Dihexa
PeptideThe divergence of -30 points is explained by the fact that the medical assessment is based exclusively on preclinical evidence without any human data [s3, s4, s6], while a portion of the biohacking community reports anecdotal cognitive improvements and actively uses the compound [c1, c2, c3]. The discrepancy reflects the typical pattern seen with experimental peptides: community enthusiasm substantially exceeds the actual scientific evidence base.
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TL;DR
Dihexa is an experimental hexapeptide derived from Angiotensin IV that potentiates HGF/c-Met signaling and improved cognitive deficits in animal models. No human RCTs exist, making efficacy and safety in humans entirely unknown. The risk profile is rated high (4/5), as uncontrolled HGF/c-Met activation carries theoretical oncogenic potential. Use outside controlled research settings is scientifically unjustifiable.
Description
Experimental hexapeptide derived from Angiotensin IV that activates the HGF/c-Met signaling pathway and improved cognitive deficits in animal studies. No human RCTs available [s1, s2].
Dihexa (PNB-0408; chemical name: N-Hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is a synthetic hexapeptide developed in the laboratory of Dr. Joseph Harding at Washington State University [s1, s3]. It is a structural analogue of Angiotensin IV, a component of the renin-angiotensin system [s1, s2]. Compared to its precursor molecule Norleucine1-Angiotensin IV (Nle1-AngIV), Dihexa was chemically modified to exhibit improved blood-brain barrier penetration and metabolic stability [s3]. In preclinical animal models (predominantly rats and mice), Dihexa has been shown to ameliorate cognitive deficits induced by scopolamine or other models [s3, s4]. The postulated effects include synaptogenesis (formation of new synaptic connections) and potential neuroprotective properties [s3, s5]. The prodrug Fosgonimeton (AT-1501), a phosphate prodrug of Dihexa, is currently in clinical trials for Alzheimer's and Parkinson's disease [s1]. No published clinical studies in humans exist for Dihexa itself [s6]. All dosing information in the biohacking community is based on extrapolations from animal studies and anecdotal reports [s7, s10, s11]. Human safety is unknown. A theoretical cancer risk via c-Met activation is discussed, but could not be confirmed in short-term animal studies [s1, s4, s12]. The compound is available exclusively for research purposes and is not approved for human use [s8, s9].
Legal Status (DE)
Dihexa is not approved as a medicinal product anywhere in the world and is classified in Germany as a non-marketable research chemical. There is no approval by BfArM, EMA, or FDA for therapeutic use in humans. Distribution as a dietary supplement is not permitted. The possession and acquisition for research purposes is legally ambiguous; use in humans operates in a legal grey area under the German Medicinal Products Act (AMG) [s8, s9].
Mechanism of Action
Dihexa's primary mechanism of action consists of potentiation of hepatocyte growth factor (HGF) at its receptor c-Met (also known as HGFR, Hepatocyte Growth Factor Receptor) [s3]. Specifically, Dihexa binds with high affinity to HGF itself and enhances its activity at subthreshold concentrations: in the presence of Dihexa, an otherwise ineffective HGF concentration induces c-Met phosphorylation [s3]. The HGF/c-Met signaling pathway regulates cellular processes such as cell growth, differentiation, survival, and migration. In the central nervous system, this pathway promotes synaptogenesis (formation of new synaptic connections), neurogenesis, and neuronal plasticity [s3, s5]. Preclinical studies observed that Dihexa increases dendritic spine density and synaptophysin-positive structures in transgenic mouse tissue [s4]. Unlike earlier Angiotensin IV analogues, Dihexa shows no significant affinity for the classical AT4 receptor (IRAP); the cognitive effects are instead mediated primarily via the HGF/c-Met pathway [s3]. c-Met activation is simultaneously the basis for theoretical oncogenic concerns, as dysregulated c-Met signaling has been described in various cancers (e.g., hepatocellular carcinoma, glioblastoma) [s12]. However, short-term safety studies in animals showed no neoplastic changes [s1, s4].
Dosing
Kognitive Verbesserung (anekdotisch, oral)
- Dose
- 10 mg
- Frequency
- 2–3× pro Woche
- Route
- oral
- Duration
- 8–12 Wochen, dann 2–4 Wochen Pause
- Timing
- Morning, with fatty meal (for potentially improved absorption)
- With food
- empfohlen
Kognitive Verbesserung (anekdotisch, transdermal in DMSO)
- Dose
- 10–25 mg in DMSO solution (approx. 6–10 mg/ml)
- Frequency
- 1–3× pro Woche
- Route
- oral
- Duration
- Zyklisch, nicht Dauereinnahme
- Timing
- Apply to inner forearm
- With food
- optional
Kognitive Verbesserung (anekdotisch, subkutan)
- Dose
- 0.02–0.3 mg (20–300 µg)
- Frequency
- Unklar, variiert stark
- Route
- injektion-subkutan
- Duration
- Nicht standardisiert
- Timing
- No validated protocols available
- With food
- optional
No scientifically validated upper limit for humans is available. All dosages are exclusively community-based and extrapolated from animal studies. Use without medical supervision is not recommended [s6, s7].
The oral bioavailability of Dihexa is estimated in the community at approximately 2–3%, resulting in highly uncertain effective systemic doses [c3, c5]. Subcutaneous administration likely achieves considerably higher bioavailability than oral. DMSO as a carrier carries its own risks (skin irritation, unknown interactions). None of these dosing methods are clinically validated [s6, s7, c3].
Calculate reconstitution, plan dosing, look up injection technique
Side Effects
| Side Effect | Frequency | Severity |
|---|---|---|
| Potenzielle Tumorpromotion / onkogenes Risiko c-Met activation is involved in tumor progression in multiple cancers (hepatocellular carcinoma, glioblastoma). Short-term animal studies showed no neoplastic changes, but long-term human data are entirely lacking [s1, s4, s12]. | theoretisch | schwer |
| Unbekannte systemische Toxizität As no Phase I studies with Dihexa have been conducted in humans, the complete systemic toxicity profile is unknown [s6, s9]. | theoretisch | schwer |
| Kopfschmerzen, Schlafstörungen (anekdotisch) Community reports occasionally mention headaches and sleep disturbances at higher doses. Causality not established [c1, c4]. | gelegentlich | leicht |
| Hautirritation bei transdermaler DMSO-Anwendung DMSO as a vehicle can cause local skin irritation, redness, and scaling, particularly with undiluted or frequent application [c3, c5]. | gelegentlich | leicht |
| Mögliche Wechselwirkungen mit anderen Substanzen (z.B. Isotretinoin) A single community report describes a possible antagonization of Dihexa's effect by isotretinoin. Mechanism and causality entirely unclear [c2]. | selten | moderat |
Contraindications
c-Met activation by Dihexa could theoretically promote tumor growth or metastasis. In active malignancy, any c-Met activation is contraindicated [s12].
No safety data available for pregnant or breastfeeding individuals. HGF/c-Met signaling pathways play a role in fetal development; uncontrolled activation could pose risks [s6].
In the still-developing brain and body, the risks of uncontrolled synaptogenesis and c-Met activation are unknown and potentially substantial [s6, c7].
Individuals with a family history of cancers with c-Met overexpression should avoid Dihexa [s12].
Absent immune surveillance combined with possible promotion of cell proliferation via c-Met activation increases the theoretical tumor risk [s12].
Interactions
Synergistic
In the biohacking community, Dihexa is frequently combined with Cerebrolysin in so-called TBI recovery stacks. No scientific evidence exists for synergism or safety of this combination [c1].
Anecdotal combination in peptide stacks; both theoretically address neuronal repair mechanisms. No scientific evidence of synergism [c1].
In the biohacking community, Semax is frequently combined with Dihexa, as Semax acts via BDNF/NGF upregulation while Dihexa is proposed to promote synaptogenesis downstream via HGF/c-Met signaling pathways. The distinct targets could theoretically be complementary. Clinical evidence is lacking.
Selank reduces stress-induced suppression of BDNF and neuronal disturbances, which could theoretically facilitate LTP promotion by Dihexa. The combination is described anecdotally in peptide stacks. No controlled studies are available.
P21 is described as a long-term neurogenesis-promoting peptide, while BPC-157 provides acute neuroprotection and Dihexa targets synaptogenesis. This combination is discussed in theoretical TBI recovery protocols. Scientific evidence is lacking.
Alpha-GPC increases cerebral acetylcholine levels and supports cholinergic signaling, while Dihexa promotes synaptogenesis via HGF/c-Met activation. These complementary mechanisms could theoretically produce additive improvements in cognitive performance. Clinical evidence for this combination is lacking.
Citicoline supports both acetylcholine synthesis and phospholipid metabolism in the brain. In combination with Dihexa's synaptogenesis-promoting effect, complementary coverage of various neuroplastic mechanisms may arise. No controlled studies exist for this combination.
ALCAR supports mitochondrial function and neuronal energy metabolism, while Dihexa targets synaptic plasticity and neurogenesis. A combination could theoretically strengthen both the metabolic foundation and structural neuroplasticity. Clinical evidence is lacking.
Caution
A single community report describes possible antagonization of Dihexa's effects by isotretinoin. Mechanism and clinical relevance are entirely unclear [c2].
Pharmacomechanistically expected direct antagonism: c-Met inhibitors would abolish the effects of Dihexa. No clinical evidence [s12].
Cumulative c-Met overactivation could amplify the theoretical oncogenic risk. No evidence from human studies [s12].
Studies
Tier B — Moderate Evidence
Outcome: c-Met phosphorylation, synaptogenesis markers, cognitive behavioral tests (Morris Water Maze)
Effect Size: Significant improvement in cognitive tests in scopolamine-induced memory deficit models; induction of c-Met phosphorylation at subthreshold HGF concentrations [s3]
Outcome: Synaptophysin expression, synapse density, cognitive function
Effect Size: Increased synaptophysin expression at 1.44 and 2.88 mg/kg Dihexa in APP/PS1 mice [s4]
Tier C — Low Evidence
Outcome: Summary of preclinical evidence on Dihexa
Effect Size: No primary outcome; summary assessment of the literature
Outcome: Safety and efficacy assessment without human data
Effect Size: No effect size; recommendation: no human application
Community Evidence
Top reported benefits
- Subjectively improved memory and concentration (in a subset of users)
- Potential support for neurocognitive deficits (e.g., Asperger syndrome, TBI)
- Long-lasting effects in some long-term users (1× weekly over months)
Top reported issues
- No noticeable effect in many oral users (poor bioavailability)
- Uncertainty regarding correct dosing and administration method
- Concerns about cancer risk via c-Met activation
- Quality issues with suppliers (peptide degradation)
- DMSO odor and skin irritation with transdermal application
The community extensively discusses the unresolved oncogenic risk from c-Met activation [c1, c4]. Many users are frustrated by unreliable oral bioavailability and the resulting uncertainty regarding effective doses [c3, c5]. Quality issues with research chemical suppliers are frequently mentioned [c6]. The substance is considered in the community as "not suitable for beginners" and is rated as one of the riskiest experimental nootropics [c1, c4].
Scientific Sources
- Dihexa - Wikipedia
Wikipedia contributors (2024). WikipediaCLink - Dihexa — Dosage, Half-Life & Research
Peptide Reference Editorial Team (2025). Peptide ReferenceCLink - Peptide legal in Deutschland? Rechtslage 2026
Peptide Culture Editorial Team (2026). Peptide Culture BlogCLink - Dihexa: An Angiotensin IV Analog and Proposed HGF/c-Met Activator — Safety and Oncogenesis Review
Superpower.com Editorial Team (2025). Superpower.com GuidesCLink - Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial
Hua X, Church K, Walker W, L'Hostis P, Viardot G, Danjou P, Hendrix S, Moebius HJ (2022). Journal of Alzheimer's DiseaseAPMID:35253776DOI - Fosgonimeton in mild-to-moderate Alzheimer's disease (LIFT-AD)
Moebius HJ, Church K, Johnston J, Kneip M, Taylor RW, Stein LR, Berthiaume AA [et al., Athira Pharma] (2025). Therapeutic Advances in Neurological DisordersADOI - HGF/c-MET Targeted Therapeutics: Novel Strategies for Cancer Medicine
Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G (2012). Nature Reviews CancerAPMID:22530990DOI - What is dihexa peptide?
Creative Peptides (2024). Creative Peptides Resource LibraryCLink - The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System
McCoy AT, Benoist CC, Harding JW, et al. (2013). Journal of Pharmacology and Experimental TherapeuticsCPMID:23959930DOI - AngIV-Analog Dihexa Rescues Cognitive Impairment and Increases Synaptogenesis in APP/PS1 Mice
Multiple authors (transgenic mouse study) (2021). PubMed Central (PMC8615599)CPMID:34858496 - Dihexa Peptide: Complete Guide to Synaptogenesis (2026)
RWA Center Editorial Team (2026). RWA Center BlogCLink - Dihexa - Cognitive Vitality Report
Alzheimer's Drug Discovery Foundation (2023). Alzheimer's Drug Discovery Foundation (ADDF) Cognitive VitalityBLink - Dihexa Peptide: Benefits, Dosage, Side Effects & How It Works
PeptideDeck Editorial Team (2025). PeptideDeckCLink - Are Peptides Legal? Complete 2026 Status by Country
Guide to Peptide Editorial Team (2026). GuideToPeptide.comCLink - Dihexa Risks, Warnings, and Legal Status
Peptide Protocol Wiki Editorial Team (2025). Peptide Protocol WikiCLink
Community Sources
Storage
Unopened
Store cool (2–8°C) and protected from light, according to manufacturer instructions. Lyophilized powder at -20°C for long-term storage.
Opened
Store reconstituted solution at 2–8°C and use within a few days. Avoid repeated freeze-thaw cycles.
Notes
Dihexa tends to precipitate in aqueous solutions at higher concentrations (>15 mg/ml). Concentration in DMSO should be kept below 6–10 mg/ml [c5]. No validated stability data for end users are available.