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Mk63.0
MK-677 Research
Mostly mechanism / observationalLimited safety
13 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most MK-677 studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from mixed-quality randomised trials published 1996–2018 with a typical study size of 26 participants.
Based on 13 studies · 9 RCTs · 895 total participants
Confidence
Moderate
By outcome
GH / IGF-1 & body composition
Mostly mechanism / observational10 studies
Glucose & insulin sensitivity
Mostly mechanism / observational4 studies
Safety profile
Mostly mechanism / observational3 studies
Alzheimer’s & cognition (failed)
Too few graded studies2 studies
Bone turnover
Too few graded studies1 study
Aging & somatopause
Too few graded studies1 study
Older research base
Newest study from 2018
199620072018
1RCTn=65 · small study2008
Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated ... Increased fat-free mass did not result in changes in strength or function.
Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, Heymsfield SB, Bach MA, Vance ML, Thorner MO. · Ann Intern Med (2008)
2-year, double-blind, randomized, placebo-controlled, modified-crossover trial in 65 healthy adults aged 60-81; oral MK-677 25 mg once daily
Raised GH and IGF-1 into the young-adult range and increased fat-free mass (+1.1 kg vs −0.5 kg placebo; P<0.001)
CRITICAL: the increased fat-free mass did NOT result in any change in strength or physical function
Despite evidence of target engagement as indicated by an increase in serum insulin-like growth factor-1, the human growth hormone secretagogue MK-677 25 mg was ineffective at slowing the rate of progression of Alzheimer disease.
Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML; MK-677 Protocol 30 Study Group. · Neurology (2008)
Double-blind, multicenter RCT: 563 patients with mild-to-moderate Alzheimer's randomized to MK-677 25 mg or placebo daily for 12 months
Target engagement confirmed: serum IGF-1 rose 60.1% at 6 weeks and 72.9% at 12 months
PRIMARY ENDPOINTS FAILED: no significant difference vs placebo on CIBIC-plus, ADAS-Cog, ADCS-ADL, or CDR-sob over 12 months
The increase in plasma IGF-1 levels was not paralleled by improvement in most functional performance measures. MK-0677 has an unfavorable safety profile in this patient population.
Adunsky A, Chandler J, Heyden N, Lutkiewicz J, Scott BB, Berd Y, Liu N, Papanicolaou DA. · Arch Gerontol Geriatr (2011)
Randomized, double-blind phase-IIb trial in 123 elderly hip-fracture patients: MK-0677 25 mg/day vs placebo
IGF-1 rose 51.4 ng/ml vs placebo (P<0.001), but the primary stair-climbing-power endpoint was not significant (P=0.292); most functional measures did not improve (gait speed was the lone significant one)
TRIAL TERMINATED EARLY due to a safety signal of congestive heart failure in a limited number of patients
Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.
Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, Schilling LM, Cole KY, Skiles EH, Pezzoli SS, Hartman ML, Veldhuis JD, Gormley GJ, Thorner MO. · J Clin Endocrinol Metab (1996)
Randomized, double-blind, placebo-controlled trial in 32 healthy subjects aged 64-81; dose-ranging oral MK-677 (2, 10, 25 mg) for 14 and 28 days
25 mg/day raised 24-h mean GH ~97% and restored IGF-1 to the young-adult range — the foundational human GH/IGF-1 result
IMPORTANT SIDE EFFECT: significant increase in fasting glucose (5.4 → 6.8 mmol/L at 4 weeks; P<0.01) — an early signal of the metabolic cost
MK-677 reverses diet-induced nitrogen wasting, suggesting that if these short-term anabolic effects are maintained in patients who are catabolic ... it may be useful in treating catabolic conditions.
Murphy MG, Plunkett LM, Gertz BJ, He W, Wittreich J, Polvino WM, Clemmons DR. · J Clin Endocrinol Metab (1998)
Double-blind, randomized, placebo-controlled two-period crossover study in 8 healthy volunteers under caloric restriction; oral MK-677 25 mg daily
MK-677 reversed diet-induced negative nitrogen balance (+0.31 vs −1.48 g/day; P<0.01) and raised GH, IGF-1, and IGFBP-3
Cortisol and prolactin responses were not significantly increased; generally well tolerated short-term
2-month treatment with MK-677 in healthy obese males caused a sustained increase in serum levels of GH, IGF-I, and IGF-binding protein-3 ... an oral glucose tolerance test showed impairment of glucose homeostasis at 2 and 8 weeks.
Short-term treatment of healthy obese male volunteers with the GH secretagogue MK-677 increases markers of both bone resorption and formation ... Future long-term studies are needed to investigate if prolonged treatment with MK-677 increases bone mass.
Svensson J, Ohlsson C, Jansson JO, Murphy G, Wyss D, Krupa D, Cerchio K, Polvino W, Gertz B, Baylink D, Mohan S, Bengtsson BA. · J Bone Miner Res (1998)
Randomized, double-blind, parallel, placebo-controlled trial in 24 obese males; MK-677 25 mg/day for 8 weeks
Raised both bone-formation markers (P1CP +23%, osteocalcin +15%) and bone-resorption markers (CTX +26%) — increased bone turnover, not proven bone gain
Large increases in IGF-1 and IGFBP-5; transient IGFBP-4 rise
MK-0677 increased serum IGF-1 levels with minimal adverse effects in hemodialysis subjects. Studies are needed to evaluate whether long-term therapy ... improves PEW, lean body mass, physical strength, quality of life and survival.
We conclude that short-term administration of ibutamoren mesylate can increase GH, IGF-I, and IGFBP-3 levels in some children with GH deficiency.
Codner E, Cassorla F, Tiulpakov AN, Mericq MV, Avila A, Pescovitz OH, Svensson J, Cerchio K, Krupa D, Gertz BJ, Murphy G. · Clin Pharmacol Ther (2001)
Placebo-controlled dose-ranging study in 18 prepubertal children with idiopathic GH deficiency; oral ibutamoren mesylate (MK-0677) 0.2 or 0.8 mg/kg/day for 7-8 days
At 0.8 mg/kg/day, median GH peak, GH AUC0-8, serum IGF-1, and IGFBP-3 rose significantly from baseline — target engagement extended to a distinct (pediatric, GH-deficient) population
Effect was partial: GH/IGF-1 increased in SOME children only, consistent with MK-677 amplifying residual pituitary GH capacity rather than replacing it
Activation of the ghrelin receptor with MK-0677 inhibited the Aβ burden, neuroinflammation, and neurodegeneration, which suggested that MK-0677 might have potential as a treatment of the early phase of AD.
Jeong YO, Shin SJ, Park JY, Ku BK, Song JS, Kim JJ, Jeon SG, Lee SM, Moon M. · Int J Mol Sci (2018)
Mouse study: MK-0677 given to 5XFAD Alzheimer-model mice reduced amyloid-beta deposition, gliosis, and neuronal/synaptic loss
Mechanistic support for a ghrelin-receptor neuroprotection hypothesis in AD
CONTRAST: this animal benefit did NOT translate to humans — the 563-patient human Alzheimer's RCT (Sevigny 2008) was negative