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AMIRAVOResearch Library

Semax vs Dihexa

Semax and dihexa are both discussed as experimental cognition-related compounds, but they come from different hormone families and have very different evidence and regulatory histories 1,10. Semax is a heptapeptide analogue of the ACTH(4-10) fragment and is listed in a 2022 review among peptide drugs registered in the Russian Federation 1,5. Dihexa is a modified angiotensin IV-derived molecule developed at Washington State University and studied only in animals and cells, and a key 2014 mechanism paper on it was retracted in 2025 10,11,12. As of the FDA page current on 22 April 2026, both appear among bulk substances once placed in compounding category 2 whose nominations were later withdrawn 7.

Unbranded reference vial illustrating Semax; not an actual product
Semax
Approved outside the US
Unbranded reference vial illustrating Dihexa; not an actual product
Dihexa
Not approved — research use only

Side by side

FieldSemaxDihexa
ClassSynthetic heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro), described as a melanocortin derivative 1,6Modified angiotensin IV analogue (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide), designed as a small, metabolically stabilised molecule 10
Origin and structureAnalogue of the N-terminal ACTH(4-10) fragment, synthesised at the Institute of Molecular Genetics of the Russian Academy of Sciences 1,5Derived from the three N-terminal amino acids of the angiotensin IV analogue Nle1-angiotensin IV, with terminal modifications to resist degradation 10
Proposed mechanismIn rats, bound specific sites in basal forebrain membranes and raised BDNF protein levels 1; in rodents, modulated striatal serotonin and dopamine systems 2A now-retracted 2014 paper proposed binding to hepatocyte growth factor and enhanced c-Met signalling 11,12; a 2021 mouse study linked effects to PI3K/AKT signalling 13
Half-lifeNot located; the FDA found no human pharmacokinetic studies by any route (2026 review) 18Not located in the sources reviewed; developers describe it as metabolically stabilised in rat work 10
Highest human trial phaseRussian clinical studies in ischemic stroke without a stated phase 3,4; no studies found on ClinicalTrials.gov 9No human studies; no studies found on ClinicalTrials.gov 16
FDA statusNot FDA-approved; listed by FDA among withdrawn category 2 nominations with immunogenicity and impurity concerns (page current 22 April 2026) 7; in July 2026 the FDA proposed it not be added to the 503A compounding bulks list 18Not FDA-approved; FDA states it has identified no human exposure data (page current 22 April 2026) 7; not in any 503A nomination category as updated 14 May 2026 17
Published human outcomesRussian-language stroke studies reported changes in plasma BDNF and functional scores versus comparison groups 3,4None located in the sources reviewed
Safety signalsFDA found insufficient clinical information to characterise its safety and noted that in mice it potentiated amphetamine-induced striatal dopamine release 18FDA reports no human exposure data and lacks information on whether it would cause harm 7
WADA statusNot named on the 2026 Prohibited List; the List uses 'including, but not limited to' wording 8Not named on the 2026 Prohibited List; S0 covers substances with no governmental approval for human use 8
Who funded the evidenceMostly Russian academic institutes, including the Institute of Molecular Genetics 1,5,6Washington State University researchers, several also affiliated with M3 Biotechnology, Inc. 11,15

Semax: what the data says

Semax research is concentrated in Russian laboratories. In rats (animal data), intranasal Semax bound specific sites in basal forebrain membranes and increased BDNF protein levels 1. In rodents, it raised striatal serotonin metabolite levels and enhanced amphetamine-induced dopamine release 2. In rat stroke models (animal data), it was associated with lower expression of inflammation-related proteins and genes 6.

Human data come from Russian clinical studies, mostly in Russian. A study of 110 people after ischemic stroke reported higher plasma BDNF and faster Barthel-index recovery in those given Semax 3. A 1997 study compared 30 treated patients with 80 conventionally treated controls in acute stroke and reported faster recovery of some neurological functions 4. A 2022 review lists Semax as a nootropic drug registered in Russia 5.

Dihexa: what the data says

All dihexa evidence identified is preclinical. In rats (animal data), dihexa reversed scopolamine-induced deficits in a water-maze task and increased hippocampal synapse formation in its developers' 2013 study, which later received an expression of concern 10. A 2014 paper proposing that it acts through hepatocyte growth factor and c-Met was retracted in 2025 11,12. In APP/PS1 mice (animal data), a separate group reported restored water-maze performance and lower inflammatory cytokines 13.

Not all results point the same way: in a 40-rat model of Huntington's-like toxicity, dihexa did not protect against motor or cognitive deficits 14. The FDA states that it has identified no human exposure data for dihexa acetate by any route 7.

Key research differences

  • Hormone family: Semax is derived from the ACTH(4-10) fragment, whereas dihexa is derived from angiotensin IV 1,10.
  • Human data: Semax has Russian clinical studies in stroke 3,4, while no human studies of dihexa were identified and the FDA reports no human exposure data 7.
  • Registration: a 2022 review lists Semax as registered in the Russian Federation 5; dihexa has no approval anywhere in the sources reviewed 7,17.
  • Literature integrity: a central 2014 dihexa mechanism paper was retracted in 2025 and the 2013 paper carries an expression of concern 10,12; no comparable notices were found for the Semax papers reviewed 1,2.
  • Proposed mechanism: Semax work centres on BDNF and monoamine systems in rodents 1,2, while dihexa work proposed hepatocyte growth factor/c-Met and PI3K/AKT signalling 11,13.

Where the evidence is limited

No study has compared Semax and dihexa directly. The Semax clinical studies are small, often non-randomised, published mainly in Russian, and come largely from the developer's own research network 3,4,5. Dihexa has no human data, and its foundational papers carry an expression of concern and a retraction 10,12. Rodent findings for either compound may not carry over to people, and one dihexa animal study reported no protective effect 14.

Frequently asked questions

Is Semax or dihexa more studied in humans?
Semax has small Russian clinical studies in stroke 3,4. No human studies of dihexa were identified, and the FDA reports no human exposure data 7.
Can Semax and dihexa be compared directly?
Not on current evidence. No head-to-head study exists, and they come from different hormone families (ACTH and angiotensin IV) 1,10.
Why is the dihexa research questioned?
A 2014 paper proposing its hepatocyte growth factor/c-Met mechanism was retracted in 2025, and the 2013 development paper received an expression of concern 10,12.
Are Semax or dihexa approved by the FDA?
Neither is FDA-approved. The FDA lists both among withdrawn category 2 compounding nominations, noting limited or no human safety information (page current 22 April 2026) 7. In a July 2026 briefing document, the FDA also proposed that Semax not be added to the 503A bulks list 18.

References

  1. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain Journal of Neurochemistry. 2006
  2. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents Neurochemical Research. 2005
  3. The efficacy of semax in the treatment of patients at different stages of ischemic stroke (in Russian) Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2018
  4. Effectiveness of semax in acute period of hemispheric ischemic stroke: a clinical and electrophysiological study (in Russian) Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 1997
  5. Development of Peptide Biopharmaceuticals in Russia Pharmaceutics. 2022
  6. Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4-7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia-Reperfusion International Journal of Molecular Sciences. 2021
  7. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks (content current as of 04/22/2026) FDA (Human Drug Compounding). 2026
  8. Prohibited List (2026 List, in force 1 January 2026) World Anti-Doping Agency. 2026
  9. ClinicalTrials.gov registry search: semax (no registered studies returned, searched 24 October 2026) ClinicalTrials.gov. 2026
  10. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents (Expression of Concern 2021) Journal of Pharmacology and Experimental Therapeutics. 2013
  11. RETRACTED: The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-Met system Journal of Pharmacology and Experimental Therapeutics. 2014
  12. Retraction notice to "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System" Journal of Pharmacology and Experimental Therapeutics. 2025
  13. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway Brain Sciences. 2021
  14. Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats Journal of Huntington's Disease. 2024
  15. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease Journal of Alzheimer's Disease. 2015
  16. ClinicalTrials.gov registry search: dihexa and PNB-0408 (no registered studies returned, searched 24 October 2026) ClinicalTrials.gov. 2026
  17. Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act (updated May 14, 2026) FDA. 2026
  18. FDA Briefing Document, Pharmacy Compounding Advisory Committee, July 23-24, 2026: Semax-Related Bulk Drug Substances (Semax (free base) and Semax acetate) FDA. 2026

For research use only. Not for human or veterinary use. Not a drug, food, or dietary supplement. This page compares published research and is not medical advice or a recommendation.