Dihexa vs PE-22-28.

Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide; also referenced as PNB-0408) is a small, orally active peptidomimetic derived from angiotensin IV (Ang IV), a C-terminal fragment of the renin-angiotensin system. It was designed at Washington State University by chemically modifying Ang IV to increase lipophilicity and metabolic stability, yielding a brain-penetrant molecule investigated as a procognitive / antidementia research agent. It is a research chemical, not a drug; it has never been an approved medicine.

PE-22-28 is a synthetic seven-residue peptide corresponding to residues 22 to 28 of spadin, itself a fragment derived from the sortilin propeptide (also called neurotensin receptor-3). It was developed as a shortened, more stable analog of spadin intended to block the TREK-1 potassium channel. It has been studied as a fast-acting antidepressant candidate in rodent models. It is a preclinical research compound with no human data.

Dihexa was developed from Ang IV, whose procognitive effects were originally studied at the AT4/IRAP site, but its proposed primary mechanism is potentiation of hepatocyte growth factor (HGF) signaling through its receptor tyrosine kinase c-Met, which drives dendritic spine formation (spinogenesis) and synaptogenesis in hippocampal neurons. Activating HGF/c-Met is thought to remodel synaptic connectivity rather than act as a classical neurotransmitter. Important caveat: the central biochemical evidence that dihexa works by binding HGF and augmenting HGF/c-Met activation came from a paper that has since been retracted for data fabrication, so the molecular mechanism should be treated as unproven. The downstream behavioral phenotype (improved spatial learning in rodents) was reported in separate, non-retracted work.

PE-22-28 acts by inhibiting the TREK-1 two-pore-domain potassium channel, which is implicated in mood regulation and in resistance to conventional antidepressants. By blocking TREK-1, it is proposed to increase serotonergic neurotransmission and promote hippocampal neurogenesis. Reported potency is high, with a sub-nanomolar IC50 and improved metabolic stability compared with spadin. These effects are characterized in cell and animal systems.

There is NO human data on dihexa: no completed clinical trials, no published human pharmacokinetics or safety. The non-retracted foundational study (McCoy et al., J Pharmacol Exp Ther 2013, PMID 23055539) reported that orally administered dihexa reversed scopolamine-induced learning deficits and improved Morris water maze performance in aged (24-month) rats, and induced spinogenesis in cultured hippocampal neurons at picomolar concentrations. Later angiotensin-IV-analog work continued in disease models (e.g., a 2024 study of an Ang IV analog in a 3-nitropropionic-acid Huntington's-like rat model, PMID 38489193). Crucially, the most-cited mechanistic paper tying dihexa's cognitive effects to HGF/c-Met (Benoist et al., J Pharmacol Exp Ther 2014, PMID 25187433) was RETRACTED in 2025 (retraction notice PMID 40312093) after a Washington State University investigation found falsified/fabricated figure data; the widely repeated "thousands of times more potent than BDNF" claim derives from this now-discredited line of work and should not be cited as established fact. The honest summary: rodent behavioral evidence exists, but the headline mechanistic and potency claims rest partly on retracted literature, and human efficacy is entirely unestablished.

Evidence for PE-22-28 is preclinical only. In the foundational study, shortened spadin analogs including PE-22-28 showed stronger TREK-1 inhibition, longer in-vivo stability and antidepressant-like activity in behavioral tests such as forced swim and novelty-suppressed feeding, along with induction of neurogenesis after a short treatment course (Djillani et al., Frontiers in Pharmacology 2017). A review of TREK-1 blockers situates spadin and its analogs within antidepressant drug discovery (Djillani et al., Pharmacology and Therapeutics 2019). Related work describes the sortilin/NTSR3 origin of spadin and its role in the membrane expression of TREK-1, which supplies the mechanistic rationale for the shortened analogs (Frontiers in Pharmacology, 2018). Separate mouse work using genetic and pharmacological inhibition of TREK-1 reported changes in depression-related behavior and hippocampal neuronal plasticity (CNS Neuroscience and Therapeutics, 2021); that work supports the target as biologically interesting but does not test this peptide. The design of the supporting studies limits the conclusions available. They are rodent experiments run in academic laboratories, largely the group that originated spadin, over short treatment courses. The behavioral readouts are screening assays rather than models of depression: forced swim, tail suspension and novelty-suppressed feeding are sensitive to known antidepressants, which makes them useful filters, but a long list of compounds that performed well in them has failed in human trials. The reports are not blinded multi-centre studies, are not pre-registered, and have not been replicated head to head by an independent group. No completed or registered human clinical trial exists for PE-22-28. There is consequently no Phase 1 safety or tolerability dataset, no human pharmacokinetic profile, no measured central nervous system exposure in people, and no published toxicology package. This is a weaker position than that of compounds it is informally compared with: approved rapid-acting antidepressants such as esketamine were established through randomized, placebo-controlled trials with standard depression rating scales before approval, and even TREK-1 or novel-mechanism candidates that ultimately failed generally reached Phase 1 and produced human exposure and tolerability data. Antidepressant-like signals in rodents do not establish human efficacy or safety.

No human safety data exist; there is no published clinical adverse-event profile, and dihexa is sold only as a research chemical of variable purity. The principal theoretical concern follows directly from its proposed mechanism: c-Met is a validated oncology target because aberrant HGF/c-Met signaling promotes tumor proliferation, invasion, angiogenesis, and metastasis, so a chronic c-Met potentiator raises an unresolved oncogenic-risk question that no human study has addressed. Its reported long circulating half-life and high lipophilicity also mean tissue accumulation and off-target effects are poorly characterized. Because foundational mechanistic data were retracted for fabrication, even the basic biology underlying any risk assessment is uncertain.

No human safety data exist for PE-22-28; all information comes from short-term rodent studies. There is no published Phase 1 tolerability study, no human pharmacokinetic or elimination data, no immunogenicity assessment, and no repeat-dose or reproductive toxicology package in the public literature. Because TREK-1 is expressed in tissues outside the brain, including cardiovascular, smooth muscle and immune-related tissues, systemic and off-target effects are theoretically possible; the channel also contributes to cellular responses to mechanical and thermal stimuli, so blocking it chronically could have consequences that short rodent behavioral experiments were never designed to detect. Effects on mood-related circuitry are themselves a caution: psychoactive compounds acting on serotonergic signaling and neurogenesis can produce agitation, sleep disruption or worsening mood, and no monitored human exposure exists to characterize any of this. Purity, identity and long-term toxicology of material sold as a research chemical are not controlled. Such products are made outside pharmaceutical good manufacturing practice, carry no verified certificate of analysis for peptide content, impurity profile or endotoxin, and are labeled for laboratory use only. Buyers cannot confirm what the vial holds or whether a reconstituted solution is sterile. The lack of reported adverse events reflects the lack of supervised human use rather than a safety record. With no clinical trials, no pharmacovigilance reporting and no registry, harms occurring in unsupervised use would not be captured. It is not a medicine and is not intended for human use.

Dihexa is investigational/research-use-only: it is not approved by the FDA or any major regulator for any indication, has no DailyMed monograph, and has not completed human clinical trials. It is not a dietary supplement and is widely sold only as a "research chemical." It is not a WADA-listed named substance, though non-approved experimental compounds are broadly disallowed in sport.

PE-22-28 is not approved by the FDA or any other regulator and has no approved medical use. It exists only as a preclinical research compound. This summary is educational and includes no dosing guidance.