Selank

A note on the evidence. Selank's clinical studies are published in Russian journals. Being in Russian is not a reason to leave a paper out; where a full text can be obtained it is read in the original, and a paper is omitted only when neither an abstract nor a full text can be reached. Russian-language references are marked in the reference list.

Three clinical studies compare Selank with benzodiazepines:

• Generalized anxiety and neurasthenia (62 patients). Selank and medazepam had similar anxiolytic effects. Selank also had anti-fatigue and mildly stimulating effects [2].
• Phobic, anxiety and somatoform disorders (60 patients). In a study comparing it with phenazepam, Selank showed a pronounced anxiolytic and mild nootropic effect that lasted a week after the last dose [6].
• Added to phenazepam. Adding Selank made phenazepam work sooner. It also reduced phenazepam's side effects, including memory problems, sedation, fatigue and sexual problems, both during treatment and after withdrawal [3].

In 52 healthy volunteers, a single dose changed resting-state connectivity between the right amygdala and temporal cortex on fMRI compared with placebo [7].

Animal evidence. The rodent work is small and its results are more mixed than the clinical summaries suggest. In the elevated plus maze, groups of six rats were dosed for 14 days: intranasal Selank at 300 µg/kg a day, oral diazepam at 1 mg/kg, both, or saline. Even without any stressor, the two-week handling and dosing routine made anxiety measures worse in every arm - open-arm time fell 4.5-fold on saline and 5.7-fold on diazepam - and Selank alone was the only arm in which none of those changes reached significance and locomotor activity was unchanged. Under unpredictable chronic mild stress the saline group deteriorated furthest, with open-arm time down 13.6-fold, and only the Selank-plus-diazepam group finished no different from its own pre-stress baseline, spending 8.9 times longer in the open arms than saline controls [8].

In naloxone-precipitated morphine withdrawal, a single intraperitoneal dose of 0.3 mg/kg cut the total withdrawal index by 39.6% and raised the tactile sensitivity threshold ninefold, somewhat less than diazepam at 2 mg/kg, which managed 49.3% and thirteenfold [1].

Enkephalin-degrading enzymes. People with generalized anxiety disorder - but not panic disorder or agoraphobia - had a markedly shortened plasma enkephalin half-life and reduced total enkephalinase activity, which the investigators put down to low levels of the body's own enkephalinase inhibitors. Selank inhibited enkephalin hydrolysis in plasma dose-dependently, with an IC50 of 15 µM, and was more potent than bacitracin or puromycin [4]. A companion study measuring the same enzymes in human serum put Selank's IC50 at 20 µM and Semax's at 10 µM, and found the pentapeptide fragments of both active while their tri-, tetra- and hexapeptide fragments were not [9]. In patients, enkephalin half-life lengthened during treatment [2].

GABA-A receptors. In radioligand binding on brain-cell membranes, Selank behaved as a positive allosteric modulator of tritiated GABA binding, concentration-dependently and with some subtype selectivity. Its combination with a benzodiazepine was not additive: Selank blocked the modulatory activity of both diazepam and olanzapine, which suggests binding sites that are distinct but may partly overlap [5]. In human IMR-32 neuroblastoma cells, which carry working GABA-A receptors, 1 nmol per well for an hour changed none of 84 GABA-system and neurotransmission genes on its own. Added to GABA it all but abolished the expression changes GABA produced by itself, and added to olanzapine it increased the number of genes affected. The authors read that as the peptide acting on GABA's interaction with the receptor rather than on the transcription of the system [10].

Route and strain change the result. At 300 µg/kg a day for 5 days in mice, anxiolytic and nootropic effects appeared only in BALB/c animals, which start out more anxious and less exploratory, and not in C57BL/6. The receptor changes split by route as well: intraperitoneal dosing raised the number of GABA receptor binding sites in the frontal cortex by 38% without touching hippocampal NMDA receptors, while intranasal dosing raised NMDA binding site density by 23% without touching GABA receptors [11]. Whatever the peptide does, it is not one fixed action independent of how it is given.

Immune effects. At 100 nM in vitro, Selank completely suppressed IL-6 gene expression in peripheral blood cells from patients with depression but not in cells from healthy controls, while IL-6 protein in the same cultures rose. Over 14 days of treatment in generalized anxiety disorder and neurasthenia, the serum Th1/Th2 cytokine balance shifted, with the two moving in opposite directions [12].

Studies describe Selank as well tolerated and free of the side effects typical of most anxiolytics [4], and it reduced phenazepam's side effects when added to it [3]. Those statements come from small, short studies without detailed adverse-event reporting in the indexed abstracts.