Nootropic Peptides: Semax, Selank & Cognitive Enhancement
Guide to nootropic research peptides: Semax, Selank, Semax-Selank Mix, PE-22-28 and Adamax. Mechanisms, comparisons and research applications.
Nootropic Peptides: Semax, Selank & Cognitive Enhancement
Most small-molecule nootropics work by nudging neurotransmitter levels up or down. Peptide-based nootropics do something different. They tap into neurotrophin signaling — BDNF, NGF, and the downstream cascades that govern synaptic plasticity and neuronal survival. That distinction matters, because it means these compounds don't just tweak arousal or attention. They influence the structural machinery of learning itself.
The five peptides covered here — Semax, Selank, the Semax + Selank Mix, PE-22-28, and Adamax — come from different research lineages but share a common thread: each one targets a specific mechanism in the brain's plasticity and mood-regulation systems.
What Makes Peptide Nootropics Different
Upstream Receptor Targeting
A peptide nootropic is a short-chain amino acid sequence that modulates cognitive function through neurotrophin signaling, neurotransmitter regulation, or neuroprotective pathways. Several of the most studied compounds originated in Russian neuroscience programs during the late Soviet era and have accumulated decades of clinical investigation — particularly Semax and Selank, both of which hold regulatory approval in Russia.
Their specificity is what sets them apart from racetams or stimulant-based nootropics. Rather than broadly increasing acetylcholine or dopamine tone, these peptides activate defined receptor pathways (TrkB, GABA-A subtypes, TREK-1 channels) that sit upstream of cognitive performance.
Semax — The BDNF Amplifier
Semax is a synthetic heptapeptide built on the ACTH(4-10) fragment with a Pro-Gly-Pro tail added at the C-terminus. It was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences and has been prescribed in Russia as a nootropic since 2011.
BDNF and TrkB Receptor Cascade
The core effect of Semax is upregulation of brain-derived neurotrophic factor, the protein most directly responsible for synaptic plasticity and long-term potentiation. Semax also raises nerve growth factor levels and activates the TrkB receptor cascade — the same pathway that exercise and environmental enrichment stimulate, but through a more targeted pharmacological route. On the neurotransmitter side, Semax influences dopamine and serotonin metabolism without binding directly to their receptors, which gives it a different side-effect profile than classical stimulants.
In research settings, Semax has been investigated across a range of cognitive paradigms: hippocampal-dependent memory consolidation, neuroprotection after ischemic injury, sustained attention in ADHD-like models, and even optic nerve regeneration. The intranasal route is standard for administration, since it provides rapid CNS access through the nasal mucosa and bypasses the blood-brain barrier entirely.
ACTH(4-10)-derived heptapeptide. BDNF amplifier targeting synaptic plasticity and neuroprotection via TrkB.
Selank — Anxiolytic Meets Immunomodulator
Selank is a synthetic analog of tuftsin (Thr-Lys-Pro-Arg), an endogenous immunomodulatory peptide, extended with a Gly-Pro sequence. Also a product of Russian neuropharmacology, Selank occupies an unusual niche: it acts on both the immune system and the brain's anxiety circuitry.
GABA-A Modulation Without Benzodiazepine Risks
On the neurological side, Selank enhances GABA-A receptor sensitivity without acting as a direct agonist. This is a critical distinction from benzodiazepines — you get anxiolytic effects without the sedation, tolerance buildup, or dependence risk that plagues classical GABAergic drugs. Selank also inhibits enkephalinase, slowing the breakdown of endogenous enkephalins, and modulates serotonin turnover.
The immune angle is equally interesting. Through its tuftsin-derived structure, Selank regulates interleukin-6 expression, placing it at the crossroads of the immune-neuro axis. Research applications have focused on anxiety models (where Selank performs comparably to benzodiazepines), cognitive flexibility under shifting task demands, HPA axis function under chronic stress, and innate immune enhancement.
Tuftsin-derived anxiolytic with GABA-A modulation, enkephalinase inhibition, and immunomodulatory properties.
Semax + Selank — The Combination Rationale
The Semax + Selank combination is probably the most widely used nootropic peptide stack in current research, and the logic behind it is straightforward.
Semax drives the plasticity side — BDNF upregulation, NGF stimulation, enhanced encoding and consolidation. Selank handles the emotional regulation side — GABAergic anxiolysis, stress resilience, stable mood under cognitive load. Combined, they address a well-documented problem in performance research: anxiety degrades cognitive output. High arousal narrows attention, impairs working memory, and disrupts executive function. By pairing a plasticity driver with an anxiolytic that doesn't cause sedation, the combination targets both halves of the performance equation.
Ideal for Dual-Variable Research
This makes the stack particularly relevant for research into sustained high-performance cognitive states where focus and emotional stability need to coexist. For labs new to peptide nootropics, this combination provides the widest experimental platform.
Dual-action nootropic stack: BDNF-driven plasticity paired with GABAergic anxiolysis for balanced cognitive research.
PE-22-28 — A Different Antidepressant Mechanism
PE-22-28 takes a completely different approach. It's a synthetic analog of spadin, an endogenous peptide that blocks the TREK-1 potassium channel. TREK-1 is a two-pore-domain background potassium channel with high expression throughout the brain, and its role in mood regulation was only identified relatively recently.
Rapid-Onset Mechanism via TREK-1 Blockade
When TREK-1 is blocked, neuronal excitability increases in mood-regulating circuits. Serotonergic signaling improves within days rather than the weeks typically required by SSRIs. PE-22-28 also stimulates hippocampal neurogenesis — the formation of new neurons in the dentate gyrus — and produces a secondary BDNF increase through the TREK-1 inhibition pathway.
The significance for depression research is hard to overstate. One of the biggest clinical problems with SSRIs is the delay between first dose and therapeutic effect. TREK-1 blockade appears to sidestep that delay entirely, making PE-22-28 a candidate for rapid-onset antidepressant research.
Spadin-family TREK-1 channel blocker. Rapid-onset serotonergic signaling and hippocampal neurogenesis.
Adamax — Semax with Better Brain Penetration
Adamax is a structural derivative of Semax that incorporates an adamantane group. The adamantane moiety increases lipophilicity, which translates to better blood-brain barrier penetration and a longer biological half-life compared to standard Semax.
In preclinical work, Adamax appears to produce a stronger BDNF response than its parent compound. The trade-off is that it has a thinner evidence base — Semax has decades of clinical data behind it, while Adamax is still primarily a preclinical tool. For research groups specifically interested in maximizing neurotrophin stimulation or studying enhanced BBB-penetrant peptide analogs, Adamax fills a gap that standard Semax leaves open.
Adamantyl-modified Semax with enhanced BBB penetration, longer half-life, and stronger BDNF response.
Choosing the Right Peptide for Your Research
The choice depends entirely on the research question.
Reconstitution Note
Intranasal peptides ship in lyophilized form. Reconstitute with Bacteriostatic Water before use.
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