][5].
- The class produced real drugs: pralmorelin (GHRP-2) as a diagnostic agent in Japan, macimorelin approved by the FDA in 2017, and anamorelin approved in Japan for cancer cachexia [8][9][12].
- GHRPs are not fully selective. They also raise prolactin, ACTH and cortisol, and increase appetite [2][6][13].
US status (October 2026): See the peptide status tracker.
A hexapeptide arrived before its hormone
In the early 1980s, endocrinologist Cyril Bowers’ group was working with small synthetic peptides. In 1984 it published the activity of a hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, now known as GHRP-6. It released growth hormone (GH) specifically and in a dose-related way, without releasing LH, FSH, TSH or prolactin in the models studied [1]. It was active in rats, monkeys, lambs and calves. After intravenous injection GH rose within 2 minutes and peaked at 10 to 20 minutes [1].
The finding was a puzzle. The hexapeptide did not resemble GHRH, and in 1990 Bowers showed in 18 healthy men that its effect added synergistically to that of GHRH, indicating that it acted through an independent pathway. The authors read this as reflecting “a new physiological system” still to be characterized [2]. There was a drug, but the physiology to explain it was missing.
- 1984: first description of GHRP-6 [1]
- 1996: GHS-R receptor cloned at Merck [3]
- 1999: ghrelin identified as its ligand [4]
Merck found the orphan receptor
Industry took up the idea. At Merck, scientists searched for the receptor targeted by these GH secretagogues (GHSs), small synthetic molecules. In 1996 they reported in Science the cloning of a G protein-coupled receptor in the pituitary and hypothalamus of swine and humans, and showed it was the target of the GHSs [3]. They called it GHS-R. No endogenous hormone was known to activate it. It was an orphan receptor. Their conclusion: “The GHSs mimic an undiscovered hormone” [3].
Ghrelin was identified in 1999
The prediction came true three years later. The team of Masayasu Kojima and Kenji Kangawa in Osaka purified from rat stomach the specific endogenous ligand of GHS-R: a 28-amino-acid peptide with an octanoylated serine 3, a modification essential for its activity. They named it ghrelin, from the Proto-Indo-European root ghre, “grow” [4]. GH regulation no longer depended only on hypothalamic GHRH, but also on a signal from the stomach [4].
A second function soon emerged. In a double-blind crossover trial in 9 healthy volunteers, ghrelin infusion was associated with a 28% increase in energy consumed at a free-choice buffet, with an increase in every participant [5]. The authors described it as the first circulating hormone shown to stimulate food intake in humans [5]. GHRP-2, an analog from the same family, reproduced the effect: in 7 healthy men, its subcutaneous infusion was associated with 35.9% more food intake than saline [6]. It is the reverse of the usual story: first the synthetic molecule, then the natural hormone.
The first approved use was a diagnostic test
GHRP-2, under the name pralmorelin, is listed in Japan as a diagnostic agent for endocrine function [8]. In a Japanese multicenter study of 77 healthy adults and 58 patients with severe GH deficiency, a 100 µg intravenous dose produced a peak GH of 84.6 µg/L in healthy adults vs 1.36 µg/L in patients, with good reproducibility and a 15 µg/L cutoff equivalent to that of the insulin tolerance test [7]. It is an alternative to the insulin tolerance test, which can cause severe hypoglycemia and is contraindicated in some patients [7][10].
The United States followed the same logic with an oral molecule. Macimorelin, a GH secretagogue receptor agonist, was approved by the FDA in 2017 for the diagnosis of adult GH deficiency [9]. In the validation trial against the insulin tolerance test, the prespecified 2.8 ng/mL cutoff achieved 87% sensitivity and 96% specificity. In a post hoc analysis with 5.1 ng/mL, it was 92% and 96%. Reproducibility was 97% and no serious adverse events were reported with macimorelin [10].
Anamorelin turned appetite into therapy
If ghrelin opens the appetite, an agonist could help where appetite is missing. Anamorelin, an oral ghrelin-receptor agonist, was tested in ROMANA 1 and ROMANA 2: 979 patients with advanced non-small-cell lung cancer and cachexia at 93 sites in 19 countries. At 12 weeks it was associated with increased lean body mass (median gain of 0.99 kg vs a loss of 0.47 kg in ROMANA 1, and a gain of 0.65 kg vs a loss of 0.98 kg in ROMANA 2), with no improvement in handgrip strength [11]. There were no differences in treatment-related grade 3 to 4 adverse events. The most common was hyperglycemia, in under 1% (ROMANA 1) and 1% (ROMANA 2) of patients on anamorelin [11].
Europe did not approve it. Japan did: on December 11, 2020 it authorized anamorelin for cachexia in non-small-cell lung, gastric, pancreatic and colorectal cancer, supported by Japanese trials with lean-mass gains of 1.56 kg and 1.89 kg [12]. It is a clear example of a therapeutic drug that came out of the pathway GHRP-6 opened.
The class is not selective
In Bowers’ study in healthy men, prolactin and cortisol rose about twofold at the highest GHRP-6 dose [2]. In young adults, GHRP-2 and hexarelin induced increases in prolactin, ACTH and cortisol, and the ACTH and cortisol release was similar to that of CRH [13]. Increased appetite, useful in cachexia, is unwanted in other settings [6]. Later molecules, such as ipamorelin, were designed to separate GH from the adrenal axis. See ipamorelin and the search for selectivity and the ipamorelin status page.
FDA flagged both for compounding risk
The FDA placed GHRP-2 and GHRP-6 on its list of bulk drug substances that may present safety risks in compounding. For GHRP-2 it notes a risk of immunogenicity and says it is aware of reports of serious adverse events, including increased insulin requirement, deaths of critically ill patients in studies, infection and pancreatitis, though causality has not been established. For GHRP-6 it mentions a potential effect on cortisol and increased blood glucose due to lower insulin sensitivity [14]. The broader GH and IGF-1 debate is in CJC-1295, ipamorelin and MK-677.
For your clinic, the practical point is sourcing. A “research use only” label on a GHRP-2 or GHRP-6 vial does not make it lawful for patient use. The research-use-only peptides guide explains why, and are peptides legal covers the wider framework.
Pharmacology preceded physiology
Rarely has pharmacology preceded physiology so clearly. A 1984 synthetic peptide predicted a receptor, the receptor predicted a hormone, and the hormone gave rise to drugs approved for diagnosis and for cachexia [1][3][4][9][12]. GHRPs remain well-characterized laboratory tools for studying the ghrelin-GH axis. The approved descendants are where the clinical value landed.
References
- Bowers CY, et al. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984;114(5):1537-45. PMID 6714155. Link
- Bowers CY, et al. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab. 1990;70(4):975-82. PMID 2108187. Link
- Howard AD, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974-7. PMID 8688086. Link
- Kojima M, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-60. PMID 10604470. Link
- Wren AM, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992. PMID 11739476. Link
- Laferrère B, et al. Growth hormone releasing peptide-2 (GHRP-2), like ghrelin, increases food intake in healthy men. J Clin Endocrinol Metab. 2005;90(2):611-4. PMID 15699539. Link
- Chihara K, et al. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur J Endocrinol. 2007;157(1):19-27. PMID 17609397. Link
- KEGG DRUG. D02040: Pralmorelin hydrochloride (JAN); GHRP (TN). Diagnostic reagents for endocrine function; New drug approvals in Japan. Link
- U.S. Food and Drug Administration. MACRILEN (macimorelin) for oral solution. Prescribing information, initial U.S. approval 2017. Link
- Garcia JM, et al. Macimorelin as a diagnostic test for adult GH deficiency. J Clin Endocrinol Metab. 2018;103(8):3083-3093. PMID 29860473. Link
- Temel JS, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol. 2016;17(4):519-531. PMID 26906526. Link
- Wakabayashi H, et al. The regulatory approval of anamorelin for treatment of cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer in Japan: facts and numbers. J Cachexia Sarcopenia Muscle. 2021;12(1):14-16. PMID 33382205. Link
- Arvat E, et al. Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Comparison with the effects of GHRH, TRH and hCRH. Peptides. 1997;18(6):885-91. PMID 9285939. Link
- U.S. Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. Link
This is general information, not medical or legal advice. Rules vary by state and change. Confirm your own facts with counsel.