GHRP-6

GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) is the compound that started this field. It was built from opioid peptide fragments in the search for a growth hormone releaser that did not work through GHRH, and the receptor it acts on — the growth hormone secretagogue receptor — was later shown to be the receptor for ghrelin.

How strong it is. In 11 healthy adults, 90 ug intravenously produced a growth hormone area under the curve of 1,435 against 484 for 100 ug of GHRH. Given together, the response was 3,772, significantly more than the sum of the two given separately [1].

Where it acts. The same study gave the answer. In 12 patients whose pituitary was functionally disconnected from the hypothalamus, the GHRH response was normal but the GHRP-6 response was completely blocked, and the synergy disappeared. The main site of action is therefore the hypothalamus [1].

Age. Growth hormone secretion declines with age, and so does the response to GHRH. The response to GHRP-6 does not: in young and late-adulthood groups, GHRP-6 alone and GHRP-6 plus GHRH produced statistically indistinguishable responses, while GHRH alone was weaker in the older group. The authors read this as evidence that the age-related decline is functional and reversible [2].

Pharmacokinetics. Nine healthy men received 100, 200 or 400 ug/kg intravenously. Disposition was biexponential with a distribution half-life of 7.6 minutes and an elimination half-life of 2.5 hours, and area under the curve rose in proportion to dose [3].

Other settings. GHRP-6 has been used with GHRH to probe pituitary reserve in polycystic ovary syndrome [5] and in type 2 diabetes, where hyperglycemia blunted the response [6]. A Cuban group has pursued it as a tissue-protective agent, reporting benefit in animal models of acute lung injury [7]; none of that work has reached controlled human trials.

GHRP-6 activates GHS-R1a, the receptor later shown to be ghrelin's. When it was cloned it matched no other known G-protein-coupled receptor, which is why the field predicted a natural ligand before ghrelin was identified [8].

A dual site, weighted to the hypothalamus. Most of the effect is hypothalamic [1], so GHRP-6 works partly by opposing somatostatin and partly by releasing endogenous GHRH - which is why combining it with GHRH is supra-additive rather than additive, and why arginine, which suppresses somatostatin, potentiates peptides of this class. In the hexarelin study that showed this, arginine raised the growth hormone response in elderly subjects from 1,649 to 4,139 µg·min/L but did nothing in young ones, where the response was already near its ceiling [9]. The 1998 review of the class concluded the hypothalamic step may involve a further factor beyond GHRH and somatostatin that was never identified [8].

Potency. In primary rat pituitary cells GHRP-6 released growth hormone with an EC50 of 2.2 ± 0.3 nmol/L, the reference against which the rest of the family was scaled, and in conscious swine with an ED50 of 3.9 ± 1.4 nmol/kg and a maximum of 74 ± 7 ng/mL - the highest maximum of the group, although GHRP-2 was about six times more potent, with an ED50 of 0.6 nmol/kg and a lower maximum of 56 ± 6 ng/mL [10].

Age. How much the response falls with age depends on which peptide and which comparison. With GHRP-6 itself, 9 young and 9 older adults given 90 µg intravenously showed no significant difference, alone or combined with GHRH, while the GHRH response alone was clearly lower in the older group - the result that made the age-related decline look functional and reversible [2]. The close analog hexarelin does decline with age, roughly halving [9], and the review of the class describes the GHRP response as decreasing in aging [8]. The honest summary is that GHRP-6 holds up better than GHRH, not that it is age-independent.

Selectivity. The receptor's other job is appetite - it is ghrelin's receptor, so hunger comes with the growth hormone. Selectivity for growth hormone is poor: ACTH and cortisol rise at growth hormone-releasing doses [4], and in swine GHRP-6 and GHRP-2 both did so while Ipamorelin, designed without the central Ala-Trp dipeptide, did not, at any dose tested [10]. A radio-competitive binding assay at GHSR1a maps which positions in the shared Ala-Trp-(D-Phe)-Lys core carry which effect, and finds receptor-binding activity still present in urine after nasal dosing [11].

GHRP-6 is a hexapeptide of molecular weight about 872 Da, supplied as an acetate salt; the published human route is intravenous [3]. GHRP-6 and GHRP-2 are both detectable in urine and are prohibited in sport [12].

The human record is single intravenous doses, up to 400 ug/kg, in small groups of healthy volunteers and patients, with no serious adverse effects reported [1][3]. That is not a safety dataset for repeated use.

The known pharmacological effects to expect are increased appetite, and a rise in ACTH and cortisol at growth hormone-releasing doses [4]. Hexarelin, a close analog, loses about half its growth hormone effect over 16 weeks of twice-daily dosing [14], and the same is likely here, though it has not been measured. There is no data on glucose, IGF-1 over time, or long-term outcomes.