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Peptide Atlas
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MK-677

Tier 1 · Human trials
Also known as Ibutamoren · MK-0677 · Nutrobal

Multiple double-blind, randomized, placebo-controlled human trials exist (healthy volunteers, GH-deficient adults, elderly and hip-fracture patients, including the pivotal 2-year Nass et al. 2008 trial). Human RCT-grade data support GH/IGF-1 elevation and body-composition effects. However, functional-outcome endpoints repeatedly failed and Merck discontinued development; certain PK, sleep, and combination-use claims rest on lower-tier or single sources.

Half-life
~6 h
Routes
Oral · Intravenous · Subcutaneous · Intranasal
Goals
gh stimulation · body composition · fat loss · longevity · cognitive
Cost / mg
Not recorded

How it works

MK-677 (ibutamoren) is an orally active, non-peptide molecule that mimics the hunger hormone ghrelin. It switches on the ghrelin receptor (GHS-R1a) in the pituitary gland and hypothalamus, prompting the body to release more of its own growth hormone (GH), which in turn raises IGF-1. Unlike injected GH, it amplifies the body's natural pulsing pattern of GH release without shutting down the normal feedback system. Because it survives stomach digestion, it can be taken by mouth once daily and keeps GH and IGF-1 elevated for up to about 24 hours. Through the same ghrelin pathway it also increases appetite and can affect sleep, insulin sensitivity, and repair processes.

Overview

Overview

MK-677 (ibutamoren, MK-0677, Nutrobal, L-163,191) is an orally active, non-peptide growth hormone secretagogue and a potent full agonist of the ghrelin receptor (GHS-R1a). It was originally developed by Merck in the 1990s as a candidate treatment for growth hormone deficiency, sarcopenia, and osteoporosis in elderly populations. Patchett and colleagues (1995) described it as the first nonpeptidyl substance with potent, long-lasting oral GH-secretagogue activity in humans, and Howard, Feighner, and colleagues (1996) used it as the pharmacological tool that identified GHS-R1a.

Structurally, MK-677 is a small molecule built on a spiroindoline/spiropiperidine scaffold that survives gastrointestinal degradation, allowing once-daily oral dosing with sustained GH and IGF-1 elevation for up to ~24 hours. GH-releasing activity has also been demonstrated after intravenous, subcutaneous, and intranasal administration.

Mechanism

MK-677 binds GHS-R1a on pituitary somatotrophs and hypothalamic neurons, mimicking endogenous ghrelin. It activates a Gq/11-coupled phospholipase C/IP3/calcium cascade that triggers exocytosis of GH-containing vesicles, and centrally it stimulates GHRH-releasing arcuate neurons while suppressing somatostatin tone (its GH effect is synergistic with GHRH). Importantly, it amplifies natural pulsatile GH secretion — increasing pulse amplitude without changing frequency — and does not suppress the hypothalamic-pituitary axis, leaving negative feedback intact. (One source instead characterizes the net pharmacology as tonic 24-hour activation rather than pulsatile, owing to its half-life plus daily dosing.)

Clinical Evidence

MK-677 has an unusually long clinical research record (>20 years) for a compound in this space:

  • Healthy volunteers under caloric restriction: In a double-blind, placebo-controlled cross-over trial (n=8), 25 mg once daily reversed diet-induced protein catabolism, improving mean nitrogen balance to +0.31 g/day vs -1.48 g/day on placebo. Single-dose peak GH reached 55.9 µg/L (22.6 µg/L after a week) vs ~7-9 µg/L placebo, with IGF-1 and IGFBP-3 increases.
  • GH-deficient adults: 10 mg raised IGF-1 by 52% and 24-h mean GH by 79%; 50 mg raised IGF-1 by 79% and GH by 82%, with the GH response greater in the least-deficient subjects.
  • Elderly adults: GH and IGF-1 rose to young-adult ranges; the pivotal Nass et al. 2008 2-year trial (N=65, 25 mg/day) sustained a 1.5-2x IGF-1 rise without tachyphylaxis and produced a modest fat-free-mass gain (~+1.1 kg).
  • Dose-response (expert estimates): IGF-1 approximately +15-25% at 5 mg, +25-40% at 10 mg, +40-60% at 25 mg, +60-90% at 50 mg.

Key limitation: across RCTs in elderly and hip-fracture patients, large IGF-1 increases (e.g., +84% vs +17% placebo; +51 ng/mL) did not translate into consistent, statistically significant improvements in functional strength or performance. One 24-week trial did show improved gait speed, but most functional endpoints were unchanged. Merck discontinued development after functional endpoints repeatedly failed, and no NDA was submitted.

Additional class-level or early findings include Phase 2 work in muscle wasting, sleep, and bone density; reported height-velocity increases in short children during GHRP treatment; and reduced amyloid deposition and neuronal loss in an Alzheimer's mouse model (5XFAD) — the last two being animal or class-level rather than MK-677-specific controlled findings.

Regulatory Status

MK-677 has not received FDA approval for any indication and remains investigational. It is not legal as a dietary supplement ingredient, is prohibited by WADA, and appears on the DoD Prohibited Dietary Supplement Ingredients List. Despite this, it is widely distributed through gray-market channels as a research chemical and is one of the most prevalent performance-enhancing compounds sold online, marketed for muscle, fat loss, and energy.

What the research shows

288 findings extracted from the 29 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 34 human trial findings, 31 human study findings, 8 animal findings and 11 expert opinion findings.

  • human trialMK-0677 demonstrated an increase in pulsatile GH secretion for as long as the medications were given for up to 2 years1

  • human trialMK-677 reverses diet-induced protein catabolism3

  • human trialDuring diet and study drug treatment, mean daily nitrogen balance was 0.31 +/- 0.21 g/day in the MK-677 treatment group compared with -1.48 +/- 0.21 g/day in the placebo group3

  • human trialMK-677 improved nitrogen balance integrated over 7 days of treatment with area under curve day 8-14 of +2.69 +/- 5.0 compared to placebo -8.97 +/- 5.26 g.day3

  • human trialStudy involved eight healthy volunteers ages 24-39 years in a double-blind, randomized, placebo-controlled, two-period cross-over design3

  • human trialMK-677 reverses diet-induced protein catabolism4

  • human trialDuring caloric restriction with MK-677 treatment, mean daily nitrogen balance was 0.31 +/- 0.21 g/day compared with -1.48 +/- 0.21 g/day in placebo group4

  • human trialMK-677 improved nitrogen balance integrated over 7 days of treatment with area under curve of +2.69 +/- 5.0 g.day versus -8.97 +/- 5.26 g.day for placebo4

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  • human trialIGF-I concentration increased significantly during MK-677 to 264 +/- 31 ng/mL compared with 188 +/- 19 ng/mL with placebo4

  • human trialIGF binding protein-3 increased to 3273 +/- 330 ng/mL with MK-677 treatment compared with 2604 +/- 253 ng/mL placebo4

  • human trialIn two double-blind RCTs in healthy older adults and postmenopausal women, it demonstrated effects on fat-free mass, abdominal visceral fat, and bone turnover markers at 25 mg daily5

  • human trialOral administration of MK-677 stimulates the GH/insulin-like growth factor-I (IGF-I) axis in GH-deficient adults8

  • human trialAfter treatment with 10 mg MK-677, IGF-I concentrations increased 52 +/- 20% (65 +/- 6 to 99 +/- 9 micrograms/L)8

  • human trialAfter treatment with 10 mg MK-677, 24 h mean GH concentrations increased 79 +/- 19% (0.14 +/- 0.01 to 0.26 +/- 0.02 microgram/L)8

  • human trialFollowing treatment with 50 mg MK-677, IGF-I concentrations increased 79 +/- 9% (84 +/- 3 to 150 +/- 6 micrograms/L)8

  • human trialFollowing treatment with 50 mg MK-677, 24-h mean GH concentrations increased 82 +/- 29% (0.21 +/- 0.02 to 0.39 +/- 0.04 microgram/L)8

  • human trialSerum IGF binding protein-3 concentrations increased with 10 mg MK-677 (1.2 +/- 0.1 to 1.7 +/- 0.1 micrograms/L)8

  • human trialSerum IGF binding protein-3 concentrations increased with 50 mg MK-677 (1.7 +/- 0.1 to 2.2 +/- 0.2 micrograms/L)8

  • human trialThe GH response to MK-677 was greater in subjects who were the least GH/IGF-I deficient at baseline8

  • human trialMK-0677 at 25mg/day increased mean stair climbing power by 12.5 W at 24-weeks in elderly hip fracture patients10

  • human trialGait speed increased by 0.7-score difference in MK-0677 treated patients compared to placebo (p = 0.011)10

  • human trialMK-0677 group experienced fewer falls during the study compared to placebo10

  • human trialIncrease in plasma IGF-1 levels was not paralleled by improvement in most functional performance measures10

  • human trialMK-0677 treatment increased serum IGF-I levels by 84% compared with an increase of 17% on placebo11

  • human trialThere were no significant differences between MK-0677 and placebo in improvement in functional performance measures or in the overall SIP-NH score11

  • human trialMK-0677 patients showed greater improvement relative to placebo in three of four lower extremity functional performance measures, in the physical domain of the SIP, and in the ability to live independently, but these differences were not statistically significant11

  • human trialMK-0677 treatment increased serum IGF-I but uncertainty exists regarding clinically significant effects on physical function11

  • human trialIn the pivotal two-year Nass trial, MK-677 increased fat-free mass by 1.1 kg23

  • human trialMerck discontinued development after functional endpoints consistently failed23

  • human trialMerck's trials confirmed GH and IGF-1 restoration in healthy elderly adults, with increased fat-free mass but no improvement in functional strength or outcomes23

  • human trialIn clinical trials, MK-677 increased GH levels 2-10 fold and IGF-1 levels 1.5-3 fold, with effects lasting 6-14 days after a single dose27

  • human trialA 2-year trial in older adults showed sustained GH and IGF-1 elevation27

  • human trialChapman IM et al. demonstrated dose-dependent GH elevation restoring IGF-1 to young adult levels in elderly subjects28

  • human trialModest fat-free-mass gain of approximately +1.1 kg observed in human double-blind RCTs28

  • human studyMK-677 has been studied in multiple clinical trials involving hundreds of participants over periods of up to 2 years2

  • human studyAverage IGF-1 elevation of 40-89% has been documented across clinical trials, with sustained effects during chronic administration2

  • human studyGHSs might improve growth velocity in children9

  • human studyGHSs stimulate appetite9

  • human studyGHSs improve lean mass in wasting states and in obese individuals9

  • human studyGHSs decrease bone turnover9

  • human studyGHSs increase fat-free mass9

  • human studyGHSs improve sleep9

  • human studyThe GH-releasing activity of GHRPs including MK-0677 is marked and dose-related12

  • human studyProlonged administration of GHRPs increases IGF-1 levels in both animals and humans12

  • human studyThe GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations, increasing from birth to puberty, persisting in adulthood, and decreasing thereafter12

  • human studyBy the sixth decade of life, the activity of GHRPs is reduced but still marked and higher than GHRH12

  • human studyGHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as acromegaly, anorexia nervosa and hyperthyroidism12

  • human studyReduced GH responses after GHRP administration have been reported in idiopathic GH deficiency, idiopathic short stature, obesity and hypothyroidism12

  • human studyIn patients with pituitary stalk disconnection or Cushing's syndrome, somatotrope responsiveness to GHRPs is almost absent12

  • human studyMK-677 co-administered with LGD-4033 increased body mass by 6.0%16

  • human studyMK-677 co-administered with LGD-4033 increased total lean body mass by 3.1%16

  • human studyMK-677 co-administered with LGD-4033 increased trunk lean body mass by 6.6%16

  • human studyMK-677 co-administered with LGD-4033 increased appendicular lean body mass by 4.3%16

  • human studyMK-677 co-administered with LGD-4033 increased total fat mass by 15.4%16

  • human studyMost measured variables returned to pre-cycle values post-cycle except total fat mass, appendicular fat mass, bone area, total cholesterol and low-density lipoprotein-cholesterol16

  • human studyEarly investigational work established that MK-677 could reliably elevate GH and IGF-1 levels in healthy subjects following oral administration21

  • human studyMurphy et al. 1998 showed sustained 24-hour GH and IGF-1 elevation at 25 mg/day24

  • human studyNass et al. 2008 conducted a 2-year trial in healthy elderly adults (N=65)24

  • human studyIGF-1 increases approximately 40-60% above baseline in most published cohorts24

  • human studyMK-677 raises GH in a dose-dependent manner after a single oral dose24

  • human studyMK-677 increases both pulse amplitude and mean 24-hour GH concentrations while preserving the pulsatile secretion pattern24

  • human studyPivotal long-term study by Nass R et al. randomized elderly subjects to 25 mg MK-677 daily versus placebo for 12 months; IGF-1 increased 1.5-2x and was sustained throughout the trial without tachyphylaxis25

  • human studyMK-677 has been shown to increase serum GH and IGF-1 levels to young-adult ranges in elderly populations while preserving the natural pulsatile pattern of GH secretion26

  • human studyMK-677 increases GH pulse amplitude without altering pulse frequency26

  • human studyCompleted Phase 2 trials for muscle wasting, sleep, and bone density28

  • animalMK-0677-treated 5XFAD mice showed reduced Aβ deposition, gliosis, and neuronal and synaptic loss in the deep cortical layers17

  • animalFollowing initial oral administration of MK-0677, GH secretion was increased 7.9- to 9.8-fold at 1.0 mg/kg, 5.6-fold at 0.5 mg/kg, or 3.9-fold at 0.25 mg/kg19

  • animalWith repeat MK-0677 administration, the GH response was decreased by 41-77%19

  • animalSerum IGF-I levels were significantly increased over control levels at all dosage levels by 480 min on the first day of MK-0677 administration19

  • animalWith repeated administration, IGF-I levels were increased up to 126% and remained elevated through 14 days19

  • animalMK-0677 stimulated increases in cortisol secretion on the first day of treatment19

  • animalA decreased cortisol response was observed following repeated daily treatment with MK-067719

  • animalChronic oral administration of MK-0677 was associated with significant increases in GH and IGF-I levels that were maintained for the duration of the treatment19

  • expert opinionFew long-term, rigorously controlled studies have examined the efficacy and safety of GHSs9

  • expert opinionMK-677 elevates 24-hour GH exposure and IGF-1 by approximately 40-90% at standard 25 mg/day research doses20

  • expert opinionMK-677 is extensively characterised in the clinical literature with studies up to 2 years duration20

  • expert opinionAt 5 mg daily: IGF-1 +15-25% from baseline20

  • expert opinionAt 10 mg daily: IGF-1 +25-40%20

  • expert opinionAt 25 mg daily: IGF-1 +40-60%20

  • expert opinionAt 50 mg daily: IGF-1 +60-90%20

  • expert opinionMerck's investigational new drug program was discontinued following pivotal trial results; no NDA was submitted23

  • expert opinionActivation produces sustained increases in pulsatile growth hormone secretion, insulin-like growth factor 1 (IGF-1), typically 1.5-2x baseline at 25 mg/day, appetite, and slow-wave sleep duration in some users25

  • expert opinionHypothalamic receptor activation modulates sleep architecture, increasing REM and Stage 4 deep sleep by up to 50%28

  • expert opinionGHS can significantly improve body composition while ameliorating specific hypogonadal symptoms including fat gain and muscular atrophy29

How it works

Based on 7 human trial findings, 6 human study findings, 16 animal findings, 12 in vitro findings, 39 expert opinion findings and 2 theoretical findings.

  • human trialMK-677 is an orally active nonpeptide mimic of GH-releasing peptide3

  • human trialMK-677 is an orally active nonpeptide mimic of GH-releasing peptide4

  • human trialMK-677 (ibutamoren) is an orally active, non-peptide ghrelin receptor agonist that stimulates pulsatile growth hormone secretion and elevates IGF-1 levels5

  • human trialMK-677 is a GH releasing peptide (GHRP)-mimetic8

  • human trialIGF-1 levels in MK-0677 treated patients increased by 51.4 ng/ml compared to placebo (p < 0.001)10

  • human trialMK-0677 is an orally active growth hormone secretagogue11

  • human trialMK-677 preserves pulsatile GH release pattern even during continuous stimulation27

  • human studyMK-677 elevates GH through the same physiological pathway as endogenous ghrelin — pulsatile pituitary release — rather than providing exogenous GH2

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  • human studyMK-677 does not suppress the hypothalamic-pituitary axis: it amplifies the natural GH pulsatility pattern rather than replacing it, and negative feedback mechanisms remain intact2

  • human studyMK-677 amplifies endogenous GH pulse amplitude by 2-5 fold while maintaining the normal pulsatile rhythm2

  • human studyIbutamoren is incorporated into human hair6

  • human studyGHSs promote pulsatile release of GH that is subject to negative feedback and can prevent supra-therapeutic levels of GH9

  • human studyThe GH-releasing activity of GHRPs is synergistic with GHRH12

  • animalAnimal studies indicate that MK-677 and related secretagogues share an overlapping binding site with endogenous ghrelin on the ghrelin receptor5

  • animalAnimal studies indicate that oral MK-677 at 4 mg/kg in rats increased peak serum GH, body weight, tibia length, epiphyseal plate width, and IGF-I5

  • animalPreliminary animal data suggest that ghrelin receptor agonism can reverse stress-induced suppression of food-seeking behavior in fasted mice5

  • animalGhrelin improves cognitive impairments and attenuates neuronal death and neuroinflammation in several neurological disorders17

  • animalMK-0677 inhibited the decrement of pCREB levels in dentate gyrus of the hippocampus compared to vehicle-treated 5XFAD mice17

  • animalActivation of the ghrelin receptor with MK-0677 inhibited the Aβ burden, neuroinflammation, and neurodegeneration17

  • animalIn conscious male rats, both central and systemic injection of MK-0677 induced fos-like immunoreactivity specifically within the arcuate nucleus indicating selective neuronal activation18

  • animalMK-0677 induced-activation was generally confined close to the wall of the third ventricle18

  • animalIntravenous injection of MK-0677 in urethane anaesthetized rats increased the electrical activity of a population of antidromically identified neuroendocrine arcuate neurons18

  • animalThe activity of neuroendocrine arcuate neurons excited by MK-0677 injection could be attenuated by a subsequent systemic injection of somatostatin18

  • animalSystemic and central administration of MK-0677 activates a population of neurons in the arcuate nucleus18

  • animalMK-0677 is a novel, orally active GH secretagogue that stimulates an immediate and long-lasting increase in serum GH levels in dogs19

  • animalSignificant elevations in IGF-I levels were associated with the increased GH secretion19

  • animalCortisol secretion was also increased following MK-0677 administration19

  • animalCirculating IGF-I concentrations regulate GH and cortisol response to MK-067719

  • animalIGF-I mediated negative feedback on both the GH and cortisol axes19

  • in vitroMK-677 binds to and activates the growth hormone secretagogue receptor type 1a (GHSR1a) in the hypothalamus and pituitary gland2

  • in vitroMK-677 acts as a ghrelin receptor (GHS-R1a) agonist, binding the receptor with an affinity of 6.5 nM5

  • in vitroIn vitro mechanistic work characterizes growth hormone secretagogues as orthosteric super-agonists rather than allosteric regulators for activation of the G protein Gα(o1) by the ghrelin receptor5

  • in vitroMK-0677 (ibutamoren) is an orally active non-peptide growth hormone secretagogue that binds to the ghrelin receptor stimulating the secretion of endogenous growth hormone13

  • in vitroMK-0677 is a ghrelin agonist that potently stimulates the GHS-R1a ghrelin receptor17

  • in vitroMK-0677 is a nonpeptidyl growth hormone secretagogue18

  • in vitroMK-0677 has been shown to directly stimulate growth hormone release from isolated pituitary cells18

  • in vitroMK-677 is a selective agonist at GHSR-1a with EC50 in the low nanomolar range in in vitro receptor assays20

  • in vitroMK-677 is a full agonist at GHSR-1a (no partial agonism)20

  • in vitroMK-677 has minimal activity at closely related receptors (motilin, neuromedin U)20

  • in vitroMK-677 has no significant activity at GHRH receptor, somatostatin receptors, or classical monoamine receptors20

  • in vitroMK-677 binds to ghrelin receptor on pituitary somatotrophs, triggering calcium-mediated GH vesicle release without affecting pulse frequency28

  • expert opinionMK-677 is a non-peptide, orally active growth hormone secretagogue that acts as a potent agonist of the ghrelin receptor (GHSR1a)2

  • expert opinionMK-677 is a growth hormone secretagogue7

  • expert opinionMK-0677 is a non-peptidyl GHRP mimetic that acts via GHRP receptors and is considered the most interesting molecule among non-peptidyl GHRPs12

  • expert opinionIbutamoren (MK-0677) is a potent, long-acting, selective non-peptide growth hormone secretagogue that can be taken orally14

  • expert opinionIbutamoren mesylate, or MK-0677, is an orally active, nonpeptide growth hormone secretagogue that has been developed to stimulate excretion of endogenous growth hormone15

  • expert opinionMK-677 is a growth hormone secretagogue16

  • expert opinionMK-677 (ibutamoren, L-163,191) is an orally bioavailable non-peptide growth hormone secretagogue that mimics ghrelin by agonism at the GHSR-1a receptor20

  • expert opinionUnlike injectable ghrelin-mimetics, it produces tonic rather than pulsatile receptor activation20

  • expert opinionMost growth-hormone secretagogue research using injectable peptides (GHRP-6, hexarelin, ipamorelin) produces transient pulses; MK-677 produces sustained tonic activation because its half-life (4-6 hours) combined with daily oral dosing spans the full 24-hour cycle20

  • expert opinionMK-677 (Ibutamoren) is a non-peptide, orally active compound with the ability to stimulate endogenous growth hormone secretion by activating the ghrelin receptor (GHS-R1a)21

  • expert opinionMK-677 amplifies the natural GH-IGF-1 axis without directly administering exogenous growth hormone21

  • expert opinionGhrelin, an endogenous ligand produced primarily in the stomach, exerts its effects through the growth hormone secretagogue receptor type 1a (GHS-R1a)21

  • expert opinionGHS-R1a activation triggers downstream signaling cascades that promote GH release, appetite regulation, and energy homeostasis21

  • expert opinionGHS-R1a activation modulates sleep architecture, insulin sensitivity, and cellular repair pathways21

  • expert opinionGhrelin receptor agonists amplify GH secretion through dual mechanisms—enhancing GHRH stimulation while simultaneously inhibiting somatostatin activity21

  • expert opinionMK-677 appears to augment existing GH pulses rather than abolish their natural rhythm21

  • expert opinionMK-677, also known as Ibutamoren, is a "growth hormone secretagogue," a substance that stimulates the production of growth hormone.22

  • expert opinionMK-677 is an oral non-peptide ghrelin receptor agonist23

  • expert opinionBinds the ghrelin receptor (GHSR-1a) as an agonist, stimulating pulsatile GH secretion and sustained IGF-1 elevation via oral administration23

  • expert opinionMK-677 is a spiropiperidine: a synthetic small molecule built around a non-peptide scaffold23

  • expert opinionMK-677 (ibutamoren mesylate) is a non-peptide GH secretagogue24

  • expert opinionMK-677 is an oral ghrelin receptor (GHS-R1a) agonist24

  • expert opinionPatchett and colleagues (1995) described MK-677 as the first example of a nonpeptidyl substance with potent, long-lasting oral activity as a GH secretagogue in humans24

  • expert opinionHoward, Feighner, and colleagues (1996) identified GHS-R1a (growth hormone secretagogue receptor type 1a) using MK-677 as a pharmacological tool24

  • expert opinionMK-677 is a ghrelin mimetic that binds the same receptor ghrelin binds24

  • expert opinionMK-677 binds GHS-R1a with high affinity and activates a Gq/11-coupled signaling cascade24

  • expert opinionMK-677 amplifies physiological GH pulses rather than creating a flat pharmacological concentration24

  • expert opinionMK-677 is a non-peptide, orally bioavailable agonist of the GHS-R1a (ghrelin) receptor25

  • expert opinionMK-677 is a non-peptide, small-molecule spiroindoline that survives oral absorption25

  • expert opinionMK-677 binds the GHS-R1a receptor on pituitary somatotrophs and on hypothalamic neurons, mimicking endogenous ghrelin25

  • expert opinionMK-677 is a potent, orally active, non-peptide agonist of the growth hormone secretagogue receptor type 1a (GHS-R1a), also known as the ghrelin receptor26

  • expert opinionMK-677 activates GHS-R1a in the hypothalamic feeding centers, stimulating appetite through the same pathway as endogenous ghrelin26

  • expert opinionMK-677 is an oral non-peptide ghrelin mimetic (growth hormone secretagogue) that stimulates growth hormone release by activating the ghrelin receptor27

  • expert opinionMK-677 works by mimicking the hormone ghrelin, binding to the ghrelin receptor (GHSR) in the brain to stimulate growth hormone (GH) release from the pituitary gland27

  • expert opinionMK-677 does not suppress endogenous GH production27

  • expert opinionMK-677 is an orally-active, non-peptide growth hormone secretagogue that mimics ghrelin's effects on GHS-R1a28

  • expert opinionMK-677 produces sustained IGF-1 elevation28

  • expert opinionHepatic IGF-1 synthesis remains elevated for 24+ hours28

  • expert opinionGHS including sermorelin, GHRP-2, GHRP-6, ibutamoren, and ipamorelin are potent GH and IGF-1 stimulators29

  • theoreticalMK-677 activates the Gq/11-coupled phospholipase C (PLC)/inositol trisphosphate (IP3)/calcium signaling cascade, triggering exocytosis of GH-containing vesicles26

  • theoreticalMK-677 acts on GHS-R1a receptors in the hypothalamus, stimulating GHRH-releasing neurons in the arcuate nucleus while suppressing somatostatin tone26

Dosing

Based on 3 human trial findings, 2 human study findings, 1 animal finding, 2 expert opinion findings and 1 anecdotal finding.

  • human trialTypical dose 25mg/day PO5

  • human trialFrequency: Once daily, based on human RCT protocols5

  • human trialMK-677 administered orally at 10 or 50 mg once daily8

  • human studyA single 25 mg oral dose typically increases peak GH levels by 2-5 fold2

  • human studyCycle length 8w-2y5

  • animalDaily MK-0677 administration increased IGF-I levels over 24 h, but alternate day MK-0677 administration did not show such sustained increase19

  • expert opinionMK-677 is administered as an oral capsule, once daily dosing24

  • expert opinion25 mg is the validated trial dose; higher doses (50 mg, 100 mg) showed diminishing IGF-1 returns and proportionally larger side effects in early Merck trials25

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  • anecdotalMost users find 10-25 mg a sweet spot; 25 mg is the common ceiling25

How the body handles it

Based on 5 human trial findings, 7 human study findings, 12 animal findings, 1 in vitro finding and 13 expert opinion findings.

  • human trialMK-677 produced a peak GH response of 55.9 +/- 31.7 micrograms/L after single dose and 22.6 +/- 9.3 micrograms/L after a week of dosing3

  • human trialMean IGF-I concentration increased significantly during MK-677 to 264 +/- 31 ng/mL compared with 188 +/- 19 ng/mL with placebo3

  • human trialMean IGF binding protein-3 for the last 5 days of MK-677 treatment was significantly increased to 3273 +/- 330 ng/mL compared with placebo 2604 +/- 253 ng/mL3

  • human trialNo significant difference in IGF binding protein-2 was found between MK-677 and placebo treatments3

  • human trialMK-677 produced peak GH response of 55.9 +/- 31.7 micrograms/L after single dose and 22.6 +/- 9.3 micrograms/L after one week of dosing4

  • human studyMK-677 provides sustained elevation of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels for up to 24 hours from a single daily dose2

  • human studyMK-677 is detectable in hair for at least 4 weeks after a single dose5

  • human studyA single 10 mg dose of ibutamoren (MK-677) administered to a male volunteer resulted in hair concentration of 1.3 pg/mg in the 0 to 1 cm segment 4 weeks after exposure6

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  • human studyAfter consumption of 60 capsules of 10 mg ibutamoren over 90 days, hair concentration reached 224 pg/mg in the 0 to 4 cm segment 4 weeks after drug discontinuation6

  • human studyibutamoren mesylate is an orally available small-molecule GH secretagogue9

  • human studyMK-0677 demonstrates GH-releasing activity after intravenous, subcutaneous, intranasal and oral administration12

  • human studyOral bioavailability ~60-65% absorbed through GI tract with single daily dose maintaining effect for 24 hours28

  • animalMK-0677 and its O-dealkylated metabolite can be extracted from equine hair and analysed by liquid chromatography tandem mass spectrometry13

  • animalMK-0677 can be detected in all hair samples collected following oral administration to a Thoroughbred racehorse, up to 209 days in mane and 358 days in tail13

  • animalInternal incorporation of MK-0677 via bloodstream was indicated for hair samples collected at later time points (≥52 days)13

  • animalA combination of internal incorporation and external deposition was indicated for hair samples collected at the earlier time point (2 days)13

  • animal22 metabolites of ibutamoren were identified (17 phase I and 5 phase II)14

  • animalOxidation of ibutamoren leads to hydroxylated metabolites (mono and di)14

  • animalThe study detected dissociated side chains (benzyl group and 2-amino-2-methylpropanamide) and hydrogenated metabolites14

  • animalGlucuronic acid conjugated analogs of ibutamoren were detected during phase II of the study, but no sulfonic acid conjugated analogs were observed14

  • animalThe major metabolites can be detected up to 96 hours after a single dose, and ibutamoren can persist for up to 72 hours14

  • animal13 metabolites were subsequently detected in urine and nine in plasma collected post-administration, alongside the parent compound in both matrices15

  • animalThe longest duration of detection was observed for an O-dealkylated metabolite of MK-067715

  • animalMK-0677 and the O-dealkylated metabolite were found to be excreted largely unconjugated in urine and plasma15

  • in vitroFourteen phase I metabolites were identified in vitro15

  • expert opinionOral bioavailability approximately 60% at 25 mg dose20

  • expert opinionTmax: 1-2 hours after oral dose20

  • expert opinionPlasma half-life: 4-6 hours20

  • expert opinionDuration of GH-releasing effect: 12-24 hours (single dose); tonic at daily steady state20

  • expert opinionHigh-fat meal delays Tmax by ~1 hour and reduces Cmax ~20% but does not affect total AUC20

  • expert opinionSteady state reached: 5-7 days of once-daily dosing20

  • expert opinionPrimary metabolism: hepatic, CYP3A420

  • expert opinionMK-677 achieves systemic bioavailability through oral administration, making it pharmacologically distinct from injectable peptide secretagogues21

  • expert opinionMK-677 has an elimination half-life of approximately 24 hours23

  • expert opinionMK-677 has a plasma half-life of approximately 5 hours24

  • expert opinionPlasma half-life is approximately 4-6 hours; biologically effective duration on the GH/IGF-1 axis is roughly 24 hours25

  • expert opinionMK-677 has an elimination half-life of approximately 24 hours26

  • expert opinionMK-677 is resistant to gastrointestinal degradation and can be administered orally once daily26

Safety and side effects

Based on 12 human trial findings, 24 human study findings, 11 expert opinion findings and 1 anecdotal finding.

  • human trialNeither serum cortisol nor PRL response was significantly greater after 7 days of MK-677 dosing compared with placebo3

  • human trialMK-677 (25 mg) was generally well tolerated and without clinically significant adverse experiences3

  • human trialMK-677 25 mg was generally well tolerated and without clinically significant adverse experiences4

  • human trialNo significant difference in serum cortisol or prolactin response after 7 days of MK-677 dosing compared with placebo4

  • human trialThe drug was generally well tolerated, with no significant changes from baseline in circulating concentrations of cortisol, PRL, and thyroid hormones8

  • human trialFasting and postprandial insulin and postprandial glucose increased significantly after MK-677 treatment8

  • human trialTrial was terminated early due to a safety signal of congestive heart failure in a limited number of patients10

  • human trialMK-0677 has an unfavorable safety profile in elderly hip fracture patients10

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  • human trialA congestive heart failure signal emerged in the elderly hip fracture trial, prompting its early termination23

  • human trialSafety signals included elevated fasting glucose, increased HbA1c, and congestive heart failure events in an elderly hip fracture trial23

  • human trialMK-677 consistently worsens insulin sensitivity and raises fasting glucose27

  • human trialOne clinical trial in elderly patients with congestive heart failure was terminated early due to increased heart failure events in the MK-677 group27

  • human studyCase reports document hepatotoxicity, gynecomastia, hypogonadotropic hypogonadism, and dyslipidemia, particularly when combined with SARMs5

  • human studyThe minimal detectable dose of ibutamoren in hair has been established through this study6

  • human studySide effects of MK-677 include oedema, increased appetite and muscle pain7

  • human studyReports of hepatotoxicity from MK-677 are scarce7

  • human studyMK-677 consumption for 2 months can cause transaminitis in otherwise healthy individuals7

  • human studyLiver function tests returned to normal limits after stopping MK-677 supplement7

  • human studyGHSs are well tolerated9

  • human studyThere is concern for increases in blood glucose because of decreases in insulin sensitivity with GHS use9

  • human studyGHRPs undergo partial desensitization during continuous infusion, less during intermittent administration12

  • human studyMK-677 co-administered with LGD-4033 negatively impacted bone mineral content, decreasing by 3.60%16

  • human studyMK-677 co-administered with LGD-4033 negatively impacted bone area, decreasing by 1.1%16

  • human studyMK-677 co-administered with LGD-4033 negatively impacted bone mineral density, decreasing by 2.1%16

  • human studyMK-677 co-administered with LGD-4033 increased serum cholesterol by 14.8%16

  • human studyMK-677 co-administered with LGD-4033 increased triglycerides by 39.2%16

  • human studyMK-677 co-administered with LGD-4033 increased low-density lipoprotein-cholesterol by 40.0%16

  • human studyMK-677 co-administered with LGD-4033 decreased high-density lipoprotein-cholesterol by 36.4%16

  • human studyMK-677 co-administered with LGD-4033 increased aspartate aminotransferase by 95.8%16

  • human studyMK-677 co-administered with LGD-4033 increased alanine aminotransferase by 205.0%16

  • human studyMK-677 co-administered with LGD-4033 decreased free testosterone by 85.7%16

  • human studyMK-677 co-administered with LGD-4033 decreased total testosterone by 62.3%16

  • human studyMK-677 co-administered with LGD-4033 decreased sex hormone-binding globulin by 79.6%16

  • human studyFollicle-stimulating hormone was below clinical reference values at 1.2 IU/L on-cycle and 1.3 IU/L post-cycle following MK-677 and LGD-4033 co-administration16

  • human studyNotable side effects include transient appetite increase, mild edema, and dose-dependent insulin resistance24

  • human studyMK-677 trial documented side effects: increased appetite, modest fasting glucose elevation (HbA1c +0.3%), and edema25

  • expert opinionSide effects include transient fluid retention, appetite stimulation, insulin resistance at high doses20

  • expert opinionMK-677 produces no appreciable cortisol or prolactin elevation at standard doses20

  • expert opinionA number of health risks have been associated with the use of MK-677 (Ibutamoren).22

  • expert opinionMK-677 is not FDA approved and remains investigational24

  • expert opinionSide effects include water retention, increased appetite, glucose-tolerance changes25

  • expert opinionA halted elderly hip-fracture trial in 2007 left lingering questions about cardiac safety25

  • expert opinionMK-677 is not FDA-approved for any indication25

  • expert opinionMK-677 is banned for competitive athletes by WADA25

  • expert opinionSafety concerns, particularly regarding insulin resistance and congestive heart failure risk in elderly populations, have limited its clinical development26

  • expert opinionMK-677 increases appetite as a side effect due to ghrelin mimicry27

  • expert opinionNot FDA approved; WADA prohibited28

  • anecdotalIsolated recurring signals include glucose intolerance, edema, and lethargy28

What people use it for

Based on 2 human study findings, 1 animal finding, 13 expert opinion findings and 2 anecdotal findings.

  • human studyAn increase in height velocity has been reported in short children during chronic GHRP treatment12

  • human studyMK-677 was studied across multiple clinical populations, including elderly adults with reduced GH secretion, patients with GH deficiency, and individuals with catabolic conditions21

  • animalMK-0677 might have potential as a treatment of the early phase of AD17

  • expert opinionMK-677 was originally developed by Merck as a potential treatment for growth hormone deficiency, sarcopenia, and osteoporosis in elderly populations2

  • expert opinionMK-0677 is one of the most prevalent performance-enhancing compounds currently available online13

  • expert opinionMK-0677 has been evaluated for the treatment of a range of clinical conditions but is not available therapeutically15

  • expert opinionMK-677 is the only orally bioavailable, long-acting, selective ghrelin-receptor agonist with a substantial (>20 years) clinical research record20

  • expert opinionIt is not approved for human use, which makes it an unapproved drug.22

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  • expert opinionIt is also not legal for use as an ingredient in dietary supplements or any other consumer or commercial products.22

  • expert opinionIt can only be used for research purposes.22

  • expert opinionMK-677 is on the DoD Prohibited Dietary Supplement Ingredients List and the World Anti-Doping Agency Prohibited List.22

  • expert opinionAs of April 2026, MK-677 is not FDA-approved for any indication23

  • expert opinionMK-677 is distributed through unregulated gray-market channels as a research chemical23

  • expert opinionMK-677 has not received FDA approval for any clinical use26

  • expert opinionMK-677 is WADA-prohibited and is sold illegally as a research chemical or supplement27

  • expert opinionGrowth hormone secretagogues (GHS) have emerged as a potential novel adjunctive therapy for some of the symptoms of hypogonadism29

  • anecdotalMK-677 is currently marketed with claims to help build muscle or increase muscle mass, decrease body fat, and increase energy.22

  • anecdotalCommunity experience reports include sleep, appetite, and water retention as consistent themes28

Other findings

Based on 2 human study findings and 7 expert opinion findings.

  • human studyLinearity for ibutamoren hair detection was verified from 0.5 to 250 pg/mg6

  • human studyThe limit of detection for ibutamoren in hair was 0.1 pg/mg6

  • expert opinionMK-0677 is widely available to purchase online, sold as 'supplement' products15

  • expert opinionMK-677 is a non-peptide small molecule with a spiroindoline core designed at Merck in the 1990s20

  • expert opinionMolecular weight 528.67 g/mol20

  • expert opinionMK-677 was originally developed by Merck & Co. in the 1990s as part of research to identify orally bioavailable compounds capable of stimulating GH release21

  • expert opinionMK-677 never received regulatory approval for clinical use21

  • expert opinionMK-677 was developed by Merck (compound code MK-0677) in the 1990s25

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  • expert opinionCurrent data on clinical efficacy of GHS largely remain lacking29

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Contested

Whether MK-677 raises cortisol is not consistent across sources.

Human RCTs report no significant cortisol or prolactin elevation at standard doses (MK-677, an orally active growth hormone secretagogue, reverses ..., Oral Administration of Growth Hormone (GH) Releasing Peptide-Mimetic MK-677 Stimulates the GH/Insulin-Like Growth Factor-I Axis in Selected GH-Deficient Adults 1, MK-677 Ibutamoren UK 2026 Research Reference - Peptides Lab UK, MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism - PubMed), whereas a dog study found MK-0677 increased cortisol on the first day of treatment (attenuated with repeat dosing) (Repeat administration of the GH secretagogue MK-0677 increases and maintains elevated IGF-I levels in beagles.).

Contested

Sources disagree on whether MK-677 preserves the body's natural pulsatile GH release or instead drives sustained, tonic stimulation.

Most references state that MK-677 amplifies GH pulse amplitude while leaving pulse frequency unchanged, thereby preserving the physiological pulsatile secretion pattern (MK-677 (Ibutamoren): Research Evidence & Safety Profile | PeptideInsight; MK-677: 42 Studies Reviewed | PepCodex; MK-677: History, Development, and Mechanism of Action | HealthRX.com; MK-677 Guide: Ibutamoren Benefits, Evidence & Risks | PeptideMark; MK-677 (Ibutamoren) Research Guide at Path to Peptides). One reference directly contradicts this: the MK-677 Ibutamoren UK 2026 Research Reference (Peptides Lab UK) states that its 4-6 hour half-life combined with once-daily dosing keeps trough concentrations pharmacologically active, so it 'produces tonic rather than pulsatile receptor activation' and, in its own words, 'does not preserve physiological GH pulsatility.' The disagreement is therefore not one of emphasis but about whether pulsatility is retained at all.

Limited evidence

IGF-1 rises reliably but functional benefits were not demonstrated.

Multiple RCTs in elderly/hip-fracture patients confirmed large IGF-1 increases but failed to show statistically significant improvements in most functional performance measures (MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study., The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture., Superpower), and Merck discontinued development after functional endpoints failed. A review notes few long-term, rigorously controlled efficacy/safety studies exist for GHS.

Limited evidence

Cardiac safety concern based on a terminated trial in a specific frail population.

The congestive heart failure signal that led to early termination arose in an elderly hip-fracture trial; whether it generalizes to other populations is not established, and the number of affected patients was limited (MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study.). Sources describe it as leaving 'lingering questions' rather than a definitive causal finding.

Single source

Severe adverse endocrine/lipid/liver changes come from a single combination-use case study.

The dramatic decreases in testosterone/SHBG, large LDL and triglyceride increases, and ~2-3x liver enzyme elevations are from one human observational study of MK-677 combined with the SARM LGD-4033 (LGD-4033 and MK-677 use impacts body composition, circulating biomarkers, and skeletal muscle androgenic hormone and receptor content: A case report.), so these effects cannot be attributed to MK-677 alone.

Single source

Some pharmacokinetic and sleep specifics rest on single, lower-tier sources.

The 'up to 50% increase in REM and Stage 4 deep sleep' figure and ~60-65% bioavailability appear in a single tier-3 source (MK-677: 42 Studies Reviewed (2026) | PepCodex); detailed PK parameters (CYP3A4 metabolism, Tmax, high-fat meal effect, dose-response IGF-1 percentages) come largely from one tier-3 source (MK-677 Ibutamoren UK 2026 Research Reference - Peptides Lab UK).

Limited evidence

Neuroprotective and growth-velocity uses are early/animal or class-level only.

The Alzheimer's-model benefit is from mice (MK-0677, a Ghrelin Agonist, Alleviates Amyloid Beta-Related Pathology in 5XFAD Mice, an Animal Model of Alzheimer's Disease.), and reported height-velocity increases in children and other therapeutic uses are from GHRP-class observations rather than MK-677-specific controlled trials (Growth hormone-releasing peptides., The Safety and Efficacy of Growth Hormone Secretagogues.).

Inconsistency

Two sources give wildly different single-dose durations — roughly 24 hours versus 6-14 days.

Reference guides disagree by more than an order of magnitude on how long a single dose of MK-677 keeps GH and IGF-1 elevated. The PtP Wiki research guide (MK-677 (Ibutamoren): Research Guide | PtP Wiki) states effects last 'up to 24 hours from a single daily dose,' with a plasma half-life of ~4-6 hours and a pharmacodynamic duration of ~24 hours that is used to justify once-daily dosing. The PeptideMark guide (MK-677 Guide: Ibutamoren Benefits, Evidence & Risks (2026) | PeptideMark) instead states that clinical effects last '6-14 days after a single dose.' A multi-day effect is hard to reconcile with the ~4-6 hour plasma half-life and the once-daily-dosing rationale both described by the PtP Wiki source, so the 6-14 day figure should be treated with caution.

What you may have heard

The injectable and intranasal routes listed for MK-677 come from a review of the whole GH-releasing peptide family, not from data on MK-677 itself, which the literature describes as an orally active molecule.

The review Growth hormone-releasing peptides attributes marked, dose-related GH-releasing activity "after intravenous, subcutaneous, intranasal and even oral administration" to GH-releasing peptides as a class; MK-0677 is named within it only as the most interesting non-peptidyl member of that class, not as the specific compound tested by each route. Across compound-specific references MK-677 is consistently characterized as a non-peptide, orally active molecule engineered for oral bioavailability, with oral listed as its studied route and injection reserved for the peptide secretagogues it was designed to replace. Presenting the class-level routes as established MK-677 routes overstates how the compound is actually characterized and used.

What you may have heard

The exact receptor-binding figure and the "no activity anywhere else" selectivity profile each rest on a single source, and the two sources describe the compound's potency in different terms.

The specific ghrelin-receptor binding affinity of 6.5 nM is reported only in MK-677: Mechanism, Dosing & Evidence (Pepteligence), which also notes that nonpeptide secretagogues like MK-677 can behave both as simple agonists and as positive or negative allosteric modulators at the same receptor. The detailed selectivity panel — full agonism at GHSR-1a with minimal activity at motilin and neuromedin U receptors and no significant activity at GHRH, somatostatin, or monoamine receptors — appears only in the commercial vendor reference MK-677 Ibutamoren UK 2026 Research Reference (Peptides Lab UK), which expresses potency not as a binding affinity but as an "EC50 in the low nanomolar range." Neither the precise affinity value nor the selectivity panel is independently corroborated between the two references.

Other

Second-hand summaries of the pivotal Nass et al. 2008 trial disagree on how long it ran and how much IGF-1 rose.

The description of the pivotal Nass et al. 2008 trial rests on secondary summaries that do not agree on its basic parameters. "MK-677 (Ibutamoren): Oral GH Secretagogue (2026)" describes it as a 12-month randomized trial of 25 mg daily versus placebo in elderly subjects, with IGF-1 rising 1.5-2x baseline and sustained without tachyphylaxis. "MK-677 (Ibutamoren): History, Development, and Mechanism of Action | HealthRX.com" instead describes a 2-year trial in 65 healthy elderly adults, with IGF-1 rising roughly 40-60% above baseline. The review "Growth Hormone Secretagogues as Potential Therapeutic Agents" notes that MK-0677 sustained pulsatile GH secretion for up to 2 years but does not attach that duration to the Nass trial. None of these is the primary trial publication, and the duration and IGF-1 figures differ between them.

Contested

The two sources disagree on how much IGF-1 rises at the standard 25 mg/day dose.

peptideslabuk.com (MK-677 Ibutamoren UK 2026 Research Reference - Peptides Lab UK) reports a dose-response of IGF-1 +40-60% above baseline at 25 mg/day (and +60-90% at 50 mg). thepeptidetoolkit.com (MK-677 (Ibutamoren): Oral GH Secretagogue (2026)) instead reports IGF-1 rising to 1.5-2x baseline at 25 mg/day, i.e. a +50-100% increase, citing the Nass 2008 12-month trial. These two 25 mg figures overlap only partially and the toolkit's upper end (100%) exceeds the lab reference's 25 mg range entirely, so they cannot both be stated as the single value for that dose.

Using it with other compounds

Check a stack
  • TesamorelinSame downstream effect

    Worth caution

    Tesamorelin is a stabilized GHRH analog that raises GH/IGF-1 through the GHRH receptor, distinct from MK-677's ghrelin-receptor pathway. Both feed the same GH/IGF-1 axis, so they can be additive on GH output. Note a practical tension: tesamorelin is used specifically to reduce visceral fat, whereas MK-677 raises appetite and can promote fluid retention and insulin resistance, which may partly counter the body-composition goal.

    Tier 3Largely anecdotal — commonly discussed

    What the research doesn't fully establish

    Both peptides' mechanisms clearly converge on the GH/IGF-1 axis as a shared downstream endpoint, despite distinct upstream targets (GHS-R1a vs GHRHR). MK-677 mechanisms show 'GH-vesicle exocytosis in pituitary somatotrophs' and 'GH/IGF-1 axis (IGF-1, IGFBP-3 elevation)' with approved tags including GH_axis and IGF1_signaling. Tesamorelin mechanisms show 'GH release from anterior pituitary somatotrophs' and 'Hepatic JAK2/STAT5 induction of IGF-1' with matching approved tags GH_axis and IGF1_signaling. Both mechanisms explicitly document IGF-1 elevation. Regarding lipolysis: Tesamorelin's mechanisms explicitly list 'Lipolysis' and 'Reduction of visceral adipose tissue' as effects. MK-677's mechanisms do not explicitly mention lipolysis as a direct effect—it lists 'Increased fat-free/lean mass' and 'Reversal of diet-induced protein catabolism,' which are anabolic rather than lipolytic. The claim of shared lipolysis dimension is therefore only partially supported by the provided mechanisms (supported for tesamorelin, not documented for MK-677). However, the core same_downstream relationship on GH_axis and IGF1_signaling is clearly justified by both mechanisms converging on pituitary GH release and subsequent IGF-1 elevation through distinct receptor pathways.

    Timing Monitor fasting glucose/insulin, since both GH-raising agents plus MK-677's appetite drive can worsen insulin sensitivity.

    Shares GH axis · IGF1 signaling · lipolysis

  • SermorelinSame downstream effect

    May be complementary

    Sermorelin is a GHRH-receptor agonist, a different upstream trigger from MK-677's ghrelin-receptor action, yet both raise pulsatile GH and IGF-1 and both are reported to deepen slow-wave sleep. Using a GHRH signal plus a ghrelin-mimetic can enhance the GH pulse more than either alone, and their overlapping sleep benefits reinforce each other.

    Tier 3Largely anecdotal — commonly discussed

    What the research doesn't fully establish

    Both peptides' mechanisms clearly converge on the same downstream GH/IGF-1 axis despite different upstream triggers. MK-677 activates GHS-R1a (ghrelin receptor) via Gq/11-phospholipase C cascade; Sermorelin activates GHRH receptor via Gs/adenylyl cyclase/cAMP. Both mechanisms result in pulsatile GH secretion from pituitary somatotrophs and subsequent IGF-1 elevation. Both approved tags explicitly include GH_axis, IGF1_signaling, protein_synthesis, and sleep_architecture. The mechanism descriptions confirm both increase pulsatile GH release, elevate IGF-1, improve body composition through protein synthesis/lean mass gains, and increase slow-wave/deep sleep. The proposed explanation that they use different upstream pathways (ghrelin vs GHRH) but converge on common downstream GH release and sleep effects is directly supported by the provided mechanisms. This is a classic example of convergent pathway activation producing overlapping phenotypes.

    Timing Both are commonly dosed at night to work with the natural GH pulse and sleep architecture; keep IGF-1 in a physiological range.

    Shares GH axis · IGF1 signaling · protein synthesis · sleep architecture

  • SemaglutideStack with caution

    Worth caution

    MK-677 increases appetite while semaglutide suppresses it — opposing effects on food intake. Some use GLP-1 agonists deliberately to offset MK-677's hunger, but the two also pull insulin sensitivity in different directions (MK-677 can raise glucose/reduce insulin sensitivity; semaglutide improves glycemic control), so glucose should be monitored.

    Tier 4Theoretical — not established
  • TirzepatideStack with caution

    Worth caution

    MK-677 is a ghrelin-receptor agonist that increases hunger and can raise blood glucose and reduce insulin sensitivity — directly opposing tirzepatide's appetite suppression and glucose-lowering effects. Stacking them works at cross-purposes on both appetite and glycemic control, so their metabolic goals partly cancel out.

    Tier 4Theoretical — not established

    What the research doesn't fully establish

    The proposed relationship claims MK-677 'can raise blood glucose and reduce insulin sensitivity,' but this is not stated in MK-677's mechanism description. The mechanism provided for MK-677 describes GH/IGF-1 axis activation, increased appetite, and lean mass gain—but does not explicitly mention glucose elevation or insulin sensitivity reduction. While tirzepatide's mechanism clearly includes glucose-dependent insulin secretion, HbA1c reduction, and improved insulin sensitivity, the mechanism material for MK-677 does not establish opposing effects on these parameters. The explanation relies on external pharmacological knowledge rather than the provided mechanism descriptions. Without explicit statements in MK-677's mechanism about glucose or insulin effects, the claimed opposition cannot be judged as supported by the given material.
  • IpamorelinSame mechanism

    Worth caution

    MK-677 (ibutamoren) is an oral non-peptide that hits the same ghrelin receptor (GHS-R1a) as ipamorelin. Running both means competing for the identical receptor and GH-release pathway, so the effect is redundant rather than additive. MK-677 also produces a long, sustained receptor activation plus notable appetite stimulation and water retention — layering ipamorelin on top adds little extra GH while compounding those side effects. Most people should use one GHS-R1a agonist, not two.

    Tier 3Largely anecdotal — commonly discussed

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish they target the same receptor (GHS-R1a/GHSR-1a ghrelin receptor) and activate overlapping downstream pathways (Gq/11-coupled phospholipase C → IP3/intracellular calcium → GH-vesicle exocytosis). Both produce pulsatile GH secretion and IGF-1 elevation through the GH/IGF-1 axis. The shared dimensions (GH_axis, IGF1_signaling) are explicitly supported by both descriptions. The mechanism material confirms both are ghrelin receptor agonists operating through the same receptor and GH-release pathway, justifying the 'same_mechanism' classification and the claim of redundancy rather than additivity.

    Timing Pick one ghrelin-receptor agonist rather than stacking; MK-677's long half-life keeps the receptor occupied for many hours.

    Shares GH axis · IGF1 signaling

  • CJC-1295Complementary

    Worth caution

    MK-677 is an oral ghrelin-receptor agonist that raises GH/IGF-1 via a different receptor than CJC-1295. The mechanisms are complementary (pulse amplitude from GHRH vs. secretagogue-driven pulses), but because MK-677 produces sustained IGF-1 elevation, combining the two can push IGF-1 high — monitor levels and watch for water retention/appetite effects.

    Tier 3Largely anecdotal — commonly discussed

    What the research doesn't fully establish

    The mechanisms clearly establish complementary action on the GH axis through distinct receptors: CJC-1295 targets GHRH-R (direct GHRH pathway via cAMP-PKA cascade), while MK-677 targets GHS-R1a (ghrelin-mimetic pathway via Gq/11-PLC-IP3-calcium cascade). Both peptides share three approved tags (GH_axis, protein_synthesis, IGF1_signaling) and both increase pulsatile GH secretion and IGF-1 elevation, but through different mechanisms. The explanation correctly identifies the complementary nature: CJC-1295 amplifies endogenous pulsatile GH with preserved pulse pattern via GHRH-R, while MK-677 drives GH-vesicle exocytosis and modulates hypothalamic GHRH/somatostatin via GHS-R1a. The proposed shared dimensions are explicitly supported by the approved tags and mechanism descriptions for both peptides. The caveat about combined IGF-1 elevation and monitoring is a reasonable inference from the stated effects (2-10 fold GH increase for CJC-1295, sustained IGF-1 elevation for MK-677) but does not contradict the complementary relationship claim.

    Timing MK-677 is long-acting/daily; monitor IGF-1 if combined with a GHRH analog.

    Shares GH axis · protein synthesis · IGF1 signaling

  • AOD-9604Stack with caution

    Worth caution

    MK-677 raises GH/IGF-1 (which can support lipolysis) but also markedly stimulates appetite and can promote fluid retention, potentially working against AOD-9604's fat-loss goal. Worth understanding the appetite trade-off before combining.

    Tier 4Theoretical — not established
  • HexarelinSame mechanism

    Worth caution

    MK-677 is an oral ghrelin-mimetic that hits the same GHS-R1a receptor hexarelin does. Combining them is redundant — both compete for and desensitize the same receptor — and MK-677's long half-life keeps that receptor occupied around the clock, which can blunt the pulse a short-acting injectable like hexarelin is trying to create. Pick one GHS-R1a agonist rather than layering two.

    Tier 2Supported by animal / early studies

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish GHS-R1a as their primary shared target. Hexarelin's mechanism explicitly states it 'binds to the growth hormone secretagogue receptor (GHS-R1a)' and MK-677's mechanism confirms it 'switches on the ghrelin receptor (GHS-R1a)'. Both activate the same Gq/11-coupled phospholipase C / IP3 / intracellular calcium cascade leading to GH-vesicle exocytosis. Both share the GH_axis and IGF1_signaling approved tags and produce overlapping effects (pulsatile GH secretion, elevated IGF-1). The proposed explanation about receptor desensitization and the contrast between pulsatile (hexarelin) vs. continuous (MK-677) receptor occupancy is mechanistically sound given their described pharmacokinetic profiles and the shared GHS-R1a pathway. The claimed shared dimensions (GH_axis, IGF1_signaling) are directly supported by both mechanisms.

    Shares GH axis · IGF1 signaling

  • DSIPComplementary

    May be complementary

    Both are used to improve sleep quality but through completely different routes: DSIP deepens slow-wave (delta) sleep via GABA-A enhancement and opioid/enkephalin signaling, while MK-677 raises GH/IGF-1 and has been reported to increase REM and deep sleep. Stacking them targets sleep architecture from two angles, which can be additive. Note that MK-677 also raises appetite and can cause vivid dreams or morning grogginess in some users, so evaluate how the combination affects your own sleep.

    Tier 4Theoretical — not established

    What the research doesn't fully establish

    Both peptides' mechanisms explicitly target sleep architecture through distinct pathways. DSIP increases slow-wave (delta) sleep via GABAergic tone, NMDA inhibition, and enkephalin release. MK-677 modulates sleep architecture through GH/IGF-1 axis elevation and hypothalamic signaling. The mechanisms confirm they operate on different neurobiological systems affecting sleep, supporting the 'complementary' relationship claim with 'sleep_architecture' as a shared dimension. The explanation accurately reflects the distinct routes (GABA/opioid vs. GH/IGF-1) described in both mechanism profiles.

    Timing Both are typically taken in the evening/before bed to align with the natural nighttime GH pulse and sleep onset.

    Shares sleep architecture

  • KlothoStack with caution

    Worth caution

    A key part of Klotho's longevity/anti-senescence profile is that it dampens IGF-1/insulin intracellular signaling. MK-677 does the opposite — it strongly and continuously raises circulating IGF-1 (and IGFBP-3). If someone is using Klotho specifically for anti-aging benefit, a sustained IGF-1 elevation from MK-677 works against that mechanism, so the goals partly conflict and this pairing is worth understanding rather than assuming synergy.

    Tier 4Theoretical — not established

    What the research doesn't fully establish

    The mechanisms clearly establish opposing effects on IGF-1 signaling. Klotho's mechanism explicitly includes 'Regulation' and 'dampening' of the IGF-1/insulin signaling axis as part of its anti-senescence profile. MK-677's mechanism explicitly shows 'Elevated IGF-1 (and IGFBP-3)' and 'GH/IGF-1 axis elevation' as primary effects. Both peptides share the IGF1_signaling tag. The proposed relationship correctly identifies that these represent mechanistically opposing actions on the same pathway—Klotho downregulates while MK-677 upregulates circulating IGF-1. The caution verdict is justified because sustained elevation of IGF-1 from MK-677 would directly counteract the IGF-1 dampening that Klotho employs for longevity benefits. This is a genuine mechanistic conflict supported by the provided descriptions.

    Shares IGF1 signaling

  • Follistatin-344Complementary

    May be complementary

    MK-677 elevates GH/IGF-1 and improves nitrogen balance, supporting protein synthesis from the anabolic-hormone side, while Follistatin releases the myostatin brake. The two attack muscle growth from separate angles, making them additive rather than redundant.

    Tier 4Theoretical — not established

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish the claimed shared dimensions. Follistatin explicitly targets IGF-1R signaling as a 'partial mediator of hypertrophy' and is tagged with IGF1_signaling and protein_synthesis. MK-677 directly elevates IGF-1 levels and IGFBP-3, with approved tags for both IGF1_signaling and protein_synthesis, plus reversal of protein catabolism via improved nitrogen balance. The proposed complementary relationship is justified: Follistatin removes inhibitory signals (myostatin/activin blockade, SMAD2/3 inhibition, mTOR disinhibition), while MK-677 provides positive anabolic drive via the GH/IGF-1 axis. These represent mechanistically distinct pathways (ligand sequestration + receptor antagonism vs. GHS-R1a agonism → GH secretion) converging on the same downstream effectors (IGF-1 signaling, protein synthesis, mTOR activation). The mechanisms support the claim that they are additive rather than redundant.

    Shares protein synthesis · IGF1 signaling

Safety and side effects

Safety & Side Effects

In short-term healthy-volunteer and GH-deficient RCTs, MK-677 was generally well tolerated, with no significant increase in cortisol, prolactin, or thyroid hormones at standard doses. Growth hormone secretagogues as a class are described as generally well tolerated, with the principal concern being glucose/insulin effects.

Commonly reported effects

  • Increased appetite (via the ghrelin pathway)
  • Fluid retention / edema
  • Muscle pain
  • Modest fasting glucose elevation (HbA1c ~+0.3%) and reduced insulin sensitivity — some sources state MK-677 consistently worsens insulin sensitivity and raises fasting glucose, particularly at higher doses

Dose considerations

Higher doses (50 mg, 100 mg) showed diminishing IGF-1 returns and proportionally larger side effects in early Merck trials.

Cardiac signal

A congestive heart failure safety signal emerged in an elderly hip-fracture trial, prompting its early termination and leading to the conclusion that MK-0677 had an unfavorable safety profile in that frail population. This arose in a specific, frail patient group with a limited number of affected patients; sources describe it as leaving lingering questions about cardiac safety rather than a definitive causal finding, and it is not established whether it generalizes to other populations.

Liver and endocrine reports

  • Hepatotoxicity (transaminitis): Consumption for ~2 months has been reported to cause elevated liver enzymes in otherwise healthy individuals, with normalization after stopping; such reports are described as scarce.
  • Case reports document hepatotoxicity, gynecomastia, hypogonadotropic hypogonadism, and dyslipidemia, particularly when combined with SARMs.
  • In a single human observational combination study, MK-677 15 mg with the SARM LGD-4033 10 mg for 5 weeks produced dramatic changes: total fat mass +15.4%, LDL +40.0%, triglycerides +39.2%, HDL -36.4%, ALT +205%, AST +95.8%, and total/free testosterone -62.3%/-85.7%. These effects cannot be attributed to MK-677 alone — they reflect combination use, and most (except fat mass, bone area, and cholesterol/LDL) reverted after cessation.

Notes on contested findings

While human RCTs report no significant cortisol elevation at standard doses, a dog study found MK-0677 raised cortisol on the first day of dosing (attenuated with repeated dosing). The '~50% increase in REM and Stage 4 deep sleep' figure rests on a single lower-tier source.

MK-677 is investigational and not approved for human use. It is prohibited by WADA and is not a legal dietary supplement ingredient. This section reports what the research describes, not guidance to use the compound.

Reconstitution and handling

Preparation & Dosing

No dose has been established for this compound. No regulatory label exists for it, so the figures below are what sources report — not guidance.

Unlike injectable peptides, MK-677 is an orally active, non-peptide small molecule and does not require reconstitution with bacteriostatic water. It is resistant to gastrointestinal degradation and is typically administered by mouth, most commonly as a capsule or oral liquid in gray-market products. GH-releasing activity has also been demonstrated after intravenous, subcutaneous, and intranasal administration in research settings.

Pharmacokinetics

  • Oral bioavailability: ~60-65% (single lower-tier source)
  • Tmax: 1-2 hours
  • Steady state: reached after 5-7 days of once-daily dosing
  • Metabolism: primarily hepatic via CYP3A4
  • Half-life: reported as ~4-6 hours (plasma) with a ~24-hour biological effect on the GH/IGF-1 axis in some sources, and ~24 hours in others
  • Food effect: a high-fat meal delays Tmax by ~1 hour and reduces Cmax ~20% but does not change total AUC

A single dose sustains GH and IGF-1 elevation for up to ~24 hours, consistent with the 4-6 hour plasma half-life and the basis for once-daily dosing; after stopping, IGF-1 typically normalizes over roughly 4-7 days. (One lower-tier vendor source claims effects on GH/IGF-1 last 6-14 days after a single dose, but this is not supported by the compound's pharmacokinetics and contradicts the once-daily-dosing rationale.) MK-677 is incorporated into hair and detectable there for at least 4 weeks after a single dose (useful for anti-doping detection).

Dosing as studied and reported

  • Validated clinical trial dose: 25 mg once daily orally (used across the healthy-volunteer, elderly, and Nass et al. trials).
  • Community/anecdotal use: typically 10-25 mg, with 25 mg a common ceiling and 10 mg a conservative starter; reported cycle lengths range from 8 weeks to 2 years.
  • Diminishing returns: 50 mg and 100 mg doses showed smaller incremental IGF-1 gains with disproportionately larger side effects.
  • Dosing frequency (animal data): in dogs, daily administration sustained IGF-1 increases over 24 h, whereas alternate-day dosing did not.

These figures describe doses used in research and reported in the community; they are not a recommendation. MK-677 is investigational, unapproved for human use, and prohibited by WADA.

Sources

Ordered by evidence quality — the strongest first.

  1. Growth Hormone Secretagogues as Potential Therapeutic Agents to ...(opens in a new tab)
    Tier 1Web · academic.oup.com
  2. MK-677 (Ibutamoren): Research Guide | PtP Wiki(opens in a new tab)
    Tier 1Web · pathtopeptides.com
  3. MK-677, an orally active growth hormone secretagogue, reverses ...(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov
  4. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism - PubMed(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov
  5. MK-677: Mechanism, Dosing & Evidence (Tier 2) | Pepteligence(opens in a new tab)
    Tier 1Web · pepteligence.com · 2026
  6. Knowing the minimal detectable dose can facilitate the interpretation of a hair test result: II. Case example with ibutamoren (MK-677), a growth hormone secretagogue.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  7. Hepatotoxicity induced by MK-677.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  8. Oral Administration of Growth Hormone (GH) Releasing Peptide-Mimetic MK-677 Stimulates the GH/Insulin-Like Growth Factor-I Axis in Selected GH-Deficient Adults 1(opens in a new tab)
    Tier 1Web · researchgate.net · 2024
  9. The Safety and Efficacy of Growth Hormone Secretagogues.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  10. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2011
  11. The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2004
  12. Growth hormone-releasing peptides.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 1997
  13. Detection of the growth hormone secretagogue MK-0677 in equine hair following oral administration.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  14. Characterization of growth hormone secretagogue small molecule ibutamoren (MK-0677) and its possible metabolites in thoroughbred horses for doping control.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  15. Equine metabolism of the growth hormone secretagogue MK-0677 in vitro and in urine and plasma following oral administration.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  16. LGD-4033 and MK-677 use impacts body composition, circulating biomarkers, and skeletal muscle androgenic hormone and receptor content: A case report.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  17. MK-0677, a Ghrelin Agonist, Alleviates Amyloid Beta-Related Pathology in 5XFAD Mice, an Animal Model of Alzheimer's Disease.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  18. The nonpeptide growth hormone secretagogue, MK-0677, activates hypothalamic arcuate nucleus neurons in vivo.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 1998
  19. Repeat administration of the GH secretagogue MK-0677 increases and maintains elevated IGF-I levels in beagles.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 1997
  20. MK-677 Ibutamoren UK 2026 Research Reference - Peptides Lab UK(opens in a new tab)
    Tier 3Web · peptideslabuk.com
  21. MK-677 Ibutamoren: Mechanism & GH Secretagogue Research(opens in a new tab)
    Tier 3Web · newtropin.com
  22. Performance Enhancing Substance: MK-677 (Ibutamoren)(opens in a new tab)
    Tier 3Web · opss.org
  23. Superpower(opens in a new tab)
    Tier 3Web · superpower.com
  24. MK-677 (Ibutamoren): History, Development, and Mechanism of Action | HealthRX.com(opens in a new tab)
    Tier 3Web · healthrx.com · 2026
  25. MK-677 (Ibutamoren): Oral GH Secretagogue (2026)(opens in a new tab)
    Tier 3Web · thepeptidetoolkit.com · 2026
  26. MK-677 (Ibutamoren): Research Evidence & Safety Profile | PeptideInsight(opens in a new tab)
    Tier 3Web · peptideinsight.com · 2026
  27. MK-677 Guide: Ibutamoren Benefits, Evidence & Risks (2026) | PeptideMark(opens in a new tab)
    Tier 3Web · peptidemark.com · 2026
  28. MK-677: 42 Studies Reviewed (2026) | PepCodex(opens in a new tab)
    Tier 3Web · pepcodex.com · 2026
  29. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2020