MK-677

MK-677 is a spiropiperidine that mimics ghrelin at GHS-R1a but, unlike the peptide GHRPs, survives oral administration and has a half-life long enough for once-daily dosing. It amplifies the natural GH pulses rather than creating a single spike, raising 24-hour mean GH and driving IGF-1 up by roughly 40 to 90 percent in trials. In the two-year Nass study in healthy older adults, 25 mg daily produced about 1.6 kg of fat-free mass gain that persisted over the study, without a matching change in strength or function. It also reliably increases appetite through the same hypothalamic pathway as ghrelin, and it worsens fasting glucose and insulin sensitivity - the trial that stopped a hip-fracture programme did so partly on the strength of glycaemic and heart-failure signals.

Targets: GHS-R1a (ghrelin receptor), Pituitary somatotrophs, IGF-1 axis, Arcuate NPY/AgRP neurons

• · 10 to 12.5 mg per day. This is the sweet spot most users settle on: meaningful IGF-1 rise with tolerable water retention and hunger.
• · 25 mg daily is what the published two-year trial in older adults used. It is also where glucose and oedema problems become common.
• · 5 to 10 mg for people who mainly want the slow-wave sleep effect and want to minimise fluid retention.

Work out your exact syringe units →

• very commonIncreased appetite— Strong and persistent, unlike the transient hunger from injectable GHRPs. This is the main reason people quit.
• very commonWater retention, puffy face and hands— Peaks in the first two to four weeks and often partially settles.
• commonIncreased fasting glucose and reduced insulin sensitivity— Documented in trials. Genuinely the most important risk, not a theoretical one.
• commonLethargy or morning grogginess— Often improves after two weeks or with morning rather than evening dosing.
• commonVivid dreams and altered sleep architecture— Slow-wave sleep increases; some people find this pleasant, others do not.
• commonJoint pain and carpal tunnel symptoms— Classic GH excess; dose-related.
• commonMuscle or joint stiffness
• uncommonElevated prolactin— Usually modest.
• rareCongestive heart failure exacerbation— Seen in the elderly hip-fracture trial population, which contributed to programme discontinuation. Relevant to anyone with existing cardiac disease.

• Active malignancy - a sustained IGF-1 elevation is a growth signal.
• Type 2 diabetes or significant insulin resistance, because MK-677 measurably worsens glycaemic control.
• Congestive heart failure or significant cardiac disease.
• Active proliferative diabetic retinopathy.
• Pregnancy and breastfeeding.

• redundantipamorelin — Same receptor. Stacking adds MK-677's side effects without a proportional GH benefit.
• redundantghrp-6 — Same receptor and the same appetite pathway.
• synergymetformin — Commonly co-used specifically to offset the glucose deterioration; a reasonable pairing if you insist on running MK-677 long-term.
• conflictsemaglutide — Directly opposing appetite signals, though some people run both deliberately to keep the GH effect without the hunger.
• cautioninsulin — Insulin requirements will rise.
• synergycjc-1295-no-dac — Different receptors, so the GHRH arm does add something - but you are also stacking two sources of IGF-1 elevation.

• · Fasting glucose, fasting insulin and HbA1c at baseline, week 8 and quarterly. This is not optional with MK-677.
• · IGF-1 at baseline and week 8; keep it inside the age-adjusted reference range.
• · Blood pressure and any sign of ankle oedema or exertional breathlessness.
• · Prolactin if symptomatic.

Not approved for human use anywhere. Sold as a research chemical and widely mislabelled as a SARM, which it is not. Prohibited in sport under WADA S2, and it is a common cause of positive tests.

• Nass et al. 2008 Annals of Internal Medicine, two-year oral ghrelin mimetic trial in healthy older adults (trial)
• Merck MK-677 hip-fracture programme, discontinued after glycaemic and cardiac safety signals (trial)
• Murphy et al., MK-677 effects on GH, IGF-1 and body composition in obese males (trial)

MK-677 does something none of the injectable GHRPs do: it amplifies the amplitude of every natural GH pulse across the whole day rather than creating one artificial pulse. Because GHS-R1a signalling at the somatotroph is permissive rather than instructive - it removes somatostatin inhibition and adds a calcium stimulus on top of whatever endogenous GHRH drive is present - a long-acting agonist produces a higher 24-hour mean GH without abolishing pulsatility entirely. That is why IGF-1 rises 40 to 90 percent on MK-677 when a nightly ipamorelin injection barely moves it. The trade-offs come from the same continuous receptor occupancy. Arcuate NPY/AgRP activation is constant, so the appetite effect is not a twenty-minute wave you can plan around but a persistent background drive - the most common reason people stop. The glucose effect is the important one and it is properly documented: Nass's two-year randomised trial in healthy older adults, 65 participants aged 60 to 81, found fasting glucose increased and insulin sensitivity decreased alongside the fat-free mass gain. That trial is the best evidence in the entire grey-market portion of this class and it is honest in both directions: about 1.6 kg of fat-free mass gained and held, with no matching improvement in strength or function, plus measurable glycaemic deterioration and transient lower-limb oedema. Svensson's earlier eight-week study in obese men found increased GH, IGF-1 and IGF-binding protein-3 with increased fat-free mass and energy expenditure, which is a consistent picture. The Merck hip-fracture programme is where the safety signal that ended development lives, and the congestive heart failure component matters for anyone with existing cardiac disease. Sodium and fluid retention is IGF-1-mediated through the renal epithelial sodium channel; in a healthy 30-year-old that is puffy hands, and in a 75-year-old with reduced cardiac reserve it is decompensation.

Starting at 25 mg. The first fortnight on a full dose is genuinely unpleasant - heavy limbs, relentless hunger, a puffy face, and grogginess that makes people think they have broken something - and most of it settles if you climb into it instead. Second, ignoring glucose. This is the compound where the metabolic cost is measured rather than theorised, and running it for a year without a single HbA1c is how people acquire prediabetes for 1.6 kg of lean mass. Third, misreading the trial result. MK-677 adds fat-free mass and does not add strength or function - that is what the two-year trial found, and a good deal of the mass is water. Someone expecting a strength gain will be disappointed and will respond by taking more. Fourth, running it in the wrong body: existing congestive heart failure or significant cardiac disease is a genuine contraindication, not a caution, because fluid retention in a heart with no reserve is how the hip-fracture programme generated its safety signal. Fifth, dosing and concentration errors with liquid research-chemical product - a glycol or ethanol solution at a stated 25 mg/mL with no independent assay is a place where people take three times what they think they are taking.

1. 5 mgWeek 1 — 5 mg once daily. The lethargy, hunger and puffiness are worst in the first fortnight and often settle; starting at 25 mg is how people talk themselves out of the compound in week one. Dose at bedtime initially and switch to morning if you wake groggy.
2. 10 mgWeeks 2 to 4 — 10 mg daily. This is where a lot of people should simply stay - meaningful IGF-1 elevation with the fluid retention still manageable. Draw baseline glucose and insulin before this step if you have not already.
3. 12.5 mgWeeks 5 onward — 12.5 mg daily is the practical sweet spot most long-term users settle on. Check IGF-1, fasting glucose and fasting insulin at week 8 before deciding whether to hold or come down.
4. 25 mgTrial dose - not a target — 25 mg daily is what the published two-year trial used, so it is not unprecedented, but it is also the dose at which oedema and glucose problems became common in that trial. Going here should be a deliberate decision with quarterly bloodwork, not a default.

• GHS-R1a (ghrelin receptor), pituitary somatotroph — Nanomolar; specific Ki not resolved from a primary source here

  Sustained amplification of endogenous GH pulse amplitude across 24 hours rather than a single artificial pulse. IGF-1 rises roughly 40 to 90 percent.

• GHS-R1a, arcuate NPY/AgRP neurons — Not separately quantified

  Continuous orexigenic drive. Unlike the injectable GHRPs this does not wear off between doses, which is why appetite is the dominant complaint.

• Hepatic IGF-1 production (indirect, via GH receptor and STAT5) — Not applicable

  The main measurable output and the source of both the anabolic effect and the fluid retention.

• Renal epithelial sodium channel (indirect, IGF-1-mediated) — Not applicable

  Sodium and water retention. Peaks in the first two to four weeks and partially settles. This is the mechanism behind the oedema and the heart failure signal in frail populations.

• Slow-wave sleep architecture — Not applicable

  Increased slow-wave sleep is consistently reported, along with vivid dreams and, for some, morning grogginess. The direction here is opposite to hexarelin.

• Nass et al., effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults - a randomized trial 2 · n=65 · 52 weeks · 2008

  Fat-free mass. MK-677 25 mg daily significantly increased GH and IGF-1 and increased fat-free mass while controls declined, in adults aged 60 to 81 over 12 months of double-blind treatment within a two-year study. Fasting glucose rose and insulin sensitivity fell. Adverse effects included increased appetite and transient lower-limb oedema. Functional improvement was not demonstrated.

• Svensson et al., two-month treatment of obese subjects with the oral GH secretagogue MK-677 2 · 8 weeks · 1998

  Sustained increases in serum GH, IGF-1 and IGF-binding protein-3, with increased fat-free mass and increased energy expenditure in obese men over eight weeks.

Appetite and sleep changes appear within the first two to three days, and they are unmistakable. Water retention builds over the first one to two weeks and peaks at two to four weeks before partially settling. Lethargy is worst in weeks one and two. IGF-1 rises within one to two weeks and reaches its plateau by around four weeks - which is why week 8 is a good check rather than a first look. Fat-free mass changes accrue over two to six months and were still present at twelve months in the Nass trial. Glucose deterioration is gradual and is the reason for quarterly rather than one-off testing. On stopping, appetite and fluid retention resolve within one to two weeks and IGF-1 returns to baseline over roughly the same period.

Metformin is the pairing that actually makes sense, and it makes sense for a specific reason: MK-677's documented harm is glycaemic, metformin's documented benefit is glycaemic, and if you are going to run this for months the mitigation should match the risk. That is a rational combination rather than polypharmacy for its own sake. A GHRH analogue - Mod GRF 1-29, sermorelin, tesamorelin - is the other coherent addition, because it hits a different receptor and genuinely adds GH output; the cost is that you are now stacking two sources of IGF-1 elevation and the fluid retention adds up. Every other GHS-R1a agonist is redundant: ipamorelin, GHRP-2, GHRP-6, hexarelin, anamorelin, ghrelin. Adding an injectable GHRP to MK-677 gets you one receptor's worth of effect and two compounds' worth of side effects. GLP-1 agonists are the interesting case: semaglutide or tirzepatide will comprehensively defeat the appetite effect, and people do run the combination deliberately to keep the GH arm without the hunger. It works, and the GLP-1's favourable glucose effect also partly offsets MK-677's unfavourable one, but you are running two drugs to cancel each other's main features. Anyone on insulin needs to expect requirements to rise.

Against the injectable GHRPs: MK-677 is simply more effective at raising IGF-1, because continuous receptor occupancy beats one pulse a day, and it is oral. Everything unpleasant about it comes from the same continuity. Ipamorelin is the low-effect, low-cost-in-side-effects option; MK-677 is the opposite end of the same receptor. Against CJC-1295 with DAC: a similar philosophy - sustained rather than pulsatile - on a different receptor, with similar water retention and glucose consequences, but MK-677 has a two-year randomised trial and CJC-1295 has one phase 1/2 study. Against somatropin: GH is more powerful and more predictable, suppresses your own axis, is a controlled substance in the US for non-medical use, and costs several times more. MK-677 works through your pituitary, so feedback loops still impose some ceiling. Against anamorelin: the same pharmacology approved in Japan for cancer cachexia, and anamorelin's phase 3 programme found exactly what MK-677's trial did - mass without function. That convergence is worth noticing. Against tesamorelin for fat loss: different mechanism entirely, and MK-677 is not a fat-loss compound; it increases appetite and retains water.

$25–$80/month. Approximate grey-market pricing. Capsules at 10 to 25 mg typically run 30 to 70 USD for a month's supply; liquid solutions at a stated 25 mg/mL are usually cheaper and carry more concentration risk. As a small molecule it is far cheaper to make than any peptide here, which is reflected in the price. Insist on a third-party certificate of analysis. Figures are observed and approximate.

• ?No oral bioavailability, clearance or volume of distribution figure was resolved from a primary source, and the widely quoted 4 to 6 hour half-life has no source verified here.
• ?The specific CYP pathways handling MK-677 metabolism were not established, so drug interaction potential is genuinely unknown rather than absent.
• ?The 14-day time to steady state given here is inferred from the observed IGF-1 plateau, not from a formal pharmacokinetic Tss determination.
• ?The 40 to 90 percent IGF-1 rise figure is a range compiled from trial reports rather than a single verified number.
• ?The Merck hip-fracture programme discontinuation and its glycaemic and congestive heart failure signals are widely reported but were not verified against a primary publication in this session.
• ?The 1.6 kg fat-free mass figure was not confirmed from the Nass abstract directly, which reports increased fat-free mass without a number in the retrieved text.
• ?How much of the fat-free mass gain is water rather than contractile tissue is not resolved, and the absence of a strength or functional benefit in the trial suggests this question matters.
• ?There is no human safety data beyond two years, and no data at all in young healthy adults, who are the main users.

• 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, Patrie JT, Harrell FE Jr, Clasey JL, Heymsfield SB, Bach MA, Vance ML, Thorner MO, Annals of Internal Medicine, 2008 · PMID 18981485

  The single most important study on this compound and the best controlled human data in the grey-market half of this class. Read it for the glucose findings as much as the body composition ones.

• 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, Lönn L, Jansson JO, Murphy G, Wyss D, Krupa D, Cerchio K, Polvino W, Gertz B, Boseaus I, Sjöström L, Bengtsson BA, Journal of Clinical Endocrinology and Metabolism, 1998 · PMID 9467542

  Independent confirmation of the GH, IGF-1, IGFBP-3, fat-free mass and energy expenditure effects in a different population.

• Growth hormone-releasing hormone and growth hormone-releasing peptide as therapeutic agents to enhance growth hormone secretion in disease and aging Thorner MO, Chapman IM, Gaylinn BD, Pezzoli SS, Hartman ML, Recent Progress in Hormone Research, 1997 · PMID 9238854

  The theoretical case for oral secretagogues in aging, from the group that ran the MK-677 trials. Useful background on why 24-hour GH restoration was the design goal.

• Ibutamoren, PubChem compound record CID 178024 PubChem

  Confirms molecular formula C27H36N4O5S and molecular weight 528.7, matching the Core record and confirming this is a small molecule rather than a peptide.