Informational only. Not medical advice.INFORMATIONAL PLATFORM ONLY — NOT MEDICAL ADVICE, DIAGNOSIS, OR TREATMENT
Informational only. Not medical advice.INFORMATIONAL PLATFORM ONLY — NOT MEDICAL ADVICE, DIAGNOSIS, OR TREATMENT
Head-to-head comparison of Dihexa and PE-22-28 — mechanism, side effects, legal status, and pricing.
Dihexa (PNB-0408) is a small-molecule hexapeptide-like analog of angiotensin IV developed at Washington State University by the Harding/Wright group as a preclinical candidate for Alzheimer's disease and cognitive decline. It is NOT FDA-approved and has never been tested in human clinical trials. The often-quoted claim that it is 'roughly ten million times more potent than BDNF' refers to EC50 comparisons in an in vitro dendritic spine assay, not clinical efficacy.
PE-22-28 is a 7-amino-acid synthetic analog of spadin, a peptide fragment (residues 22-28) of the 44-aa propeptide (PE) released during post-translational maturation of sortilin (the neurotensin receptor-3). It is studied in preclinical models as a fast-acting antidepressant that works by selectively blocking the TREK-1 two-pore potassium channel. There is no established use for hair growth — that is a separate compound and the two should not be confused.
Dihexa
PE-22-28
Category
Legal Status
Mechanism
Half-life
Side Effects
COA-verified vendors · trust score ≥70 required · single-vial price — bulk/bundle deals may be lower
Dihexa
PE-22-28
COA corpus from Disclosed Labs — independently tested batches only.
Dihexa
4
COAs
99.1%
Avg purity
4
Labs
PE-22-28
13
COAs
99.6%
Avg purity
7
Labs
McCoy et al. (J Pharmacol Exp Ther 2013, PMID 23055539) is the original dihexa characterization: oral dihexa reversed scopolamine-induced memory deficits and improved Morris water maze performance in aged rats at low doses. Sun et al. (Brain Sci 2021, PMID 34827486) reported that dihexa rescued cognitive impairment in the APP/PS1 Alzheimer's mouse via PI3K/AKT signaling, with increased synaptophysin and reduced neuroinflammation. Wright & Harding (J Alzheimers Dis 2015, PMID 25649658) reviewed the brain HGF/c-Met system as an Alzheimer's target. Note: Benoist et al. (JPET 2014, PMID 25187433), which reported the HGF/c-Met-dependent synaptogenesis mechanism, was retracted in 2025 and should not be relied on as primary evidence. The 'roughly seven orders of magnitude more potent than BDNF' descriptor refers to in vitro dendritic spine EC50 values, not clinical efficacy. Dihexa has never entered human clinical trials; Athira Pharma's related analog fosgonimeton failed its Phase 2/3 LIFT-AD Alzheimer's endpoint in 2024 and was discontinued, after which Athira shifted focus to ATH-1105 for ALS.
Key references
Mazella, Borsotto and colleagues at Nice, France identified spadin (Mazella et al., PLoS Biology 2010, PMID 20405001) and subsequently developed shortened PE 22-28 analogs with ~300× improved TREK-1 affinity and longer in vivo half-life (Djillani et al., Front Pharmacol 2017, PMID 28955242). In mouse antidepressant assays (forced swim, tail suspension, novelty-suppressed feeding), acute or 4-day IP dosing at ~3–4 μg/kg produced effects comparable to chronic SSRI treatment; oral gavage at 1 mg/kg was also active. The G/A-PE 22-28 modification extended duration of action to ~21–23 hours. Chronic dosing did not produce cardiac or seizure signals in rodents. No human clinical trials have been conducted. A detailed review of TREK-1 blockers for depression is available in Djillani et al., Pharmacol Ther 2019 (PMID 30291907).
Dihexa and PE-22-28 are both in the Cognitive category and may have overlapping mechanisms. Researchers should review both profiles carefully, understand the mechanisms of action, and monitor the relevant biomarkers when combining compounds in the same class. As always, consult a licensed healthcare provider before making any decisions about combining research compounds.
This platform provides informational tools only, not medical advice. This comparison is for educational purposes only. Consult a licensed provider.
Contraindications
Lab Testing
Key references
Disclosed Labs