Dihexa (oral)

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, PNB-0408) is a metabolically stabilised angiotensin IV analogue developed by Joseph Harding's group at Washington State University as a procognitive, antidementia agent. It is orally bioavailable and crosses the blood-brain barrier, properties demonstrated in the primary 2013 Harding lab rat study and unusual for a peptide.

It is positioned as the most potent and least studied compound in the cognitive peptide space. Where Semax and Selank modulate neurotransmitter and neurotrophin levels (BDNF, serotonin, dopamine), Dihexa is claimed to be synaptogenic — driving formation of new synaptic connections rather than tuning existing ones. The Harding lab described it as seven orders of magnitude more potent than BDNF on a molar basis in an in vitro synaptic connectivity assay, a comparison that is scientifically misleading given the two act through unrelated receptor systems (TrkB versus HGF/c-Met).

The evidence base is entirely preclinical. No human trials have been published or registered to completion; a Phase 2/3 trial registered by Athira Pharma was terminated without published results. The foundational 2014 mechanism paper (Benoist et al., 2014) was retracted in April 2025 after Washington State University confirmed data fabrication in western blot images, with Leen Kawas and Joseph Harding found solely responsible. Behavioural data from the 2013 study was not directly implicated, and an independent 2021 replication exists in APP/PS1 mice.

Indications attached to the compound include Alzheimer's and Parkinson's disease, stroke recovery, spinal cord and peripheral nerve injury, and hearing loss protection — none with human data. It is not FDA approved and is available only as a research compound. This page covers the oral capsule form, 5 mg per capsule.

HGF/c-Met (proposed). Hepatocyte growth factor binding to its receptor tyrosine kinase c-Met triggers cascades promoting cell survival, proliferation, and in neurons, dendritic spine growth and synaptogenesis. The Harding lab proposed Dihexa binds HGF and facilitates its dimerisation, amplifying c-Met activation — potentiation of an existing signal rather than direct agonism. Benoist et al. (2014) reported that an HGF antagonist blocked Dihexa's procognitive effects in rats. That paper was retracted in April 2025 for falsified and fabricated western blot data; research integrity consultants found problems in 19 of 30 images from Kawas's doctoral dissertation. The Morris water maze behavioural data was not directly implicated, but the molecular evidence for HGF/c-Met as the target is compromised.

PI3K/AKT (independent). Sun et al. (2021), from a group unaffiliated with Harding or Kawas, tested Dihexa in APP/PS1 transgenic mice and found rescue of cognitive impairment with increased synaptophysin expression and neuronal survival, attributing the effect to PI3K/AKT signalling rather than direct HGF/c-Met activation. PI3K/AKT sits downstream of many receptor tyrosine kinases including c-Met, so the two accounts are not mutually exclusive, but the mechanism is unsettled.

Synaptogenesis. McCoy et al. (2013) reported a near 3-fold increase in dendritic spine number in cultured hippocampal neurons, with synaptogenic activity shown by colocalisation with synaptic markers. The "seven orders of magnitude more potent than BDNF" figure derives from this assay on a molar basis and compares unrelated receptor systems (TrkB versus HGF/c-Met).

Oral bioavailability. In the 2013 study, oral doses of 1.25 and 2.0 mg/kg were tested in rats; 2 mg/kg completely reversed scopolamine-induced learning deficits, demonstrating oral absorption and blood-brain barrier penetration.

Bottom line. Behavioural improvement in cognitively impaired animal models is supported by multiple studies including independent replication. The molecular target is uncertain. Whether any pathway operates equivalently in humans is unknown. Because c-Met is a well-established oncogenic driver, the mechanistic uncertainty carries direct safety implications rather than being academic.

Cognitive rescue (animal models). Dihexa reversed scopolamine-induced deficits in rats across intracerebroventricular, intraperitoneal, and oral routes, with treated animals indistinguishable from healthy controls in the Morris water maze (McCoy et al., 2013). Sun et al. (2021) partially replicated this in APP/PS1 mice.

Synaptogenesis (in vitro). Near 3-fold increase in dendritic spine number and colocalisation with synaptic markers, interpreted as formation of new functional synapses and tied to improvement in memory and motor dysfunction.

Anti-neuroinflammatory (animal). Decreased astrocyte and microglial activation, reduced IL-1 beta and TNF-alpha, increased IL-10 in APP/PS1 mice.

Neuroprotection (animal). Reduced neuronal loss on Nissl staining and increased synaptophysin expression in APP/PS1 mice.

Earlier-attributed effects. Increased acetylcholine and/or dopamine production; HGF activation inducing long-term neuroprotection and stroke recovery; stroke prevention via increased cerebral blood flow; prevention of learning and memory dysfunction after sustained cerebral ischaemia; slowed progression of ALS-related spinal cord injury and healing of sciatic nerve damage. The dopaminergic component is why interactions with stimulants, bromantane, and MAO inhibitors are flagged.

What it does not do (per published evidence). No enhancement demonstrated in healthy animals; no human efficacy at all; no data on persistence after discontinuation; no data on effects on intact healthy circuitry. Unregulated synaptogenesis, if real, has no data confirming the new connections are functional or appropriate.

Phenotype in practice. Users report mental clarity, sharper focus, and improved recall of recently learned material, typically described as subtle. A substantial proportion report nothing. The adverse cluster — mental overstimulation, racing thoughts, focus bordering on agitation, emotional intensity, anxiety, insomnia — reads as dose-dependent overshoot of the intended dopaminergic and synaptogenic action, hence morning dosing. A minority report the paradoxical opposite: brain fog and cognitive dulling.

No human data exists; the following is aggregated anecdote.

Weeks 1–2. Reports of improved mental clarity, focus, and information processing in a subset of users; others report nothing. Mild headache during the first few days is the most commonly reported early adverse effect.

Weeks 2–4. The window in which most responders report onset. Effects are characterised as subtle — a sense of being more present mentally — rather than dramatic. Improved recall of recently learned material is reported by a smaller number.

Weeks 4–8. Typical protocol length in practice. Use beyond 8 weeks is uncommonly reported and there is no data on benefit or risk with extended exposure in any species.

Post-discontinuation. Reports diverge: persistence of improvement for weeks to months versus fading within days. No durability data exists.

Non-response and paradoxical response. A substantial proportion report no effect. A minority report brain fog or cognitive dulling. Overstimulation, anxiety, vivid dreams, and disrupted sleep are reported particularly at higher doses.

The inter-individual variability is greater than for other cognitive peptides. Candidate explanations include inconsistent product quality in an unregulated market, genuine individual variation, dose differences, and expectation effects; without controlled data these cannot be separated. Note that every published efficacy result comes from cognitively impaired models, so the expectation of enhancement in an intact brain has no evidential basis.

Studied doses. McCoy et al. (2013), Sprague-Dawley rats: intraperitoneal 0.05, 0.25, and 0.50 mg/kg; oral 1.25 and 2.0 mg/kg. No human dose-finding or pharmacokinetic data exists. Interspecies translation requires allometric scaling and is not straightforward.

Practical oral tiers (from use in practice, not research).

• Conservative: 5–10 mg daily, 4–6 weeks.
• Standard: 10–20 mg daily, 4–8 weeks.
• Higher range: 20–30 mg daily, 4–8 weeks.

Capsules are 5 mg. The protocol table on this page shows the Standard tier. Oral is the dominant route on the basis of demonstrated oral bioavailability and blood-brain barrier penetration in the 2013 rat study.

Legacy protocol on this page. 1–4 capsules (5–20 mg) daily, single dose or divided into three, 8–12 week cycle, 4–6 week washout. Morning dosing because of sleep disturbance; fasted, 30-minute wait before eating. The divided-dosing option sits awkwardly against the morning-only instruction and the two were never reconciled. Extended use beyond 8 weeks has no long-term data in any species and is now flagged as an extreme-caution item, so the 4–8 week duration should be preferred over 8–12.

Confidence. The animal data has integrity concerns, there are zero human studies, anecdotal response is inconsistent, and the mechanism is uncertain. Dosing confidence is lower here than for any other compound. Treat 5 mg as the entry point; no dose-response safety data exists to justify the higher range. Concurrent use with other growth-factor-modulating compounds warrants extreme caution.

Other routes (not covered here). Subcutaneous: conservative 5–10 mg daily for 4–6 weeks, standard 10–20 mg daily for 4–8 weeks. Transdermal to the inner forearms, dose dependent on preparation.

Storage. Capsules in a cool, dry place away from light per manufacturer instructions.

The evidence base is entirely preclinical; no human trials are published or registered, and Athira Pharma's Phase 2/3 registration was terminated without results.

McCoy et al. (2013), Journal of Pharmacology and Experimental Therapeutics. Sprague-Dawley rats with scopolamine-induced deficits, three routes. Intraperitoneal 0.05, 0.25, 0.50 mg/kg; oral 1.25 and 2.0 mg/kg. The 2 mg/kg oral group completely reversed the Morris water maze deficit, with treated animals indistinguishable from healthy controls. In vitro: near 3-fold increase in dendritic spine number in cultured hippocampal neurons, with colocalisation to synaptic markers. Expression of concern issued in 2021 over western blot integrity; behavioural data unchallenged, mechanistic data compromised.

Benoist et al. (2014), same journal — RETRACTED April 2025. Claimed an HGF antagonist blocked the procognitive and synaptogenic effects, establishing HGF/c-Met dependence. Washington State University confirmed falsified and fabricated figures; Leen Kawas and Joseph Harding were found solely responsible, with problems in 19 of 30 images from Kawas's dissertation.

Sun et al. (2021), Brain Sciences. Independent group, APP/PS1 transgenic mice. Rescued cognitive impairment in the Morris water maze, increased neuronal survival (Nissl) and synaptophysin expression, reduced astrocyte and microglial activation, lowered IL-1 beta and TNF-alpha, raised IL-10. Proposed PI3K/AKT rather than direct HGF/c-Met. Small study; the divergent mechanism indicates the target is unsettled.

Missing: human pharmacokinetics, reproductive toxicity, carcinogenicity, genotoxicity, dose-finding, long-term data in any species, and any study in healthy animals. The "seven orders of magnitude more potent than BDNF" figure is a molar in vitro comparison across unrelated receptor systems (TrkB versus HGF/c-Met) and is not a meaningful potency statement.

Net position: behavioural efficacy in impaired animal models is replicated across two groups; the molecular mechanism is uncertain; human relevance is untested.