Dihexa vs SS-31 (Elamipretide)

Side-by-side comparison of mechanisms, dosing, interactions, and stacking potential.

DihexaSS-31 (Elamipretide)
CategoryPeptidesPeptides
Standard DoseResearch indicates 10-20 mg daily via oral or sublingual administration.Research indicates 0.05-0.25 mg/kg daily via subcutaneous injection. Clinical trials used 4-40 mg/day IV or SC.
TimingMorning dosing preferred. Can be taken with or without food (orally active).Morning dosing preferred. No food timing restrictions.
Cycle Duration2-4 week cycles with equal rest periods. Long-term safety data is extremely limited.Clinical trials ranged from single dose to 48 weeks. Optimal cycle length not established.
Evidence Levelanimal_plus_anecdotalEmerging (Phase 2/3 trials)
A

Dihexa

Peptides

Mechanism

Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is an orally active, blood-brain barrier-permeable oligopeptide derived from angiotensin IV. It binds hepatocyte growth factor (HGF) with high affinity, inhibiting HGF dimerization and synergistically promoting c-Met receptor phosphorylation and signaling. Activation of HGF/c-Met drives procognitive effects through increased dendritic arborization, spinogenesis, and synaptogenesis via the PI3K/AKT signaling pathway. Research indicates it is approximately 10 million times more potent than BDNF for new synapse formation.

Standard Dosing

Research indicates 10-20 mg daily via oral or sublingual administration.

Timing

Morning dosing preferred. Can be taken with or without food (orally active).

Cycle Duration

2-4 week cycles with equal rest periods. Long-term safety data is extremely limited.

Side Effects

  • Headache
  • Jaw tension
  • Increased emotional sensitivity (anecdotal)
  • Potential for excessive synaptogenesis (theoretical long-term concern)

Contraindications

  • Active cancer (HGF/c-Met pathway promotes tumor growth)
  • Pregnancy and breastfeeding
  • History of cancer

Best Stacking Partners

SemaxP21NSI-189

Mechanism

SS-31 (D-Arg-Dmt-Lys-Phe-NH2, also known as elamipretide/Bendavia) is a cell-permeable tetrapeptide that localizes to the inner mitochondrial membrane and binds cardiolipin via electrostatic interactions. This stabilizes cardiolipin against oxidative damage, preserving cristae integrity, reducing ROS production, and maintaining mitochondrial ATP production. SS-31 interacts with proteins in two functional groups: oxidative phosphorylation complexes and 2-oxoglutarate metabolic enzymes — all known cardiolipin binders. It restores mitochondrial function without acting as a direct antioxidant.

Standard Dosing

Research indicates 0.05-0.25 mg/kg daily via subcutaneous injection. Clinical trials used 4-40 mg/day IV or SC.

Timing

Morning dosing preferred. No food timing restrictions.

Cycle Duration

Clinical trials ranged from single dose to 48 weeks. Optimal cycle length not established.

Side Effects

  • Injection site reactions
  • Headache
  • Diarrhea (in clinical trials)
  • Nausea

Contraindications

  • Pregnancy and breastfeeding
  • Severe renal impairment (peptide clearance concern)
  • Not commercially available
  • Clinical trial participants only

Best Stacking Partners

MOTS-cHumaninEpitalon

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