MK-677
Also known as: Ibutamoren, Ibutamoren mesylate, MK-0677, L-163,191, Nutrobal
Evidence: Clinical
Overview
Ibutamoren, an orally active non-peptide ghrelin receptor agonist that raises GH and IGF-1 in human trials; studied for lean mass, bone density, and sleep quality.
MK-677 (ibutamoren, L-163,191) is a Merck non-peptide spiropiperidine built as an oral mimic of GHRP-6 (Patchett 1995); it is in this catalog for reference only. In 32 healthy adults aged 64-81, 25 mg daily for 4 weeks nearly doubled 24 h GH and raised IGF-1 from 141 to 265 mcg/L, with a rise in fasting glucose (Chapman 1996). A 2-year RCT in 65 older adults found fat-free mass +1.1 kg vs -0.5 kg on placebo, no change in visceral fat, weight +2.7 kg, higher fasting glucose and lower insulin sensitivity (Nass 2008). Other RCTs: more fat-free mass in obese men (Svensson 1998), reversed diet-induced nitrogen loss (Murphy 1998), more deep and REM sleep (Copinschi 1997), no effect on Alzheimer progression (Sevigny 2008), and a hip-fracture trial stopped for a heart-failure signal (Adunsky 2011). Not approved anywhere.
Benefits
Increased GH and IGF-1, lean mass gain, improved sleep quality
Dosing reference
- Research dose
- 10-25 mg oral once daily (RCT doses 2-25 mg; 25 mg in most trials)
- Range
- 10000 to 25000 mcg, 1x daily
Oral, once daily; trials dosed at bedtime (Copinschi 1997) or without timing restriction. 25 mg daily was the dose in most RCTs; 2 and 10 mg were less effective on IGF-1 (Chapman 1996). Fasting glucose rose and insulin sensitivity fell in trials of 4 weeks to 2 years (Chapman 1996; Nass 2008). Appetite increase subsided after a few months in the 2-year trial (Nass 2008). Not injectable.
Mechanism
MK-677 is an orally active non-peptide agonist of the growth hormone secretagogue receptor GHS-R1a, the ghrelin receptor, designed as a peptidomimetic of GHRP-6 (Patchett 1995). It amplifies existing pulsatile GH secretion, raising pulse height and trough levels without changing pulse number, and produces a sustained IGF-1 rise with once-daily dosing (Chapman 1996). Cortisol was unchanged in older adults (Chapman 1996) and rose only transiently after first doses in obese men (Svensson 1998); prolactin rose modestly. Appetite stimulation follows ghrelin-receptor activation. Note: not a peptide; included for reference.
Evidence
Clinical: at least one published human trial or an approved drug
- 25 mg daily for 4 weeks raised IGF-1 from 141 to 265 mcg/L and 24 h GH 97% in 32 adults aged 64-81; fasting glucose rose (Chapman et al., 1996)
- 2-year RCT, n=65: fat-free mass +1.1 kg vs -0.5 kg placebo, no visceral fat change, fasting glucose up, insulin sensitivity down (Nass et al., 2008)
- 8 weeks of 25 mg in 24 obese men: IGF-1 +40%, fat-free mass up, impaired glucose tolerance (Svensson et al., 1998)
- 7 days of 25 mg increased stage IV sleep ~50% and REM sleep >20% in young men; REM up ~50% in older adults (Copinschi et al., 1997)
- Hip-fracture RCT, n=123: IGF-1 up, most function measures unchanged, terminated early for a congestive heart failure signal (Adunsky et al., 2011)
- Human-trial status: multiple phase 2 RCTs 1996-2011; no clinical effect on Alzheimer progression (Sevigny et al., 2008); not approved anywhere, development discontinued
References
- Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Patchett AA, Nargund RP, Tata JR, et al., Proceedings of the National Academy of Sciences USA, 1995
- Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. Chapman IM, Bach MA, Van Cauter E, et al., Journal of Clinical Endocrinology & Metabolism, 1996
- Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Copinschi G, Leproult R, Van Onderbergen A, et al., Neuroendocrinology, 1997
- Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. Svensson J, Lonn L, Jansson JO, et al., Journal of Clinical Endocrinology & Metabolism, 1998
- MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. Murphy MG, Plunkett LM, Gertz BJ, et al., Journal of Clinical Endocrinology & Metabolism, 1998
- Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Nass R, Pezzoli SS, Oliveri MC, et al., Annals of Internal Medicine, 2008
- MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Adunsky A, Chandler J, Heyden N, et al., Archives of Gerontology and Geriatrics, 2011
- Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML; MK-677 Protocol 201 Study Group, Neurology, 2008
Side effects
Trials report increased appetite (subsiding over months), transient mild lower-extremity edema and muscle pain (Nass 2008), higher fasting glucose and reduced insulin sensitivity (Chapman 1996; Nass 2008; Svensson 1998), transient cortisol and prolactin rises after first doses (Svensson 1998), and a congestive heart failure safety signal that stopped a hip-fracture trial in elderly patients (Adunsky 2011). Lethargy, joint aches and carpal tunnel symptoms are commonly reported (anecdotal).
Storage
- Storage
- Room temperature, dry, away from light (general guidance for an oral small molecule)
- Lyophilized
- 2+ years at room temperature (general guidance)
Pharmacology
- Half-life
- Plasma half-life not located in primary literature (secondary sources cite 4-6 h); once-daily oral dosing sustains 24 h GH and IGF-1 elevation (human; Chapman 1996)
- Bioavailability
- Orally active in humans (Patchett 1995; Chapman 1996); no absolute bioavailability figure located
- Molecular weight
- 528.66 Da