Semax

What Semax is

Semax is a synthetic peptide of seven amino acids: Met-Glu-His-Phe-Pro-Gly-Pro. The first four residues are the 4–7 fragment of adrenocorticotropic hormone (ACTH), which is the shortest segment of that hormone reported to retain its effects on attention and learning in animal studies while lacking any effect on the adrenal gland. The C-terminal Pro-Gly-Pro was added to protect the fragment from aminopeptidases and carboxypeptidases and to extend its action [1].

The peptide was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences in the 1980s and 1990s, and most of its literature comes from Russian groups. It is one of two heptapeptides of this kind in the catalogue; the other, Selank, was built on the same Pro-Gly-Pro principle from a different parent peptide. The research material is a white lyophilised powder.

How the literature describes its mechanism

Semax has no single identified receptor, and the published mechanism is a set of observed effects in the brain rather than a defined pharmacology. The most consistent finding is on neurotrophins. Dolotov and colleagues reported that Semax increased the expression of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the rat hippocampus, and the authors proposed that this effect underlies the cognitive effects reported in behavioural studies [2]. Related work from the same institute reported changes in nerve growth factor and BDNF expression in the frontal cortex and retina.

Gene-expression studies have widened the picture. Medvedeva and colleagues, using transcriptome analysis in a rat model of focal cerebral ischaemia, reported that Semax altered the expression of large sets of genes involved in the immune and inflammatory response, vascular function and neurotransmission in the hours after the insult, and proposed that its effects on the ischaemic brain are mediated through those pathways rather than through a single target [3]. The melanocortin receptors, through which ACTH acts, have been examined; the ACTH(4–10) fragment binds some of them weakly, but Semax's effects do not map cleanly onto any melanocortin receptor subtype, and the question of its primary binding partner is open.

For an in-vitro programme the relevant readouts are BDNF and TrkB expression in neuronal cultures or hippocampal slices, neuronal survival under oxidative or excitotoxic stress, and transcriptomic responses. The literature also reports interactions with enkephalin-degrading enzymes, which a laboratory interested in opioid-peptide metabolism may find worth following.

The research record

The record divides into an extensive animal literature and a clinical literature that is almost entirely Russian.

In animals, Semax has been reported to improve learning and memory in rats in a range of tasks, to protect neurons in models of cerebral ischaemia and optic-nerve injury, and to reduce the behavioural consequences of stress. The neurotrophin and transcriptome papers cited above are the mechanistic core of that work [2, 3].

In humans, an early study by Kaplan and colleagues reported effects of intranasal Semax on attention and memory in healthy volunteers in a small placebo-controlled design [4]. Semax has been registered as a medicine in Russia since the 1990s, as a nasal solution for conditions including ischaemic stroke and cognitive impairment, and the clinical trials supporting that registration were published in Russian-language journals. Those studies have not been replicated outside Russia, have not been subject to review by the MHRA, the EMA or the FDA, and would not by themselves meet the standards those regulators apply. A reader should treat the compound as having a substantial preclinical record and an unreviewed clinical one.

Regulatory status in the United Kingdom

Semax has no marketing authorisation in the UK or any other country outside Russia and some neighbouring states, and is not a medicine here. It is not controlled under the Misuse of Drugs Act. Whether a peptide of this kind falls within the Psychoactive Substances Act 2016 has not been tested; the material is in any case supplied as a chemical for in-vitro laboratory use under the Terms of Sale, not for human or veterinary administration. Purchasers must be 18 or over and are responsible for compliance with the laws and institutional rules that apply to them. Our guide to the UK rules on research compounds sets this out in more detail.

Semax is not on the WADA Prohibited List by name.

Handling, storage and stability

Semax is supplied lyophilised, sealed under nitrogen in a glass vial with a rubber stopper and an aluminium crimp.

Sealed vial. Store at 2–8 °C for routine use and at −20 °C for longer storage. Protect from light. Allow the vial to reach room temperature before opening.

Reconstitution. Semax dissolves readily in water, bacteriostatic water and buffers. Add the solvent down the side of the vial and swirl; dissolution is immediate. The reconstitution calculator gives the volume for a target concentration.

Reconstituted solution. The N-terminal methionine is the weak point. Methionine oxidises to the sulfoxide in solution, especially under light and in the presence of dissolved oxygen, and the oxidised peptide is a different molecule with different activity in the published assays. Keep solutions at 2–8 °C, protected from light, in filled tubes with minimal headspace, and use within two to three weeks; aliquot and freeze at −20 °C for longer storage. Histidine makes the peptide's charge sensitive to pH around 6 to 7.

Surfaces. A small, moderately hydrophobic peptide with an aromatic residue adsorbs modestly to plastics at nanomolar concentrations. The storage and stability guide covers methionine-containing peptides specifically.

What a sound certificate for Semax looks like

Every batch we release carries an independent certificate of analysis, transcribed on the product page and in the certificate register.

Purity by RP-HPLC. Reversed-phase HPLC on a C18 column with UV detection at 214 or 220 nm, reporting the main peak as a percentage of all integrated peaks. The phenylalanine gives weak absorbance at 257 nm but 280 nm is uninformative. A good batch shows a single dominant peak at 98% or above. The impurity to look for is the methionine sulfoxide, which elutes earlier than the parent and is 16 Da heavier; a certificate for a well-handled batch shows it at well under 1%.

Identity by LC-MS. The average molecular weight is 813.9 Da and the monoisotopic mass is 813.4 Da. The peptide appears as [M+H]⁺ at m/z 814.4 or [M+2H]²⁺ at m/z 407.7; the certificate should say which it reports. The sulfoxide appears at +16.

Net peptide content. A peptide with a free amine and a histidine carries trifluoroacetate counter-ions; net peptide content should be reported where available.

Endotoxin. Where tested, a LAL result in endotoxin units per milligram.

Our guide to reading a certificate of analysis goes through a complete report line by line.

Related compounds

Selank is the sister compound, a tuftsin analogue with the same C-terminal Pro-Gly-Pro extension and an overlapping Russian literature, studied for anxiolytic rather than cognitive effects. Epithalon is another short synthetic peptide from the same research tradition. KPV is, like Semax, a fragment of a melanocortin hormone, in that case the C-terminal tripeptide of α-MSH.

Frequently asked questions

What does ACTH(4–7) mean? Residues 4 to 7 of adrenocorticotropic hormone: Met-Glu-His-Phe. This fragment has no effect on the adrenal gland but was found in animal studies to retain ACTH's effects on attention and learning.

Why is Pro-Gly-Pro added? To protect the fragment from the enzymes that would otherwise degrade it in seconds, and to prolong its action.

Is Semax a licensed medicine? In Russia, yes, as a nasal solution. In the UK, no, and the research material supplied here is not a medicine.

Why does the solution degrade? The N-terminal methionine oxidises. Keep solutions cold, dark and with little air above them.

References

1. Ashmarin IP, Nezavibatko VN, Myasoedov NF, et al. A nootropic adrenocorticotropin analog 4-10-semax (15 years experience in its design and study). Zhurnal Vysshei Nervnoi Deiatelnosti imeni I P Pavlova. 1997;47(2):420–430. PMID 9173745.
2. 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.
3. Medvedeva EV, Dmitrieva VG, Limborska SA, et al. Semax, an analog of ACTH(4–7), regulates expression of immune response genes during ischemic brain injury in rats. Molecular Genetics and Genomics. 2017;292(3):635–653. doi:10.1007/s00438-017-1297-1.
4. Kaplan AY, Kochetova AG, Nezavibathko VN, Rjasina TV, Ashmarin IP. Synthetic ACTH analogue Semax displays nootropic-like activity in humans. Neuroscience Research Communications. 1996;19(2):115–123. doi:10.1002/(SICI)1520-6769(199609)19:2<115::AID-NRC171>3.0.CO;2-B.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.