Evidence Grade D — Primarily preclinical. 17 published studies, mostly animal models. 0 registered clinical trials.
Medically reviewed by a licensed medical professional
Dihexa is a modified peptide derivative with serious evidence integrity concerns. A key foundational paper received an expression of concern for image manipulation, and a second paper was retracted after an institutional investigation found falsified and fabricated data. No human clinical trials have been conducted. These integrity issues fundamentally undermine the evidence base.
Dihexa is also known by these brand and alternate names:
17 published studies: 8 human, 4 animal, 3 in-vitro, 4 reviews
Dihexa has no marketing authorisation. No human clinical trials have been conducted. The foundational research by the originating laboratory faces serious integrity concerns: a key paper (McCoy et al., 2013) received an expression of concern for image manipulation, and a second paper (Benoist et al., 2014) was retracted after institutional investigation found falsified and fabricated data.
These integrity issues fundamentally undermine the evidence base for dihexa. Products available through unregulated channels are based on research that has been formally questioned or retracted by the scientific community. This compound carries unique evidence quality concerns beyond the standard limitations of other research compounds.
The originally proposed mechanism involved modulation of hepatocyte growth factor (HGF) signalling. However, the foundational publications describing this mechanism face severe scientific integrity concerns — one key paper received an expression of concern and another was retracted due to findings of falsified and fabricated data. The reliability of the proposed mechanism is therefore in question.
The evidence base for dihexa is severely compromised. The retraction and expression of concern on its two foundational papers mean the core claims about this compound cannot be relied upon. A related prodrug (fosgonimeton) from the same research programme was tested clinically but also failed and was discontinued. An additional safety concern is the mechanism itself: dihexa is proposed to work through the HGF/c-Met pathway, which is strongly associated with tumour growth and metastasis in many cancers. The extraordinarily long estimated half-life (8-12 days) raises accumulation concerns. Products from unregulated channels are based on research that has been formally questioned or retracted by the scientific community.
PeptideTrace tracks 0 registered clinical trials for Dihexa sourced from ClinicalTrials.gov.
No trials registered on ClinicalTrials.gov for this compound.
Dihexa (PNB-0408) is not a true hexapeptide but rather a modified tripeptide derivative with the structure hexanoyl-Tyr-Ile-Ahx-NH2 (N-hexanoic-Tyr-Ile-(6)aminohexanoic amide). Molecular formula is C27H44N4O5, molecular weight 504.67 g/mol (CAS: 1401708-83-5). The core derives from the Nle-Tyr-Ile fragment of Norleucine1-Angiotensin IV, with a hexanoyl N-terminal cap and 6-aminohexanoic amide C-terminal modification increasing hydrophobicity and blood-brain barrier permeability. Developed by Joseph Harding and John Wright at Washington State University. Animal pharmacokinetics show an extraordinarily long half-life: 12.68 days following IV administration and 8.83 days following IP in rats. Oral bioavailability has been demonstrated at 2 mg/kg in animal models. Brain penetrance was confirmed via radiolabeled infusion studies.
Research suggests Dihexa binds hepatocyte growth factor (HGF) with high affinity (Kd = 65 pM) and shifts HGF's dose-response curve to the left, rendering subthreshold HGF concentrations biologically active. It does not directly activate c-Met alone but augments c-Met receptor autophosphorylation in the presence of subthreshold HGF. Downstream signaling involves PI3K/Akt/mTOR and MAPK pathways. In vitro studies indicate Dihexa induced approximately 3-fold increases in hippocampal spinogenesis (41 versus 15 spines per 50 um dendrite) with new spines containing functional synaptic machinery. The widely cited claim of being '10 million times more potent than BDNF' refers specifically to the effective concentration for inducing synaptogenesis: Dihexa is active at picomolar (10^-12 M) concentrations versus BDNF's nanomolar range. The ADDF noted that BDNF and Dihexa were not directly compared in the original publication.
The foundational evidence faces severe integrity concerns. McCoy et al. (2013, JPET) received an Expression of Concern (September 2021) due to image manipulation. Benoist et al. (2014, JPET) was retracted in April 2025 after WSU investigation found 'falsified and/or fabricated data' attributed to Leen Kawas and Joseph Harding. Animal data from the compromised papers showed Dihexa reversed scopolamine-induced cognitive deficits in rats (N=8-10/group) via ICV, IP, and oral routes. One independent study (Sun et al., 2021, China) showed some beneficial effects in APP/PS1 mice. A clinical-stage prodrug, fosgonimeton (ATH-1017), entered Phase 2 trials for Alzheimer's disease. The ACT-AD trial (N=77) failed its primary endpoint (ERP P300 latency). Per AlzForum, fosgonimeton is now discontinued for all indications.
The information on this page is provided for educational and research reference purposes only. This is not medical advice. Always consult a qualified healthcare professional before making any health-related decisions.
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This content is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making decisions about your health.
