Semax Sharply Boosts BDNF and TrkB in the Rat Hippocampus—A 2006 Paper Still Worth Knowing
A single intranasal dose rapidly increases hippocampal BDNF protein, TrkB signaling, and gene expression—with measurable learning benefits in rats.
A small peptide modeled after a snippet of ACTH quietly ramps up two of the brain’s most important growth signals. That’s what caught my eye years ago when I first tried Semax alongside the early racetams—it felt noticeably “cleaner” than most nootropics I’d used, and this Russian study from 2006 gives a solid mechanistic clue as to why.
“A single application of Semax… resulted in a maximal 1.4-fold increase of BDNF protein levels accompanied with 1.6-fold increase of trkB tyrosine phosphorylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, respectively, in the rat hippocampus.”
What Actually Happened in This Study
The work is a straightforward set of acute and sub-chronic experiments on adult male Wistar rats. Researchers gave Semax intranasally at doses from 5 to 500 μg/kg (most data shown at 50 μg/kg—the typical human-equivalent range people still use today) and sacrificed animals at different time points to measure hippocampal BDNF and TrkB.
Key observations:
BDNF protein rose ~1.4-fold as early as 3 hours after a single dose, peaking around 6–8 h.
TrkB receptor tyrosine phosphorylation jumped ~1.6-fold in the same window—meaning the extra BDNF wasn’t just sitting there; it was actively signaling.
Exon III-specific BDNF mRNA and total trkB mRNA shot up 3-fold and 2-fold, respectively, showing genuine gene-level upregulation rather than just release from stores.
Effects were dose-dependent up to ~50 μg/kg and largely gone by 24 h after a single administration.
Repeated dosing (once daily for 6 days) still produced clear increases in BDNF/TrkB protein and mRNA without obvious tachyphylaxis in this short window.
No change in BDNF in the frontal cortex or brainstem—the effect looks fairly hippocampus-selective, at least acutely.
They also ran a water-maze learning experiment: rats treated with Semax for 6 days before training learned significantly faster (fewer trials to criterion) than saline controls, though the paper is careful not to claim the spatial-memory benefit is solely due to BDNF/TrkB.
Why This Still Matters (and What You Can Take From It)
BDNF isn’t just “brain fertilizer” – it’s probably the single best-measured correlate of new synapse formation, dendritic branching, and long-term potentiation in the hippocampus. Low BDNF is repeatedly linked to depressed mood, poor memory consolidation, and accelerated cognitive decline. Anything that reliably pushes hippocampal BDNF up in healthy animals is at least interesting for cognition and mood resilience.
Semax stands out because it does this acutely and at very low doses, without being a classic amphetamine-like stimulant or a slow SSRI-type antidepressant. The 2006 data fit nicely with later Russian clinical papers showing faster recovery from stroke, better attention in ADHD kids, and reduced anxiety—all situations where BDNF signaling is thought to be protective.
Practical takeaways that have held up for me and many others:
Intranasal is the way to go—the original Russian studies (and this one) used nasal drops or spray; bioavailability is far higher than subcutaneous.
50 μg/kg seems the sweet spot—that's roughly 4–6 mg for most adults if you convert rat intranasal to human (people usually dose 300–900 μg per spray session).
Cycling still makes sense—acute spikes are large, but we don’t have great long-term rodent data on receptor sensitization. Most experienced users do 1–3 weeks on, at least a week off.
Pairing with exercise or learning amplifies the effect—BDNF from Semax and BDNF from aerobic exercise additively increase neurogenesis in rodents.
What’s Next for Semax Research
The big open question is still better analogs. The original Semax molecule (ACTH4-10 fragment with Pro-Gly-Pro added for stability) is already pretty optimized, but N-acetyl-Semax and N-acetyl-Semax-amidate (NAS and NASA) are widely reported to have longer half-lives and smoother subjective effects. We have almost no published head-to-head comparisons yet.
There’s also intriguing (but preliminary) Russian data on Semax increasing nerve-growth factor (NGF) and even modulating enkephalin systems—hints it might do more than “just” BDNF. A proper Western-style Phase II/III program has never happened because of patent and regulatory hurdles, but the existing 30+ years of Russian clinical literature is surprisingly consistent on safety and mild-to-moderate cognitive benefit.
Safety, Ethics, and Real-World Caveats
This 2006 study used healthy rats and saw no behavioral toxicity or weight changes. Decades of Russian clinical use report very low side-effect rates—occasional nasal irritation, rare mild agitation at high doses. No known drug-drug interactions of concern, no hepatotoxicity or cardiotoxicity in the literature.
Still, it’s a research peptide in most countries, not an approved drug. Purity and accurate dosing matter enormously when you’re buying from gray-market vendors. And while the acute BDNF bump is clear, we don’t have human PET or CSF data proving the same magnitude of effect translates.
One Last Thing
If you’ve ever tried the classic nootropics stack and felt something was missing, Semax was one of the first compounds that actually gave me that “quiet clarity” without any stimulation hangover. Almost twenty years later, the basic science still looks solid.
Explore the Full Study
Dolotov OV, Karpenko EA, Inozemtseva LS, et al. “Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus.” Brain Research. 2006;1117(1):54-60.
DOI: 10.1016/j.brainres.2006.07.108
ACD-856 may interest you, it’s a TrkA/B/&C PAM.