Editorial note: this article summarises published research on GHRP-2, GHRP-6 and hexarelin. Baclabs does not sell GHRP-2, GHRP-6, hexarelin or any peptide; we supply bacteriostatic water and reconstitution consumables. Nothing here is medical advice.
GHRP-2, GHRP-6 and hexarelin are the first generation of growth hormone-releasing peptides (GHRPs): short synthetic peptides that act on the ghrelin receptor to release growth hormone (GH). They predate the discovery of ghrelin itself, and much of what is known about that receptor was learned by studying them in human volunteers in the 1990s. All three release GH strongly, more strongly than growth hormone-releasing hormone (GHRH) on its own, and all three carry the same class of side effects: hunger, and a rise in cortisol and prolactin.
GHRP-2 vs GHRP-6 vs hexarelin is therefore a comparison of degree: potency, selectivity and behaviour on repeated dosing. This article sets out the shared mechanism, the human data on each, the GHRP-6 hunger effect that vendors either promote or apologise for, and the hexarelin desensitisation studies. The broader class, including the more selective ipamorelin, is covered in the growth hormone secretagogues pillar.
How GHRPs signal: the ghrelin receptor
GHRP-6 was designed around 1980 by modifying the structure of met-enkephalin, and the resulting hexapeptide released GH without any opioid activity. It was discovered before GHRH was isolated and long before its own receptor was identified [1]. That receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), was cloned in 1996; its natural ligand, the 28-amino-acid stomach hormone ghrelin, was found in 1999 [2].
GHS-R1a is a G-protein-coupled receptor expressed in the pituitary and the hypothalamus. It couples through Gq to phospholipase C, generating inositol phosphates and releasing intracellular calcium, which triggers GH secretion from the somatotroph. The receptor has unusually high constitutive activity, signalling at about half its maximum with no ligand bound [2]. GHRH, by contrast, acts through a different receptor that raises cyclic AMP. Because the two pathways are separate, they add up: in healthy subjects GHRP-6 alone releases more GH than GHRH alone, and the two together produce a synergistic response. In patients with hypothalamic–pituitary disconnection the GHRP-6 response and the synergy both vanish, evidence that GHRP-6 acts mainly at the hypothalamus rather than directly on the pituitary [3].
The hypothalamic site of action explains the side effects. GHS-R1a in the hypothalamus is the receptor through which ghrelin drives appetite, and stimulating it also activates the hypothalamic–pituitary–adrenal axis that controls ACTH and cortisol. None of the three first-generation GHRPs discriminates between the pituitary and hypothalamic receptor populations.
GHRP-6: GH release, the hunger effect, cortisol and prolactin
In healthy men given four intravenous boluses of 50 mcg GHRP-6 overnight, GH rose as expected, but so did ACTH and cortisol, particularly in the first half of the night. Stage 2 sleep increased, while slow-wave sleep was unaffected. The authors noted that this cortisol response is the opposite of what GHRH does, which blunts cortisol [4].
The ghrp 6 hunger effect is the best-known feature of the compound and follows directly from its receptor. In rodents, GHRP-6 given centrally increases food intake and activates the hypothalamic appetite centres in the same pattern as ghrelin [5]. The clearest human measurement of a GHRP’s effect on eating used GHRP-2 rather than GHRP-6: seven lean men infused with GHRP-2 at 1 mcg/kg/h subcutaneously for 270 minutes ate 35.9 per cent more at a free-choice meal than on saline, with GH area under the curve rising more than tenfold [6]. GHRP-6 acts through the same receptor and is expected to behave the same way, but the formal human feeding study was done with GHRP-2.
GHRP-2: the most potent of the three
GHRP-2 (pralmorelin) is a further-modified hexapeptide and the most potent of the first-generation GHRPs. In the swine model used to characterise ipamorelin, GHRP-2 had an ED50 of 0.6 nmol/kg for GH release, against 3.9 nmol/kg for GHRP-6 and 2.3 nmol/kg for ipamorelin, and both GHRP-2 and GHRP-6 raised ACTH and cortisol where ipamorelin did not [7].
In humans, Arvat and colleagues compared GHRP-2 and hexarelin with GHRH, thyrotropin-releasing hormone (TRH) and human CRH. At equivalent doses both GHRPs released more GH than GHRH. Both also raised prolactin, ACTH and cortisol: the prolactin rise was smaller than that produced by TRH, but the ACTH and cortisol rise was of the same magnitude as that produced by CRH itself [8]. That is not a trivial effect. A compound that releases as much cortisol as CRH is a stress-axis stimulant as well as a GH secretagogue. GHRP-2 is also the compound in the human food-intake study above [6].
Hexarelin: potency and desensitisation
Hexarelin is GHRP-6 with a 2-methyl-tryptophan substitution that improves stability. In the Arvat comparison it behaved like GHRP-2: more GH than GHRH, and prolactin, ACTH and cortisol release alongside [8]. During sleep, hexarelin decreased slow-wave sleep and stimulated GH, ACTH, cortisol and prolactin [9]. It is also the GHRP with the best data on what happens with continuous use.
Rahim, O’Neill and Shalet gave adult volunteers 1.5 mcg/kg hexarelin subcutaneously twice daily for 16 weeks. The GH response to a test dose fell from 19.1 mcg/L·h at baseline to 10.5 mcg/L·h at week 16, a reduction of roughly 45 per cent that was already measurable by week 4. Four weeks after stopping, the response had recovered to 19.4 mcg/L·h. Serum IGF-1 and IGFBP-3 did not change significantly at any point over the 20-week study. The authors described “a partial and reversible attenuation of the GH response” and questioned whether the biological impact on the GH–IGF-1 axis was meaningful [10]. In a companion paper on the same protocol, the cortisol response to hexarelin decreased over the 16 weeks and returned to baseline after washout, while the ACTH and prolactin areas under the curve and 24-hour urinary free cortisol did not change [11].
Two points follow. First, continuous twice-daily hexarelin desensitises the receptor, and the GH response roughly halves over 16 weeks, with a measurable fall by week 4. Second, even the undiminished response at baseline did not move IGF-1, the marker that reflects meaningful GH exposure. Whether the same desensitisation applies to GHRP-2 and GHRP-6 has not been tested over comparable durations in humans, but they act on the same receptor.
GHRP-2 vs GHRP-6 vs hexarelin: side-by-side
| GHRP-6 | GHRP-2 | Hexarelin | |
|---|---|---|---|
| Structure | Hexapeptide from met-enkephalin [1] | Modified hexapeptide | GHRP-6 with 2-methyl-Trp |
| GH potency (swine ED50) [7] | 3.9 nmol/kg | 0.6 nmol/kg | Not tested in that study |
| GH vs GHRH in humans | Greater; synergistic with GHRH [3] | Greater [8] | Greater [8] |
| ACTH / cortisol | Raised [4][7] | Raised, similar to CRH [8] | Raised, similar to CRH [8]; response wanes on chronic use [11] |
| Prolactin | Not raised in swine model [7] | Raised, less than TRH [8] | Raised, less than TRH [8] |
| Hunger | Strong (rodent data; human data by inference) [5] | +35.9% food intake in men [6] | Orexigenic in animals |
| Chronic dosing data | None comparable | None comparable | ~45% GH attenuation at 16 weeks, reversible; IGF-1 unchanged [10] |
| Regulatory (US, 2023) | FDA Category 2 [12] | FDA Category 2 [12] | Not listed |
Regulatory status and doses in the literature
None of the three is licensed as a therapeutic medicine in the UK. On 29 September 2023 the FDA placed GHRP-2 and GHRP-6, along with ipamorelin and CJC-1295, in Category 2 of its compounding bulks lists, citing immunogenicity risk and reports of serious adverse events, and for GHRP-6 potential cortisol and glucose effects [12]. That bars US compounding pharmacies from preparing them. In the UK, products sold as “research chemicals” fall outside the Human Medicines Regulations 2012 only while they are not supplied for human use.
Doses reported in the human studies above were acute, weight-based and mostly intravenous: 50 mcg boluses of GHRP-6 [4], 1 mcg/kg/h infusion of GHRP-2 [6], 90 mcg intravenous GHRP-6 in the synergy studies [3], and 1.5 mcg/kg subcutaneous hexarelin twice daily in the 16-week study [10]. None of these were designed to establish a therapeutic dose, and no controlled human trial has tested any of the three for body composition or performance.
Reconstitution and diluent
All three are supplied as lyophilised powder in 2 mg or 5 mg vials and are drawn from repeatedly, so a preserved diluent is appropriate. Bacteriostatic water contains 0.9 per cent benzyl alcohol and supports multi-dose use for up to 28 days after first puncture; see storage and shelf life and, for the choice of diluent, bacteriostatic water vs sterile water. Concentration = peptide mass ÷ diluent volume: a 5 mg vial with 2 mL gives 2,500 mcg/mL, or 25 mcg per unit on a U-100 insulin syringe. Full tables are in reconstituting GHRPs and GHRHs.
Multi-dose vials need a preserved diluent. Baclabs supplies UK-stocked bacteriostatic water in 30 mL vials; see the reconstitution guide for the maths.
Frequently asked questions
Why does GHRP-6 make you hungry?
GHRP-6 activates the ghrelin receptor GHS-R1a in the hypothalamus, the same receptor through which ghrelin, the stomach’s hunger hormone, stimulates appetite. In rodents GHRP-6 increases food intake and activates the hypothalamic feeding centres like ghrelin [5]; in men, the related GHRP-2 increased food intake by 35.9 per cent during a short infusion [6].
Does GHRP-2 raise cortisol and prolactin?
Yes. In healthy volunteers GHRP-2 and hexarelin both raised prolactin, ACTH and cortisol as well as GH. The prolactin rise was smaller than TRH produces, but the ACTH and cortisol rise matched that of corticotropin-releasing hormone (CRH), the body’s own stress-axis releasing hormone [8]. Ipamorelin was developed specifically to avoid this [7].
What is the difference between hexarelin and GHRP-6?
Hexarelin is GHRP-6 with a 2-methyl-tryptophan substitution that improves stability. Both release GH more strongly than GHRH and both raise ACTH and cortisol [4][8]. Hexarelin has 16-week human data showing partial, reversible desensitisation of the GH response with no change in IGF-1 [10]; GHRP-6 has no comparable chronic study.
Does hexarelin stop working over time?
Partly. With 1.5 mcg/kg twice daily, the GH response fell from 19.1 to 10.5 mcg/L·h by week 16, then recovered to 19.4 four weeks after stopping. IGF-1 did not change at any point, so the attenuation may matter less than the fact that the peptide did not raise IGF-1 to begin with [10].
Are GHRP-2 and GHRP-6 legal?
Neither is a licensed medicine in the UK; both are sold as research chemicals, which places them outside the Human Medicines Regulations only while they are not supplied for human use. In the US, the FDA placed both in Category 2 of its compounding bulks lists in September 2023, barring compounding pharmacies from preparing them [12].
References
- Physiology and possible pathology of growth hormone secretagogues. Journal of Pediatric Endocrinology and Metabolism, 2002
- GHS-R1a constitutive activity and its physiological relevance. Frontiers in Neuroscience (PMC), 2013
- Blocked GHRP-6-induced GH secretion and absence of the synergic action of GHRP-6 plus GHRH in patients with hypothalamopituitary disconnection. Journal of Clinical Endocrinology & Metabolism, 1995
- Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Frieboes et al., Neuroendocrinology, 1995
- Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology, 2001
- Growth hormone releasing peptide-2 (GHRP-2), like ghrelin, increases food intake in healthy men. Laferrère et al., Journal of Clinical Endocrinology & Metabolism, 2005
- Ipamorelin, the first selective growth hormone secretagogue. Raun et al., European Journal of Endocrinology, 1998
- 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. Arvat et al., Peptides, 1997
- Hexarelin decreases slow-wave sleep and stimulates the secretion of GH, ACTH, cortisol and prolactin during sleep in healthy volunteers. Psychoneuroendocrinology, 2004
- Growth hormone status during long-term hexarelin therapy. Rahim et al., Journal of Clinical Endocrinology & Metabolism, 1998
- The effect of chronic hexarelin administration on the pituitary-adrenal axis and prolactin. Rahim, O’Neill & Shalet, Clinical Endocrinology, 1999
- Certain bulk drug substances for use in compounding may present significant safety risks. US FDA, 2023 (updated)
Disclaimer: This content is for educational purposes only and does not constitute medical advice. Bacteriostatic water is supplied for reconstitution of substances intended for research and for use as directed by a healthcare professional. Peptides and medicines discussed here may be unlicensed in the UK or prescription-only; consult a qualified clinician before using any medicine. Baclabs does not sell peptides.