CognitionRestricted
Selank
A 7-residue tuftsin analog with anxiolytic and cognitive-support properties.
Russian-origin neuropeptide approved in Russia as Selank; no FDA-recognized clinical evidence in the U.S.
- Routes
- Nasal
- Composition
- 7 aa
← All peptides
CognitionAwaiting Reclassification
Dihexa
Rewiring the brain's growth network
Oral · 503A Compounding
Educational content. This page describes Dihexa for informational purposes only and is not medical advice, diagnosis, or treatment. Consult a licensed provider before starting, stopping, or modifying any therapy.
Researched and maintained by the PepHookup team. Regulatory status last verified April 12, 2026.
- Primary Use
- An orally active angiotensin IV-derived peptidomimetic studied for synaptogenesis and cognition.
- Administration
- oral
- Typical Cycle
- 30–60 days
- Legal Status
- Awaiting Reclassification
Key Benefits
Alzheimer's Disease Potential
In a transgenic Alzheimer's mouse model, oral Dihexa rescued cognitive impairment and engaged PI3K/AKT survival signaling, an effect reversed by a PI3K inhibitor.[4]
What is Dihexa?
Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, also known as PNB-0408) is a small synthetic angiotensin IV derivative developed by researchers at Washington State University. Structurally it is built from a tyrosine-isoleucine core capped with a hexanoyl group and a 6-aminohexanoic amide, giving a molecular weight near 504 daltons. It was designed to overcome the limitations of natural angiotensin IV, namely its rapid metabolic degradation and inability to cross the blood-brain barrier, while preserving its procognitive properties.
Dihexa has attracted attention in neuroscience because of reports that it promotes new synapse formation in cell culture at picomolar concentrations. It was engineered to be orally active and blood-brain barrier permeable, which is unusual for a peptide-derived molecule. It remains investigational and has not entered formal human clinical trials.
Readers should know that two of the foundational Washington State University papers on this molecule were later retracted. A 2012 paper characterizing the angiotensin IV analogs as HGF/Met modifiers and a 2014 paper reporting that the procognitive effects depend on HGF/c-Met were both retracted in 2025 after a university investigation found falsified or fabricated figure data. A 2013 paper describing Dihexa's oral activity and synaptogenesis carries a 2021 expression of concern. The mechanism below should therefore be read as a proposed model rather than settled science.
How Does It Work?
Dihexa's proposed primary mechanism involves activation of the hepatocyte growth factor (HGF) / c-Met receptor system in the brain. HGF and its receptor c-Met support neuronal growth, survival, and the formation of new synaptic connections (synaptogenesis), and the molecule was designed to act as an HGF mimetic.
The originating laboratory reported that Dihexa's procognitive and synaptogenic effects depend on HGF/c-Met activation, but the central paper making that claim was retracted in 2025 for data integrity reasons. Independent support for an HGF/c-Met mechanism is more limited. A separate study from the same group showed that Dihexa protects sensory hair cells in a manner blocked by an HGF antagonist, which is consistent with the model but does not establish it for cognition.
In an Alzheimer's disease model, an independent group reported that oral Dihexa engaged the PI3K/AKT signaling pathway, promoting neuronal survival and restoring memory, with these benefits reversed by the PI3K inhibitor wortmannin. That study did not invoke HGF/c-Met, so the downstream signaling picture remains incomplete.
Quick Facts
Rewiring the brain's growth network
- Primary Use
- An orally active angiotensin IV-derived peptidomimetic studied for synaptogenesis and cognition.
- Administration
- oral
- Typical Cycle
- 30–60 days
- Categories
- cognition
- Legal Status
- Awaiting reclassification
Mechanism of Action
Dihexa was designed as an HGF mimetic intended to activate the brain's HGF/c-Met receptor system and promote synaptogenesis and neuronal survival. In a transgenic Alzheimer's model it engaged PI3K/AKT survival signaling and restored memory. The HGF/c-Met dependence originally proposed by the developing lab rests in part on a paper retracted in 2025, so the mechanism is best regarded as a working hypothesis supported by preclinical data of mixed standing.
Clinical Evidence
Procognitive Evaluation in Impaired Rats
Preclinical controlled study (carries a 2021 expression of concern)Rats with scopolamine-induced cognitive impairment
Oral Dihexa (2 mg/kg by gavage) completely reversed the scopolamine-induced learning deficit in the Morris water maze, concentrated in multiple brain regions consistent with blood-brain barrier penetration, and induced dendritic spine formation at picomolar concentrations in cultured neurons.
McCoy AT, Benoist CC, Wright JW, et al. · J Pharmacol Exp Ther, 344(1):141-54 (expression of concern 2021) (2013) · PubMed
APP/PS1 Alzheimer's Model Study
Preclinical transgenic mouse study (independent group)APP/PS1 Alzheimer's disease model mice
Oral Dihexa rescued cognitive impairment and recovered memory while activating PI3K/AKT survival signaling. The PI3K inhibitor wortmannin reversed the anti-inflammatory and anti-apoptotic effects, supporting a PI3K/AKT-dependent action.
Sun X, Deng Y, Fu X, Wang S · Brain Sci, 11(11):1487 (2021) · PubMed
Systematic Review of AngIV Cognitive Benefits
Systematic review of 32 experimental studiesMultiple animal species and cognitive paradigms
In models of cognitive deficit, eight of nine studies found that angiotensin IV and its analogs, including Dihexa, improved spatial working memory and passive avoidance. The review noted these peptides appear most effective when delivered directly into the brain.
Ho JK, Nation DA · Neurosci Biobehav Rev, 92:209-225 (2018) · PubMed
Dosing & Administration
start low, go slow
Oral
- Dosage
- 10–20 mg
- Frequency
- Once daily
- Cycle
- 30–60 days
Subcutaneous Injection
- Dosage
- 0.5–2 mg
- Frequency
- Once daily
- Cycle
- 30–60 days
Oral: Orally active and BBB-permeable in animal studies. No established or validated human dosing.
Subcutaneous Injection: Alternative route; figures are extrapolated from preclinical work, not human data.
Dihexa has not undergone human clinical trials. There are no registered trials and no validated human dosing. The figures shown are extrapolated from animal studies and anecdotal reports, and any regimen would be determined by a licensed provider.
Its reported oral bioavailability sets it apart from most peptides, but the optimal human dose, if any, remains undetermined.
Given its investigational status and the data-integrity concerns around its foundational research, particular caution is warranted.
Side Effects & Safety
Uncommon
- Headache: Reported anecdotally; no formal human safety data available
- Overstimulation: Some users report difficulty sleeping or mental over-activity
- Blood pressure changes: Theoretical concern given the angiotensin system origin of the molecule
Safety Profile
Dihexa is an investigational compound that has not undergone human clinical trials. All safety information is derived from preclinical animal studies and anecdotal reports, and some of the foundational efficacy research has been retracted.
A theoretical concern with sustained HGF/c-Met activation is the potential to promote unwanted cell growth, since this pathway is implicated in certain cancers. No tumorigenic effects have been reported in the published animal studies to date.
Individuals with cardiovascular disease, a cancer history, or those taking antihypertensive medications should be especially cautious. Use only under the supervision of a knowledgeable, licensed provider.
Contraindications
- Pregnancy or breastfeeding (no safety data)
- History of cancer or active malignancy (theoretical risk due to HGF/c-Met growth signaling)
- Cardiovascular disease or uncontrolled hypertension
- Concurrent use of ACE inhibitors or angiotensin receptor blockers
- Anyone not under direct medical supervision (investigational compound)
Compare with Similar Peptides
| Peptide | Primary Use | Administration | Cycle Length | Key Differentiator |
|---|---|---|---|---|
| Dihexa | Cognitive Enhancement | Oral, Injection | 30–60 days | Orally bioavailable angiotensin IV analog designed to drive synaptogenesis through the HGF/c-Met pathway |
| Selank | Anxiolytic & Nootropic | Intranasal | 14-21 days | Benzodiazepine-comparable anxiety relief in Russian trials without the sedation, cognitive dulling, or dependence |
| Semax | Nootropic & Neuroprotective | Intranasal | 10–21 days | Directly upregulates BDNF (the brain's primary growth factor for learning and memory) without hormonal side effects |
Regulatory Status
Under Review (Category 2)
503A CompoundingThe FDA placed this substance in Category 2 of the 503A bulk drug substances evaluation, flagging significant safety risks. 503A compounding carries FDA enforcement risk, so most pharmacies decline to prepare it and many physicians hesitate to prescribe it.
Reclassification Pending
In April 2026, HHS Secretary Robert F. Kennedy Jr. announced that nominators withdrew 12 peptides from Category 2 of the FDA's 503A bulk drug substances evaluation, including this one. The FDA referred them to its Pharmacy Compounding Advisory Committee (PCAC) for re-evaluation at meetings beginning July 2026. If PCAC recommends Category 1 status and the FDA agrees, licensed 503A pharmacies could compound it under FDA enforcement discretion again. The outcome is not final.
Regulatory Detail
Listed in Category 2 as Dihexa Acetate. No human clinical trials have been conducted. FDA lacks sufficient information to determine whether dihexa would cause harm when administered to humans. Not eligible for compounding.
FDA Action History
Listed as 'Dihexa Acetate' in 503A Category 2
What do these terms mean?
- 503A compounding
- Licensed pharmacies that prepare custom prescriptions for individual patients based on a physician's order. 503A is the section of the federal law that governs them.
- 503B outsourcing
- FDA-registered facilities that compound in larger batches under stricter federal oversight (closer to a manufacturer than a pharmacy). Used mostly by hospitals and clinics.
- Bulk drug substance
- The active pharmaceutical ingredient a compounder starts with, before it's made into a finished medication.
- Category 1
- Interim bucket for bulk substances that have been nominated and don't appear to present significant safety risks. 503A pharmacies may compound them under FDA enforcement discretion while the agency continues its review. Not the same as FDA approval.
- Category 2
- Bulk substances the FDA has flagged for significant safety risks. 503A compounding carries FDA enforcement risk, so most pharmacies decline to prepare them and many physicians hesitate to prescribe them.
- PCAC
- Pharmacy Compounding Advisory Committee. The FDA advisory committee that reviews nominated bulk substances and recommends whether they belong in Category 1, Category 2, or on the final 503A Bulks List.
Last verified April 12, 2026. PepHookup tracks public FDA actions. This is not legal or medical advice.
Frequently Asked Questions
Research & References
Ready to explore Dihexa therapy?
Looking into Dihexa? Find a provider who knows this peptide and can walk you through your options.
Find a Provider