Ipamorelin
A selective GHS-R1a agonist notable for releasing growth hormone without the cortisol and prolactin rise seen with earlier secretagogues. Human trials exist but are small and focused on postoperative ileus.
Growth Hormone
MK-677
An orally bioavailable ghrelin receptor agonist with genuine long-duration human RCT data, including a 2-year trial in older adults. Development was discontinued after efficacy endpoints were not met.
Overview
MK-677 is not a peptide — it is a small molecule designed to mimic ghrelin, which is why it survives digestion and can be taken by mouth. It binds the same receptor that ghrelin does and causes the pituitary to release growth hormone in pulses. Because it works through the body's own signalling, it raises growth hormone and IGF-1 toward younger levels rather than overriding the system. It has been studied for two full years in older adults, which is unusual for anything in this category.
MK-677 is a spiroindane-based non-peptidic agonist at GHS-R1a, the ghrelin receptor. Receptor activation is Gq/11-coupled, driving phospholipase C-mediated IP3 generation, intracellular calcium release in pituitary somatotrophs, and GH exocytosis. It additionally suppresses hypothalamic somatostatin tone. Oral bioavailability derives from its non-peptide scaffold, which resists gastrointestinal proteolysis, with a terminal half-life supporting once-daily dosing. Chronic administration produces sustained elevation of GH and IGF-1 without the tachyphylaxis seen with some secretagogues. The dominant off-target consequence is GH-mediated insulin resistance: the 2-year trial in older adults reported a rise in fasting blood glucose and reduced insulin sensitivity.
Research areas
EndocrineBody compositionSarcopeniaSleep architecture
Dosing reported in the literature
Every protocol below is reproduced from a published study or approved labelling, with its source named. These are records of what was studied — not recommendations, and not a suggestion that any of them is appropriate for any person.
| Protocol as reported | Source |
|---|---|
| 25 mg orally once daily for 2 yearsThis is the longest published human exposure. Fasting glucose rose and insulin sensitivity fell over the study period. | Nass et al., Annals of Internal Medicine 2008 |
| 25 mg orally once daily in the hip fracture recovery trial | Bach et al., Journal of the American Geriatrics Society 2004 |
Trial status
Multiple completed randomized controlled trials including a 2-year study in healthy older adults and trials in hip fracture recovery and cachexia. Development discontinued.
Phase 2 — older adults, 2 years
Completed65 healthy adults aged 60–81 randomized for 2 years. GH and IGF-1 rose to levels typical of healthy young adults. Fat-free mass increased by 1.6 kg vs 0.1 kg on placebo, without significant improvement in strength or function.
Phase 2 — hip fracture recovery
Completed123 elderly patients after hip fracture. Functional recovery endpoints were not significantly improved.
Phase 3
NoneNo phase 3 programme was completed. Development was discontinued after functional endpoints were not met.
Reported safety signals
- The 2-year trial reported an increase in fasting blood glucose and a reduction in insulin sensitivity — the most consistent and best-documented adverse effect.
- Increased appetite is a direct consequence of ghrelin receptor agonism and is near-universal.
- Transient oedema, muscle pain and fatigue were reported in the older adult trials.
- Sustained IGF-1 elevation carries theoretical proliferative concern; the trials were not powered to detect cancer incidence.
- Congestive heart failure was reported at higher rates in one elderly trial population, prompting caution in that group.
Common questions
Is MK-677 a peptide?
No. It is a non-peptide small molecule that acts at the same receptor as the peptide secretagogues. It is included here because it occupies the same research space and is frequently compared against them, but its oral bioavailability and metabolic profile are properties of its small-molecule structure.
Why did development stop if it raised GH and IGF-1?
It reliably hit its biomarker endpoints but not its functional ones. In both the 2-year older adult trial and the hip fracture trial, increases in lean mass did not translate into significant improvements in strength or functional recovery. Raising a biomarker is not the same as improving an outcome.
Primary sources
- 01
Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial
- 02
The effects of MK-677, an oral growth hormone secretagogue, in patients with hip fracture
- 03
Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue
Medical disclaimer
This page is for informational and research purposes only. Nothing here constitutes medical advice. The compounds discussed are research chemicals. Consult a qualified clinician before starting any protocol.
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