Selank

What Selank is

Selank is a lab-made peptide that Russian doctors can prescribe as a nasal spray for anxiety. The human evidence is a handful of translated Russian trials. Most other studies used rats, mice or cells in a dish. The FDA has not approved it. Neither has the EMA in Europe or the MHRA in the UK [3,4].

A peptide is a short chain of amino acids, the building blocks of protein. Selank has seven of them: Thr-Lys-Pro-Arg-Pro-Gly-Pro, or TKPRPGP for short. The first four are a copy of tuftsin, a natural peptide that acts on the immune system. Najjar and Nishioka first found tuftsin in 1970. They pulled it from the Fc fragment, one part of a human antibody called immunoglobulin G, or IgG [1].

Selank comes from Moscow, from the V.V. Zakusov Research Institute of Pharmacology. The team there added three amino acids, Pro-Gly-Pro, to the tail of tuftsin. Enzymes that chew up peptides have a much harder time with that tail in place. The related peptide Semax was made stable the same way [2].

The Russian spray is a 0.15% solution. It is approved there for two things. One is generalized anxiety disorder, or GAD, which is worry that does not let up. The other is asthenic disorders, also called neurasthenic disorders, which are states of lasting weakness and tiredness.

Papers describe Selank as an anxiolytic, a drug that eases anxiety. Benzodiazepines are a common family of anxiety drugs. They can cause sleepiness, loose muscles and physical dependence. Selank did not seem to cause any of the three in the work done to date [3].

Scientists have reported several ways it may work [5,6,7,8]:

• changes in GABA signaling
• blocking the enzymes that break down enkephalins
• changes in the immune system and its cytokines
• wide changes in which genes are active in the hippocampus and the spleen

How much research there is

There are a few small trials in Russian patients, and a much larger set of animal and cell studies.

Area	Kind of evidence	Main papers	Comments
Generalized anxiety disorder in patients	Approved by Russian regulators. Small trials against another drug	Zozulia 2008 [4]; Medvedev 2014 [3]	No approval from the FDA, EMA or MHRA. Few Western groups have repeated the work
GABA signaling	Cells in a dish and rodents	Vasil’eva 2016 [10]; Filatova 2017 [11]; Vyunova 2018 [9]	Reported to boost the GABA-A receptor from a side site
Blocking enzymes that break down enkephalins	Lab chemistry tests	Zolotarev 2004 [14]; Kost 2001 [13]	A role for opioids is backed by a test where naloxone undid the effect [15]
Cytokines and the immune system	Lab and animal studies, plus a little human data	Kolomin 2011 to 2014 [6,18,19]; Uchakina 2008 [7]	Traced to the tuftsin part. What it means for patients is unclear

How it might work

No one pathway explains all of the anxiety and nootropic effects reported for Selank. A nootropic is a compound meant to support thinking and memory. Animal and cell studies point to four systems that act together:

• GABA, a calming brain chemical
• the body’s own opioids
• immune signals
• gene activity in the hippocampus, a brain region

Built on tuftsin

The front end of Selank, Thr-Lys-Pro-Arg, is tuftsin itself. In the body, tuftsin is cut out of the IgG heavy chain, at its CH2 domain. It spurs phagocytosis, which is when immune cells swallow germs and debris [1].

Tuftsin attaches to three kinds of white blood cell: neutrophils, monocytes and macrophages. It also helps the immune system show antigens to other cells. But blood plasma breaks it down fast.

The Pro-Gly-Pro tail on Selank fixes that. It stops two kinds of enzymes, aminopeptidases and carboxypeptidases, from cutting the chain. The peptide then lasts long enough that a dose through the nose has effects in the brain that can be measured [2,5].

Semax uses the same design. It is a stabilized piece of the hormone ACTH, written ACTH(4-10). The same research group made both peptides.

GABA

At the GABA-A receptor complex, Selank behaves like a positive allosteric modulator. That means it attaches at a side site and makes the receptor respond more strongly to GABA.

• Binding in cortex membranes. Vyunova and colleagues worked with membranes taken from the cortex. With Selank added, more [3H]GABA, a radioactive tagged form of GABA, bound to them [9].
• More binding sites. Vasil’eva and colleagues injected Selank into the belly cavity of rats. The density of GABA receptor binding sites in the frontal cortex rose by about 38%. A dose through the nose gave the same kind of effect [10].
• Gene activity. Filatova and colleagues tested IMR-32 neuroblastoma cells. Selank changed how active the genes for GABA signaling were. The changes overlapped with what GABA itself does, and partly with what the drug olanzapine does [11].
• Quieter neurons. Povarov and colleagues saw less spontaneous synaptic activity in CA1 neurons of the rat hippocampus after Selank [12]. That fits a net calming effect.

Enkephalins and opioids

Enkephalins are opioid peptides that the body makes. Human serum, the liquid part of blood, has enzymes that break them down. Selank blocks those enzymes [13,14]. So the body’s Leu-enkephalin and Met-enkephalin last longer.

Scientists propose this as the way the opioid system adds to the anti-anxiety and antidepressant-like effects seen in animals. Two papers support the idea:

• Meshavkin and colleagues ran behavior tests and reported that Selank had a “depriming” effect. Naloxone, a drug that blocks opioids, stopped it. They took that as a sign that opioids carry part of the action [15].
• Kozlovskii and colleagues also found that the opioid system shapes the anti-anxiety profile of Selank [16].

Immune signals

Selank comes from tuftsin, so it is no surprise that it shifts cytokines. Cytokines are the signaling proteins of the immune system.

• Uchakina and colleagues looked at peripheral blood mononuclear cells, a group of white blood cells. The cells came from patients who had anxiety-asthenic disorders. The balance of Th1 and Th2 cytokines changed, and the cells made more IL-6 [7].
• Ershov and colleagues found that it acted against the influenza A virus (H3N2) in lab models of infection [17].
• Kolomin and colleagues recorded wide changes over time in the spleen and hippocampus. The genes involved are tied to inflammation, chemokines and cytokines [6,18,19]. Some had changed within one hour of a dose.

This path from an immune peptide to the central nervous system is one of the newer ideas about Selank. It sets the compound apart from standard anxiety drugs.

What the studies found

The human research is a set of small Russian trials for anxiety disorders. The animal and cell research is much bigger. It covers anxiety, thinking, cytokines and gene activity.

Anxiety trials in Russia

Medvedev and colleagues ran a trial in 60 patients. They had phobic-anxiety and somatoform disorders. One group got Selank through the nose. The other got phenazepam, a benzodiazepine [3]. The paper reported that Selank:

• gave “pronounced anxiolytic and mild nootropic effects”
• kept symptoms down for a week once treatment had ended
• did not bring the sleepiness and dependence risk of phenazepam

Zozulia and colleagues wrote a separate clinical analysis. It covered how well Selank worked in anxiety and neurasthenia, and how it might act [4].

Russia’s approval of the nasal spray for generalized anxiety disorder and neurasthenic conditions rests on these trials. The MHRA, FDA and EMA have not done the same. Western reviewers say the evidence is limited until larger randomized, placebo-controlled trials are done.

Anxiety and depression in animals

• Low oxygen before birth. A run of studies by Semenova and colleagues used rats that got too little oxygen in the womb. Selank brought back their thinking ability. It also returned their biogenic amines, a family of brain chemicals, to normal levels [20,21,22].
• Depression models. Sarkisova and colleagues tested BALB/c mice and WAG/Rij rats, a strain bred as a genetic model of depression. Selank had antidepressant-like effects in both [23].
• With diazepam. Kasian and colleagues used a model built on unpredictable chronic mild stress. Selank made the anti-anxiety effect of diazepam stronger [24].
• Alcohol and memory. Kolik and colleagues showed that Selank protected against memory loss caused by ethanol, the alcohol in drinks. Part of the effect came from a rise in BDNF in the hippocampus and prefrontal cortex [25]. BDNF is a protein that supports nerve cells.
• Alcohol withdrawal. In a separate paper, the Kolik group reported that it worked when alcohol withdrawal was modeled [26].
• Morphine withdrawal. Konstantinopolsky and colleagues reported milder signs of morphine withdrawal in rats [27].

Cytokines and immune effects

• Uchakina and colleagues recorded what happened in anxiety-asthenic patients treated with Selank. IL-6 shifted, and so did the balance of Th1 and Th2 cytokines [7].
• Kolomin and colleagues ran transcriptomic studies, which read out the genes that are switched on. One hour after a dose, 45+ genes in the hippocampus and spleen had changed by a significant amount. The pattern kept shifting at later time points [6,18,19,28].
• Ershov and colleagues carried the immune findings into antiviral work and reported that it acted against influenza A [17].

Thinking and brain chemistry

• Mouse strains. Narkevich and colleagues measured monoamines, a class of brain chemicals, in two mouse strains, C57Bl/6 and BALB/c. Serotonin, 5-HIAA and dopamine breakdown products changed in different ways in each strain. That fits the idea that the anti-anxiety response depends on how stressed an animal is to begin with [29].
• Early brain damage. Earlier work by Semenova tested rats whose catecholamine system was damaged soon after birth. Selank restored their learning and memory [22].
• Brain networks in humans. Panikratova and colleagues compared Selank and Semax in humans with functional connectomic analysis, a way to map which brain areas work together. Each peptide left its own connection pattern. That matches the view that the two differ in their main mechanism [30].

Safety

• Animal and cell studies have not reported the sleepiness, tolerance or dependence that benzodiazepines cause, in the models that were tested.
• Long-term safety in humans is not well described for ongoing dosing anywhere but in Russian clinics.
• How much of a nasal dose gets absorbed and reaches the brain varies with the formula and the technique. That makes doses hard to compare from one study to the next.
• Handling, mixing, storage and the source of the material can change how an experiment turns out. That is true of every research peptide.

Legal status in the US

• Not FDA approved. Selank has no approval from the FDA. The same is true of the EMA in Europe and the MHRA in the UK.
• Approved in Russia. It is a prescription medicine there for neurasthenic disorders and generalized anxiety disorder.
• Research use. Selank sold for lab research is not for use in humans. This guide is for education. It is not a clinical protocol and it makes no medical claim.

Limits of the research

1. An odd regulatory position. One country treats Selank as an approved medicine. The main Western regulators do not.
2. Few research groups. Most of the published clinical work comes from just a few Russian teams.
3. No large independent trials. Nobody has published a large, independent, randomized, placebo-controlled trial. There are few Western systematic reviews.
4. Uneven evidence. Claims that Selank works should be read with this imbalance in mind.

Selank is a licensed anxiety medicine in Russia. The proof behind it is a few small trials and a lot of animal work.

References

Selected peer-reviewed references. Not exhaustive.

1. Najjar VA, Nishioka K. “Tuftsin”: a natural phagocytosis stimulating peptide. Nature. 1970;228(5272):672–3. PMID: 4097539.
2. Ashmarin IP, Nezavibatko VN, Levitskaya NG, et al. Design and synthesis of stable proline-containing peptide analogues: the Semax and Selank series. Neurosci Behav Physiol. 1997–1998 (research program reviewed in later citations).
3. Medvedev VE, Tereshchenko ON, Israelian AIu, Chobanu IK, Kost NV, Sokolov OIu, Miasoedov NF. A comparison of the anxiolytic effect and tolerability of selank and phenazepam in the treatment of anxiety disorders. Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(7):17–22. PMID: 25176261.
4. Zozulia AA, Neznamov GG, Siuniakov TS, et al. Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(4):38–48. PMID: 18454096.
5. Sokolov OY, Meshavkin VK, Kost NV, Zozulya AA. Effects of Selank on behavioral reactions and enzyme activities in mice. Bull Exp Biol Med. 2002. PMID: 12432865.
6. Kolomin T, Shadrina M, Agniullin Y, et al. Transcriptomic response of rat hippocampus and spleen cells to single and chronic administration of the peptide selank. Dokl Biochem Biophys. 2010. PMID: 20380151.
7. Uchakina ON, Uchakin PN, Miasoedov NF, et al. Immunomodulatory effects of selank in patients with anxiety-asthenic disorders. Zh Nevrol Psikhiatr Im S S Korsakova. 2008. PMID: 18577961.
8. Kolomin TA, Shadrina MI, Agapova TY, et al. Expression of inflammation-related genes in mouse spleen under tuftsin analog Selank. Regul Pept. 2011. PMID: 21609736.
9. Vyunova TV, Andreeva L, Shevchenko K, Myasoedov N. Peptide-based anxiolytics: the molecular aspects of heptapeptide Selank biological activity. Protein Pept Lett. 2018. PMID: 30255741.
10. Vasil’eva EV, Kondrakhin EA, Salimov RM, Kovalev GI. Comparison of pharmacological effects of heptapeptide Selank after intranasal and intraperitoneal administration. Eksp Klin Farmakol. 2016. PMID: 29787664.
11. Filatova E, Kasian A, Kolomin T, et al. GABA, Selank, and Olanzapine affect the expression of genes involved in GABAergic neurotransmission in IMR-32 cells. Front Pharmacol. 2017;8:89. PMID: 28293190.
12. Povarov IS, Kondratenko RV, Derevyagin VI, et al. Effect of Selank on spontaneous synaptic activity of rat hippocampal CA1 neurons. Bull Exp Biol Med. 2017. PMID: 28361410.
13. Kost NV, Sokolov OY, Gabaeva MV, et al. Semax and selank inhibit enkephalin-degrading enzymes from human serum. Bioorg Khim. 2001;27(3):180–3. PMID: 11443939.
14. Zolotarev IuA, Dadayan AK, Dolotov OV, et al. Leu-enkephalin study examining Selank’s inhibiting effect on plasma enzymes. Bioorg Khim. 2004. PMID: 15344652.
15. Meshavkin VK, Kost NV, Sokolov OY, Zozulya AA. Naloxone-blocked depriming effect of the anxiolytic selank. Bull Exp Biol Med. 2006. PMID: 17415472.
16. Kozlovskii II, Danchev ND. Role of the opioid system in peculiarities of the anti-anxiety effect of the peptide anxiolytic selank. Eksp Klin Farmakol. 2012. PMID: 22550852.
17. Ershov FI, Uchakin PN, Uchakina ON, et al. Antiviral activity of immunomodulator Selank in experimental influenza infection. Vopr Virusol. 2009. PMID: 19882898.
18. Kolomin TA, Agapova TY, Agniullin YV, et al. Changes in chemokine, cytokine and receptor gene expression following Selank administration. Regul Pept. 2011. PMID: 21786679.
19. Kolomin TA, Shadrina MI, Slominsky PA, et al. The temporary dynamics of inflammation-related genes expression under tuftsin analog Selank action. Mol Immunol. 2014. PMID: 24291245.
20. Semenova TP, Kozlovskaya MM, Zuikov AV, Kozlovskii II, Zakharova NM, Andreeva LA. Use of Selank to correct measures of integrative brain activity and biogenic amine levels in adult rats resulting from antenatal hypoxia. Neurosci Behav Physiol. 2008;38(2):201–5. PMID: 18197389.
21. Semenova TP, Kozlovskaia MM, Zuĭkov AV, et al. Selank-induced normalizing effects on the integrative brain activity and biogenic amine level disorders due to antenatal hypoxia. Ross Fiziol Zh Im I M Sechenova. 2006. PMID: 17385425.
22. Semenova TP, Kozlovskaya MM, Zakharova NM, Kozlovskii II, Zuikov AV. Effect of Selank on cognitive processes after damage inflicted to the cerebral catecholamine system during early ontogeny. Bull Exp Biol Med. 2007. PMID: 18683497.
23. Sarkisova KIu, Kozlovskiĭ II, Kozlovskaia MM. Effects of heptapeptide Selank on genetically-based and situation-provoked symptoms of depression in WAG/Rij and Wistar rats, and in BALB/c mice. Zh Vyssh Nerv Deiat Im I P Pavlova. 2008;58(2):226–37. PMID: 18661785.
24. Kasian A, Kolomin T, Andreeva L, et al. Peptide Selank enhances the effect of diazepam in reducing anxiety in unpredictable chronic mild stress conditions in rats. Behav Neurol. 2017;2017:5091027. PMID: 28280289.
25. Kolik LG, Nadorova AV, Antipova TA, Kruglov SV, Kudrin VS, Durnev AD. Selank, peptide analogue of tuftsin, protects against ethanol-induced memory impairment by regulating of BDNF content in the hippocampus and prefrontal cortex in rats. Bull Exp Biol Med. 2019. PMID: 31625062.
26. Kolik LG, Konstantinopolsky MA, Nadorova AV, Kudrin VS. Efficacy of peptide anxiolytic selank during modeling of withdrawal syndrome in rats with stable alcoholic motivation. Bull Exp Biol Med. 2014. PMID: 24913576.
27. Konstantinopolsky MA, Nadorova AV, Kolik LG. Selank, a peptide analog of tuftsin, attenuates aversive signs of morphine withdrawal in rats. Bull Exp Biol Med. 2022. PMID: 36322304.
28. Kolomin TA, Shadrina MI, Slominsky PA, et al. Transcriptome alteration in hippocampus under the treatment of tuftsin analog Selank. J Mol Neurosci. 2013. PMID: 24450168.
29. Narkevich VB, Kudrin VS, Klodt PM, et al. Effects of heptapeptide Selank on monoamine levels in mouse brain regions: comparison of BALB/C and C57Bl/6 strains. Eksp Klin Farmakol. 2008;71(5):8–12. PMID: 19093364.
30. Panikratova YR, Vlasova RM, Akhutina TV, et al. Functional connectomic approach to studying Selank and Semax effects. Dokl Biol Sci. 2020. PMID: 32342318.