Ghrelin / GHS-receptor agonist

Capromorelin is an orally active ghrelin-receptor agonist from the Pfizer pyrazolinone-piperidine series. It has the best human trial of any compound in this group after MK-677: 395 adults aged 65-84 with mild functional limitation, randomised to four dose schedules or placebo. At six months, lean body mass had risen 1.4 kg against 0.3 kg on placebo, and — unusually for this class — a physical performance measure improved, with tandem walk better by 0.9 seconds at 6 months and stair climb by 12 months. Fasting glucose, HbA1c and insulin resistance all rose, and fatigue and insomnia were reported. The human programme was stopped; capromorelin is instead approved as a veterinary appetite stimulant for dogs and cats.

GHRP-2 (pralmorelin) is a synthetic hexapeptide that releases growth hormone through the ghrelin receptor, about as strongly as hexarelin and more strongly than GHRH. Japan licensed it as a single-dose diagnostic test for growth hormone deficiency, and that is essentially its whole clinical career. It is not selective: at growth hormone-releasing doses it also raises prolactin, and raises ACTH and cortisol about as much as CRH does. Repeated dosing over days to weeks produces complex changes in the growth hormone axis, including desensitisation depending on dose and frequency. There is no controlled trial of GHRP-2 for muscle, fat or strength in healthy people.

GHRP-6 is the original growth hormone-releasing peptide, the compound whose receptor turned out to be the ghrelin receptor. In people it releases about three times as much growth hormone as GHRH, and combining the two is strongly synergistic. Unusually for a growth hormone stimulus, the response barely declines with age. Its pharmacokinetics are known: after an intravenous bolus the distribution half-life is about 7.6 minutes and elimination about 2.5 hours. What does not exist is any trial of what taking it for weeks or months does to IGF-1, muscle or fat in healthy people; it also raises ACTH and cortisol, and it makes people hungry.

Hexarelin is a synthetic hexapeptide that releases growth hormone through the ghrelin receptor, and it does so more strongly than GHRH itself: 1 ug/kg intravenously produced about twice the growth hormone response of the same dose of GHRH in healthy young men. It has been studied mainly as a diagnostic agent for growth hormone deficiency, where hexarelin plus GHRH matches the insulin tolerance test. The problem with taking it is tachyphylaxis: over 16 weeks of twice-daily subcutaneous dosing the growth hormone response fell by about half, IGF-1 did not change at all, and body composition and bone density did not move. Like GHRP-2, it also raises prolactin, ACTH and cortisol.

Ipamorelin is a synthetic pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2) that releases growth hormone through the ghrelin receptor. Novo Nordisk designed it in the 1990s from the GHRP-1 series, and its selling point was selectivity: in pigs it released growth hormone as strongly as GHRP-6 but, unlike GHRP-6 and GHRP-2, did not raise ACTH or cortisol even at more than 200 times the effective dose. The catch is that almost nothing has been published about what it does in people. The one controlled human trial gave it intravenously for postoperative bowel paralysis, and found no benefit over placebo. No published human study has measured growth hormone, IGF-1 or body composition on ipamorelin.

MK-677 (ibutamoren) is an orally active drug that mimics ghrelin at the GHS-R1a receptor, making the pituitary release more of the body's own growth hormone in its normal pulses. It reliably raises growth hormone and IGF-1: 25 mg daily restored IGF-1 in older adults to young-adult levels within four weeks, and a two-year randomised trial found about 1.1 kg more fat-free mass at 12 months than placebo. What it has never shown is a benefit that people can feel: the same trial found no change in strength, walking, stair climbing or quality of life, and trials in hip-fracture recovery and Alzheimer's disease were negative. It consistently raises fasting glucose, HbA1c and appetite, and it was never approved for any human use.

MK-777, sold as "acetamoren", is offered as an orally active growth hormone secretagogue and a successor to MK-677. There is no published research on it. A search of PubMed for MK-777 and for acetamoren returns nothing: no pharmacology paper, no animal study, no human data, no pharmacokinetics, no structure. It has no PubChem entry under either name. Everything asserted about it — its potency, its selectivity, its supposed advantages over MK-677 — originates from sellers, not from any source that can be checked.