Dihexa

Dihexa is a chemically modified hexapeptide derivative engineered from the cognition-relevant fragment of angiotensin IV by Joseph Harding's laboratory at Washington State University ([McCoy et al., *J Pharmacol Exp Ther* 2013, 344:141–154](https://doi.org/10.1124/jpet.112.199497)). The modifications — an N-terminal hexanoyl group and a C-terminal 6-aminohexanoic acid extension — were designed to increase lipophilicity and protect against enzymatic degradation, producing a metabolically stable, orally active, blood-brain-barrier-permeant analog. Mechanistically, the cognitive activity of angiotensin IV had originally been attributed to the AT4 receptor; the Harding group's later work demonstrated that the relevant target is actually the hepatocyte growth factor (HGF) receptor c-Met. Dihexa binds HGF with high affinity and potentiates HGF activity at c-Met, driving downstream PI3K/Akt signaling and synaptogenesis. In cell-culture assays the group reported synapse-formation activity orders of magnitude greater than equivalent concentrations of brain-derived neurotrophic factor — the much-quoted "10 million times more potent than BDNF" framing originates here, and applies specifically to a synaptogenesis-in-culture endpoint, not to broad cognitive efficacy in vivo.

Dihexa is the cognitive peptide on this list with the largest gap between preclinical promise and human evidence, and the page covers that gap rather than the marketing version of it. The preclinical evidence is genuine and substantial. McCoy and colleagues' 2013 design paper documented antidementia activity in scopolamine-induced cognitive deficit models in rats, restored Morris water maze performance in aged rats, and marked synaptogenic activity in hippocampal cultures. Subsequent work from the same lineage extended the c-Met-dependence story (Benoist et al. 2014, *Journal of Pharmacology and Experimental Therapeutics*) and added evidence in APP/PS1 transgenic Alzheimer's mouse models. The molecule was developed with a clinical eye toward Alzheimer's disease and, separately, traumatic brain injury. The clinical translation never happened. There are no published human trials of Dihexa for any indication — not Alzheimer's, not cognitive enhancement, not neurodegeneration broadly. The original Harding-lab program licensed the molecule to small-cap biopharma companies that did not advance it past preclinical work. What exists in the practitioner and self-experimenter market today is sourced entirely outside any IND or regulatory program, with the corresponding sourcing-quality concerns. The "10 million times more potent than BDNF" headline that drives recreational interest is a real cell-culture finding, but its applicability to a person taking oral Dihexa for cognitive enhancement is a chain of inferences that the published evidence base does not support. The honest framing is this: Dihexa is a serious neuroscience research compound with a credible mechanistic story and a real preclinical track record, and the public conversation about Dihexa as a cognitive enhancer rests almost entirely on that preclinical work. There is no human safety database, no human efficacy data, and no established dose. Anyone considering use is acting on rodent inference and self-experiment-tier reports, and the page should be read accordingly.