Side-by-side · Research reference

MK-677vsSS-31

Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.

APhase 2Reviewed13/45 cited

BPhase 3Reviewed9/43 cited

MK-677

Oral GHS · Ibutamoren

10–25 mgDaily dose (oral)Nass 2008

Phase 2Evidence levelMurphy 1998 Nass 2008

~24 hrHalf-lifeNass 2008

Oral capsule · 1×/day

SS-31

Cardiolipin-binding · Mitochondrial protective

40 mgDaily doseSzeto 2014

Phase 3Evidence levelSzilagyi 2009 Szeto 2014

~3 hrHalf-life

SQ · Abdomen · Once daily

01Mechanism of Action

Parameter

MK-677

SS-31

Primary target

Ghrelin receptor (GHS-R1a)Murphy 1998

Cardiolipin in inner mitochondrial membraneSzeto 2014

Pathway

GHS-R1a → Gαq → Ca²⁺ → sustained GH pulses across 24 hrNass 2008

Cardiolipin binding → cristae stabilisation → ETC integrity → reduced ROS + preserved ATP synthesisSzeto 2014 Szilagyi 2009

Downstream effect

Sustained GH + IGF-1 elevation; appetite stimulation; lean mass preservationNass 2008

Mitochondrial bioenergetic preservation; cardio-, neuro-, and reno-protective effects in animal + clinical studiesSzeto 2014

Feedback intact?

Pulsatile pattern preserved despite long half-lifeMurphy 1998

—

Origin

Non-peptide spiroindane-piperidine small molecule designed at MerckMurphy 1998

Synthetic tetrapeptide D-Arg-Dmt-Lys-Phe-NH₂; cell-permeable, mitochondrial-selectiveSzeto 2014

Antibody development

—

02Dosage Protocols

Parameter

MK-677

SS-31

Standard dose

10–25 mg / day oralNass 2008

25 mg used in Nass 2008 elderly trial; 10–15 mg common community dose.

40 mg / day SQ (clinical trials)Szeto 2014

Anecdotal community range 5-10 mg/day. Phase 3 trials use 40 mg.

Frequency

Once daily, oral

Once daily

Lower / starter dose

5 mg / day

5 mg / day (anecdotal)

Evidence basis

Phase 2 trials (Nass 2008, Murphy 1998)Nass 2008 Murphy 1998

Multiple Phase 3 trials (Barth, AMD, ischemia-reperfusion)Szeto 2014 Szilagyi 2009

Duration

8–16 weeks per cycle (off-cycle to reset receptor sensitivity)

Indefinite for mitochondrial disease; cycled for healthspan use

Reconstitution

Oral, no reconstitution

Bacteriostatic water

Timing

Pre-sleep preferred for natural GH pulse alignment

Morning fasted preferred; pre-workout for exercise-induced mitochondrial stress

Half-life

~24 hrNass 2008

Once-daily dosing covers 24 hours.

~3 h plasma; tissue uptake longer

04Side Effects & Safety

Parameter

MK-677

SS-31

Increased appetite

Strong appetite increase via ghrelin agonism

—

Water retention

Mild edema, paresthesias

—

Glucose tolerance

↑ HbA1c +0.3–0.5% in 2-yr elderly trialNass 2008

—

IGF-1 elevation

+50–100% sustainedNass 2008

—

Cancer risk

Contraindicated in active malignancy (GH/IGF-1 axis)

—

Cardiovascular

No clear adverse signal in trials; congestive heart failure caution

Cardio-protective in studies; no signal of harm

Drowsiness

Common, especially during initial weeks

—

Pregnancy / OB

Avoid

Avoid — insufficient data

Injection site reaction

—

Erythema, mild pruritus

GI symptoms

—

Nausea (uncommon)

Headache

—

Reported in some Phase 3 trials

Long-term safety

—

Phase 3 data over 24+ months; no major safety signalsSzeto 2014

Absolute Contraindications

MK-677

·Active malignancy
·Pregnancy / breastfeeding
·Disrupted hypothalamic-pituitary axis
·Congestive heart failure (caution)

SS-31

·Pregnancy / breastfeeding
·Hypersensitivity to peptide

Relative Contraindications

MK-677

·Untreated diabetes
·Pre-diabetes
·Severe insulin resistance

SS-31

·None established

05Administration Protocol

Parameter

MK-677

SS-31

1. Form

Capsule or oral solution. No injection.

Add bacteriostatic water per label. Light-protected handling.

2. Site

Oral. Take with or without food.

SQ — abdomen or thigh. Rotate sites.

3. Timing

Pre-sleep preferred — aligns with natural GH pulse.

Morning fasted; pre-workout for exercise-augmented mitochondrial stress.

4. Storage

Capsule: room temp ≤25 °C, dry place.

Lyophilised: refrigerate, light-protected. Reconstituted: refrigerate ≤30 days.

5. Caveat

Monitor HbA1c every 8–12 weeks during chronic use.

29–31G, 4–8 mm insulin syringe.

06Stack Synergy

MK-677

— no documented stacks

SS-31

+ MOTS-c

Moderate

View MOTS-c →

SS-31 and MOTS-c address mitochondrial decline through complementary axes. SS-31 protects existing mitochondrial structure (cardiolipin binding, cristae stabilisation). MOTS-c upregulates AMPK/PGC-1α, triggering biogenesis of new mitochondria. Together they pair preservation with renewal — anecdotally favoured in healthspan and post-cardio-event recovery protocols.

SS-31: 5–10 mg SQ · daily morning
MOTS-c: 5 mg SQ · 2× per week pre-workout
Primary benefit: Mitochondrial preservation + biogenesis