Dihexa vs. Semax vs. Selank: Nootropic Ranking

Three peptides sit at the center of every serious nootropic conversation: Dihexa, Semax, and Selank. Each one targets a different piece of brain chemistry. Semax boosts BDNF and dopamine to sharpen focus. Selank modulates GABA and serotonin to dissolve anxiety without sedation. Dihexa drives synaptogenesis — the physical construction of new neural connections — through a growth factor pathway that's orders of magnitude more potent than anything else in the nootropic toolkit.

They're not interchangeable. Choosing between them depends on what kind of cognitive problem you're trying to solve, what level of risk you're willing to accept, and whether you prioritize well-studied safety or raw mechanistic potency.

Here's how they compare — mechanism by mechanism, study by study.

Table of Contents

• Quick Comparison Table
• Semax: The Focus and BDNF Amplifier
• Selank: The Anxiolytic With Cognitive Upside
• Dihexa: The Synaptogenesis Powerhouse
• Mechanism Comparison: Three Different Brain Targets
• Evidence Quality and Human Data
• Safety Profiles and Risk Assessment
• Practical Considerations
• Ranking: Which Peptide for Which Goal?
• The Bottom Line
• References

Quick Comparison Table

Feature	Semax	Selank	Dihexa
Derived from	ACTH fragment (4-10)	Tuftsin + PGP stabilizer	Angiotensin IV analog
Primary target	BDNF / TrkB / Dopamine	GABA-A / Serotonin / Immune	HGF / c-Met
Main cognitive benefit	Focus, memory, learning	Anxiety reduction, calm clarity	Synaptogenesis, neural repair
Onset	Minutes to hours (acute)	Days to weeks (cumulative)	Weeks (structural changes)
Administration	Intranasal spray	Intranasal spray	Oral / subcutaneous
Human clinical trials	Yes (Russia/Ukraine)	Yes (Russia)	None
Regulatory approval	Approved in Russia	Approved in Russia	None anywhere
FDA status	Not approved	Not approved	Not approved
Risk level	Low (decades of clinical use)	Low (decades of clinical use)	High (experimental, tumor concern)

Semax: The Focus and BDNF Amplifier

Semax is a synthetic heptapeptide with the amino acid sequence Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP). It's built from a fragment of adrenocorticotropic hormone (ACTH) but stripped of ACTH's hormonal activity. Russian researchers developed it in the 1980s specifically as a nootropic and neuroprotective agent.

How Semax Works

Semax's primary mechanism is BDNF amplification. Brain-derived neurotrophic factor is the brain's most important growth protein — it supports neuron survival, promotes synaptic plasticity (the ability of connections between neurons to strengthen or weaken), and drives neurogenesis (the birth of new neurons).

A single intranasal dose of Semax at 50 μg/kg produces measurable neurochemical changes:

• 1.4-fold increase in BDNF protein levels in the hippocampus
• 1.6-fold increase in TrkB tyrosine phosphorylation (TrkB is the receptor BDNF binds to — more phosphorylation means stronger signaling)
• 3-fold increase in exon III BDNF mRNA expression
• 2-fold increase in TrkB mRNA levels

These aren't subtle shifts. A 3-fold increase in BDNF gene expression means the brain is producing dramatically more of its core neuroplasticity protein.

Semax also modulates dopamine signaling, which contributes to its effects on focus, motivation, and executive function. And it activates neuroprotective pathways that reduce damage from oxidative stress and ischemia (blood flow restriction).

Clinical Evidence

Semax is approved in Russia and Ukraine for ischemic stroke, encephalopathy, optic nerve atrophy, and cognitive disorders including dementia. It's listed on the Russian List of Vital & Essential Drugs — not a fringe compound, but an established pharmaceutical in those countries.

A clinical trial in 110 post-stroke patients divided subjects into early rehabilitation (89 ± 9 days post-stroke) and late rehabilitation (214 ± 22 days) groups, each subdivided by Semax treatment. The regimen was 6,000 mcg/day intranasally for two 10-day courses with a 20-day interval between courses.

Results: Semax treatment produced higher BDNF plasma levels that positively correlated with early rehabilitation. Patients receiving Semax showed faster functional recovery and improved motor performance on the British Medical Research Council scale. The Barthel index (a measure of daily functioning independence) improved significantly with Semax, and BDNF levels correlated positively with these functional gains.

A separate study on glaucomatous optic neuropathy found that Semax outperformed traditional neuroprotective treatments using electrophysiological and computer-based assessments.

Dosage and Administration

Semax is administered intranasally — 1-2 drops per nostril, 1-3 times daily. Clinical protocols use short cycles of 5-14 days, with 1-3 month breaks between cycles. The 0.1% solution is standard for cognitive enhancement; the 1% solution is reserved for clinical neurological conditions like stroke.

Safety

Clinical trials spanning decades have reported no significant side effects or hormonal activity. The peptide's safety record in Russian clinical practice is extensive, though Western regulatory bodies have not independently evaluated it.

Selank: The Anxiolytic With Cognitive Upside

Selank takes a completely different approach to cognitive enhancement. Instead of directly boosting focus chemicals, it removes the thing that destroys focus most effectively: anxiety.

Selank is a synthetic analog of tuftsin — a naturally occurring fragment of immunoglobulin G (the most common antibody in the body). Researchers at the Institute of Molecular Genetics in Moscow extended tuftsin's sequence by adding Pro-Gly-Pro to improve metabolic stability. The result is a peptide that crosses into anxiolytic territory while maintaining nootropic and immunomodulatory properties.

How Selank Works

Selank's primary mechanism involves the GABAergic system. GABA (gamma-aminobutyric acid) is the brain's main inhibitory neurotransmitter — it calms neural activity and reduces excitability. Benzodiazepines (Valium, Xanax) work by amplifying GABA signaling. Selank does something similar but without the sedation, dependence, or cognitive impairment that benzodiazepines cause.

Specifically, Selank allosterically modulates GABA-A receptors — it binds to a site on the receptor that's different from (but may partially overlap with) the benzodiazepine binding site. This means it increases GABA's inhibitory effect without fully co-opting the benzodiazepine pathway.

A gene expression study in rat frontal cortex found that Selank altered the expression of 45 out of 84 genes involved in neurotransmission within 1 hour of administration, and 22 genes after 3 hours. These included GABA receptor subunits, transporters, ion channels, dopamine receptors, and serotonin receptors. That's a broad footprint — Selank doesn't just tweak one receptor; it rebalances multiple neurotransmitter systems.

Beyond GABA, Selank normalizes serotonin and dopamine levels, increases BDNF expression (overlapping with Semax's mechanism), and has documented immunomodulatory effects — it can modulate immune function, which may contribute to its effects on stress resilience.

Clinical Evidence

A clinical trial compared Selank to medazepam (a benzodiazepine) in 62 patients with generalized anxiety disorder (GAD) and neurasthenia. Selank (30 patients) and medazepam (32 patients) were assessed using the Hamilton Anxiety Scale, Zung Self-Rating Anxiety Scale, and Clinical Global Impression (CGI) scale.

The anxiolytic effects of both drugs were comparable. But Selank had two additional benefits that medazepam didn't: antiasthenic effects (it reduced fatigue and exhaustion) and psychostimulant effects (it increased mental energy and motivation). A benzodiazepine would typically cause the opposite — sedation and cognitive dulling.

Animal studies showed that combining Selank with diazepam amplified the anxiolytic effect of both compounds, and that Selank could increase diazepam's receptor affinity. This suggests potential for reducing benzodiazepine doses (and their side effects) when used in combination — though this remains preclinical.

Dosage and Administration

Like Semax, Selank is administered intranasally for optimal CNS delivery. It's not orally bioavailable. Preclinical studies used doses around 300 μg/kg. Clinical dosing should be guided by a practitioner familiar with peptide protocols.

Safety

Clinical studies show no drowsiness, dependence, or withdrawal symptoms — the three biggest problems with conventional anxiolytics. Reported side effects are minimal: occasional headaches, mild sinus irritation from nasal administration, and rare nausea. The safety record from Russian clinical use is clean, though Western validation remains limited.

Dihexa: The Synaptogenesis Powerhouse

Dihexa is a different animal entirely. Where Semax and Selank modulate existing neurotransmitter systems, Dihexa aims to physically rewire the brain by growing new synaptic connections.

Developed by Dr. Joseph Harding's lab at Washington State University, Dihexa (code name PNB-0408, chemical name N-hexanoic-Tyr-Ile-(6)aminohexanoic amide) emerged from research on angiotensin IV analogs. The goal was to create an orally active, blood-brain barrier-penetrant compound that could promote cognitive repair at the structural level.

How Dihexa Works

Dihexa's mechanism centers on the hepatocyte growth factor (HGF) / c-Met pathway. HGF is a growth factor that, despite its name, operates far beyond the liver. In the brain, HGF/c-Met signaling drives synaptogenesis — the formation of new synaptic connections between neurons.

Dihexa binds to HGF with extremely high affinity (Kd = 65 picomolar) and potentiates HGF's activation of the c-Met receptor. It doesn't replace HGF — it amplifies the signal of whatever HGF is already present, even at subthreshold concentrations. This activates downstream PI3K/AKT pathways that promote synaptic growth, neuronal survival, and dendritic spine formation.

The potency numbers are staggering. In a neurotrophic activity assay, Dihexa was found to be seven orders of magnitude (10 million times) more potent than BDNF at promoting new synaptic connections. That's not a typo. Dihexa operates at picomolar concentrations where BDNF requires nanomolar to micromolar levels.

Animal Study Results

Dihexa has been tested in scopolamine-induced cognitive deficit models in rats (scopolamine blocks acetylcholine receptors, mimicking Alzheimer's-like memory impairment).

• Intraperitoneal injection at 0.5 mg/kg/day completely reversed the scopolamine-induced deficit (p < 0.001), with treated animals performing indistinguishably from healthy controls
• Oral administration at 2 mg/kg reversed the deficit by day 7, confirming blood-brain barrier penetration and oral bioavailability
• The cognitive effects were dependent on HGF/c-Met activation — blocking this pathway eliminated Dihexa's benefits, proving the mechanism

These results are striking. Complete reversal of an Alzheimer's-model deficit is rare in preclinical pharmacology.

The Critical Safety Concern

Dihexa's greatest strength is also its greatest liability. The HGF/c-Met pathway doesn't just build synapses — it promotes cell growth, migration, and survival broadly. In oncology, the HGF/c-Met pathway is a well-known driver of tumor growth and metastasis. Multiple cancer drugs specifically target this pathway to shut it down.

Dihexa activates the same pathway those drugs are designed to inhibit.

No studies have demonstrated that Dihexa causes cancer. But no long-term safety studies have been conducted, period. The compound has never entered formal human clinical trials. Every claim about Dihexa's cognitive benefits in humans comes from anecdotal self-experimentation, not controlled research.

This is not a theoretical risk that can be waved away. Until long-term safety data exists, the tumor concern is the defining limitation of Dihexa as a nootropic.

Dosage and Administration

Dihexa can be administered orally (a significant advantage over nasal-only peptides) or by subcutaneous injection. Animal studies used 0.5 mg/kg IP or 2 mg/kg oral. No human dosing guidelines exist from clinical trials.

Mechanism Comparison: Three Different Brain Targets

These three peptides operate on fundamentally different levels of brain function:

Semax = Neurochemical optimization. It increases BDNF production and TrkB receptor sensitivity, giving the brain more raw material for plasticity. It also modulates dopamine for acute focus and motivation. Think of it as upgrading the brain's software — improving how efficiently existing neural circuits process information.

Selank = Neurochemical rebalancing. It corrects overactive anxiety circuits through GABA modulation while normalizing serotonin and dopamine. For people whose cognitive problems stem from stress, anxiety, or emotional dysregulation, Selank removes the interference that's degrading performance. Think of it as reducing noise so the signal comes through clearly.

Dihexa = Structural remodeling. It physically builds new synaptic connections through HGF/c-Met activation. This is hardware modification, not software tuning. The changes are potentially long-lasting because they involve actual growth of neural architecture — new dendritic spines, new synapses, new circuits.

Level of Action	Semax	Selank	Dihexa
Neurotransmitter modulation	Strong (BDNF, dopamine)	Strong (GABA, serotonin)	Minimal
Neuroprotection	Strong	Moderate	Unclear
Neuroplasticity support	Moderate (via BDNF)	Mild (via BDNF)	Extreme (via HGF/c-Met)
Structural brain changes	Indirect	Indirect	Direct (synaptogenesis)
Immunomodulation	Minimal	Significant	None documented

Evidence Quality and Human Data

The evidence pyramid matters here. Not all research is created equal.

Semax: Strongest Evidence Base

• Approved pharmaceutical in Russia and Ukraine since the 1990s
• Listed on Russia's Vital & Essential Drugs list
• Multiple human clinical trials (stroke, optic neuropathy, cognitive disorders)
• Clinical trial with 110 post-stroke patients showing BDNF correlation with recovery
• Decades of post-market safety surveillance in Russian clinical practice
• Robust preclinical mechanistic studies in Western journals

Selank: Strong Evidence Base

• Approved pharmaceutical in Russia
• Clinical trial comparing efficacy to medazepam in 62 GAD/neurasthenia patients
• Documented gene expression changes across 84 neurotransmission-related genes
• Preclinical synergy studies with diazepam
• Clean safety record from clinical use

Dihexa: Preclinical Only

• Zero human clinical trials (published or registered)
• All efficacy data from rat models
• Single primary research group (Washington State University)
• No independent replication by other labs
• No safety data beyond acute animal toxicology
• Potency claims based on in vitro assays, not human outcomes

This hierarchy is not about which peptide "sounds best." Semax and Selank have passed through the filter of human clinical testing. Dihexa has not. That distinction carries real weight when evaluating risk.

Safety Profiles and Risk Assessment

Semax: Low Risk

• No side effects or hormonal activity reported across clinical trials spanning decades
• No dependence, tolerance, or withdrawal documented
• No significant drug interactions identified
• The main limitation is lack of FDA evaluation, not evidence of harm

Selank: Low Risk

• No sedation, dependence, or withdrawal — the signature risks of anxiolytic drugs
• Minimal reported side effects (headache, nasal irritation, rare nausea)
• Clean safety record in clinical settings
• Immunomodulatory activity is generally considered beneficial, though could theoretically interact with immune-modulating medications

Dihexa: High Risk (Uncertain)

• No human safety data from clinical trials
• HGF/c-Met pathway activation raises legitimate oncogenic concerns
• Long-term effects completely unknown
• No regulatory review of safety in any country
• Combining with other growth factor modulators could amplify risks
• Self-experimentation carries unmeasured, unmitigated risk

Practical Considerations

Availability

Semax and Selank are available as pharmaceutical products in Russia and can be sourced from various international suppliers. Quality varies significantly between suppliers. Dihexa is available only as a research chemical — it has never been manufactured to pharmaceutical standards for human use.

Stacking

Semax and Selank are commonly used together because their mechanisms are complementary (BDNF/dopamine + GABA/serotonin). This combination addresses both the "drive" and "calm" sides of cognitive performance.

Stacking either with Dihexa is significantly riskier due to the lack of interaction data and Dihexa's growth factor mechanism. No studies have examined combined effects.

Duration of Effects

• Semax: Acute cognitive effects within a session; BDNF elevation persists for hours after dosing. Cumulative benefits build over a treatment course.
• Selank: Anxiolytic effects build gradually over days to weeks. Best results come from consistent use over a full treatment course rather than single doses.
• Dihexa: If the synaptogenesis mechanism works as theorized, effects would be long-lasting because they involve physical structural changes. But this also means any adverse effects could be long-lasting.

Ranking: Which Peptide for Which Goal?

Best for Acute Focus and Learning: Semax

If you need sharper concentration, better information retention, and improved working memory — and you need it relatively quickly — Semax is the strongest choice. Its BDNF and dopamine effects produce noticeable cognitive enhancement within a treatment course, backed by clinical evidence in neurological patients.

Best for Anxiety-Related Cognitive Problems: Selank

If brain fog, poor focus, or memory lapses are rooted in chronic stress, anxiety, or emotional overstimulation, Selank addresses the root cause. It removes the GABA/serotonin imbalance that degrades cognitive performance without the sedation or dependence of conventional anxiolytics.

Best for Long-Term Structural Brain Repair: Dihexa (with major caveats)

If the goal is reversing age-related cognitive decline or neurodegenerative damage at the structural level, Dihexa's synaptogenesis mechanism is the most ambitious option. It targets the physical architecture of neural connections rather than neurotransmitter levels. But the absence of human clinical data and the oncogenic risk profile make it suitable only for those who fully understand and accept the unknowns.

Overall Ranking by Risk-Adjusted Value

1. Semax — Best combination of proven efficacy, clinical evidence, and safety
2. Selank — Excellent for anxiety-driven cognitive issues, strong safety profile, slightly narrower application than Semax for pure cognitive enhancement
3. Dihexa — Highest theoretical potency, but risk profile and evidence gaps place it firmly in experimental territory

For a broader overview of cognitive peptides, see our guide to the best peptides for cognitive enhancement.

The Bottom Line

Semax, Selank, and Dihexa represent three distinct approaches to cognitive enhancement through peptide therapy. Semax optimizes neurochemistry through BDNF amplification, delivering acute focus and learning benefits backed by clinical trials and decades of medical use. Selank rebalances anxiety-driven cognitive impairment through GABA modulation, matching benzodiazepine efficacy without their side effects. Dihexa rewires neural architecture through HGF/c-Met synaptogenesis with extraordinary potency — but carries proportionally extraordinary uncertainty.

The right choice depends on the cognitive problem, risk tolerance, and how much you value proven safety versus theoretical potency. For most people, Semax and Selank — individually or combined — offer the strongest evidence-backed path to better cognitive function. Dihexa remains a fascinating research compound that may one day prove transformative for neurodegeneration. That day has not arrived.

None of these peptides are FDA-approved for cognitive enhancement. All use carries regulatory, legal, and medical considerations that should be discussed with a qualified healthcare provider before starting any protocol.

References

1. Dolotov OV, et al. "Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus." Brain Research. 2006. https://pubmed.ncbi.nlm.nih.gov/16996037/

2. Filippenkov IB, et al. "Semax and Pro-Gly-Pro Activate the Transcription of Neurotrophins and Their Receptor Genes after Cerebral Ischemia." PMC. 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC11498467/

3. Zatolokin PA, et al. "The efficacy of semax in the treatment of patients at different stages of ischemic stroke." Zhurnal Nevrologii i Psikhiatrii. 2018. https://pubmed.ncbi.nlm.nih.gov/29798983/

4. Semenova TP, et al. "Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission." Frontiers in Pharmacology. 2016. https://pmc.ncbi.nlm.nih.gov/articles/PMC4757669/

5. Semenova TP, et al. "GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells." Frontiers in Pharmacology. 2017. https://pmc.ncbi.nlm.nih.gov/articles/PMC5328971/

6. Zozulya AA, et al. "Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia." Zhurnal Nevrologii i Psikhiatrii. 2008. https://pubmed.ncbi.nlm.nih.gov/18454096/

7. Benoist CC, et al. "The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system." Journal of Pharmacology and Experimental Therapeutics. 2014. https://pubmed.ncbi.nlm.nih.gov/25187433/

8. Kozlovskii II, Bhatt R. "Peptide Selank Enhances the Effect of Diazepam in Reducing Anxiety in Unpredictable Chronic Mild Stress Conditions in Rats." Bulletin of Experimental Biology and Medicine. 2017. https://pmc.ncbi.nlm.nih.gov/articles/PMC5322660/