Neurology, Neuropsychiatry, Psychosomatics

Advanced search

Systematic analysis of basic and clinical studies of etifoxine

Full Text:


The paper presents a systematic analysis of experimental and clinical studies of etifoxine. The anxiolytic effect of etifoxine is due, firstly, to the modulation of GABA receptor activity and, secondly, to that of metabolism of neurosteroids that are themselves characterized by anxiolytic and neuroprotective properties. The results of clinical trials of etifoxine are also analyzed. In addition to its anxiolytic effect that partially persists even after treatment discontinuation, etifoxine is ascertained to be characterized by analgesic, neurotrophic and neuroprotective properties.

About the Authors

I. Yu. Torshin
Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia 9, Institutsky Lane, Dolgoprudnyi, Moscow Region 141700
Russian Federation

O. A. Gromova
Ivanovo State Medical Academy, Ministry of Health of Russia, Ivanovo, Russia 8, Sheremetevsky Passage, Ivanovo 153000
Russian Federation

V. A. Semenov
Kemerovo State Medical Academy, Ministry of Health of Russia, Kemerovo, Russia 22a, Voroshilov St., Kemerovo 650056
Russian Federation

T. R. Grishina
Ivanovo State Medical Academy, Ministry of Health of Russia, Ivanovo, Russia 8, Sheremetevsky Passage, Ivanovo 153000
Russian Federation


1. Stein D. Etifoxine versus alprazolam for the treatment of adjustment disorder with anxiety: a randomized controlled trial. Adv Ther. 2015 Jan;32(1):57-68. doi: 10.1007/s12325- 015-0176-6. Epub 2015 Jan 27.

2. Bouillot C, Bonnefoi F, Liger F, Zimmer L. A microPET comparison of the effects of etifoxine and diazepam on [(11)C]flumazenil uptake in rat brains. Neurosci Lett. 2016 Jan 26;612:74-9. doi: 10.1016/j.neulet.2015.11.042. Epub 2015 Nov 28.

3. Choi Y, Kim K. Etifoxine for pain patients with anxiety. Korean J Pain. 2015 Jan;28(1):4-10. doi: 10.3344/kjp.2015.28.1.4. Epub 2015 Jan 2.

4. do Rego JL, Vaudry D, Vaudry H. The nonbenzodiazepine anxiolytic drug etifoxine causes a rapid, receptor-independent stimulation of neurosteroid biosynthesis. PLoS One. 2015 Mar 18;10(3):e0120473. doi: 10.1371/journal.pone. 0120473. eCollection 2015.

5. Wolf L, Bauer A, Melchner D, et al. Enhancing neurosteroid synthesis-relationship to the pharmacology of translocator protein (18 kDa) (TSPO) ligands and benzodiazepines. Pharmacopsychiatry. 2015 Mar;48(2):72-7. doi: 10.1055/s-0034-1398507. Epub 2015 Feb 5.

6. Zeitler A, Kamoun N, Goyon S, et al. Favouring inhibitory synaptic drive mediated by GABAA receptors in the basolateral nucleus of the amygdala efficiently reduces pain symptoms in neuropathic mice. Eur J Neurosci. 2016 Apr; 43(8):1082-8. doi: 10.1111/ejn.13217. Epub2016 Mar 17.

7. Girard P, Pansart Y, Gillardin J. Preventive and curative effects of etifoxine in a rat model of brain oedema. Clin Exp Pharmacol Physiol. 2009 Jul;36(7):655-61. doi: 10.1111/j.1440- 1681.2008.05127.x. Epub 2009 Nov 28.

8. Ravikumar B, Crawford D, Dellovade T, et al. Differential efficacy of the TSPO ligands etifoxine and XBD-173 in two rodent models of Multiple Sclerosis. Neuropharmacology. 2016 Sep;108:229-37. doi: 10.1016/j.neuropharm. 2016.03.053. Epub 2016 Mar 30.

9. Verleye M, Heulard I, Gillardin J. The anxiolytic etifoxine protects against convulsant and anxiogenic aspects of the alcohol withdrawal syndrome in mice. Alcohol. 2009 May;43(3): 197-206. doi: 10.1016/j.alcohol.2009.02.003.

10. Dai T, Zhou X, Li Y, et al. Etifoxine promotes glia-derived neurite outgrowth in vitro and in vivo. J Reconstr Microsurg. 2014 Jul;30 (6):381-8. doi: 10.1055/s-0034-1381751. Epub 2014 Jun 23.

11. Торшин ИЮ, Громова ОА, Федотова ЛЭ, Громов АН. Эффекты этифоксина (хемореактомное моделирование). Неврология, нейропсихиатрия, психосоматика. 2016;8(2):44-49. [Torshin I.Y., Gromova O.A., Fedotova L.E., Gromov A.N. Effects of etifoxine: Chemoreactome simulation. Neurology, Neuropsychiatry, Psychosomatics. 2016;8(2):44-49. (In Russ.)]. doi: 10.14412/2074-2711-2016-2-44-4912.

12. Schlichter R, Rybalchenko V, Poisbeau P, et al. Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine. Neuropharmacology. 2000 Jul 10;39(9): 1523-35.

13. Verleye M, Akwa Y, Liere P, et al. The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain. Pharmacol Biochem Behav. 2005 Dec;82(4):712-20. Epub 2006 Jan 4.

14. Girard C, Liu S, Cadepond F, et al. Etifoxine improves peripheral nerve regeneration and functional recovery. Proc Natl Acad Sci USA. 2008 Dec 23;105(51):20505-10. doi: 10.1073/pnas.0811201106. Epub 2008 Dec 15.

15. Nothdurfter C, Rammes G, Baghai T, et al. Translocator protein (18 kDa) as a target for novel anxiolytics with a favourable side-effect profile. J Neuroendocrinol. 2012 Jan;24(1): 82-92. doi: 10.1111/j.1365-2826.2011.02166.x.

16. Ugale R, Sharma A, Kokare D, et al. Neurosteroid allopregnanolone mediates anxiolytic effect of etifoxine in rats. Brain Res. 2007 Dec 12;1184:193-201. Epub 2007 Sep 25.

17. Verleye M, Pansart Y, Gillardin J. Effects of etifoxine on ligand binding to GABA(A) receptors in rodents. Neurosci Res. 2002 Oct;44(2): 167-72.

18. Verleye M, Schlichter R, Neliat G, et al. Functional modulation of gamma-aminobutyric acid(A) receptors by etifoxine and allopregnanolone in rodents. Neurosci Lett. 2001 Apr 6; 301(3):191-4.

19. Bourin M, Hascoet M. Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the four-plate test in Swiss mice. Behav Brain Res. 2010 Apr 2;208(2):352-8. doi: 10.1016/j.bbr.2009.11.046. Epub 2009 Dec 17.

20. Verleye M, Dumas S, Heulard I, et al. Differential effects of etifoxine on anxiety-like behaviour and convulsions in BALB/cByJ and C57BL/6J mice: any relation to overexpression of central GABAA receptor beta2 subunits? Eur Neuropsychopharmacol. 2011 Jun;21(6):457-70. doi: 10.1016/j.euroneuro.2010.09.008. Epub 2010 Oct 12.

21. Papadopoulos V, Amri H, Li H, et al. Structure, function and regulation of the mitochondrial peripheral-type benzodiazepine receptor. Therapie. 2001 Sep-Oct;56(5):549- 56.

22. Verleye M, Schlichter R, Gillardin J. Interactions of etifoxine with the chloride channel coupled to the GABA(A) receptor complex. Neuroreport. 1999 Oct 19;10(15):3207-10.

23. Schumacher M, Guennoun R, Mercier G, et al. Progesterone synthesis and myelin formation in peripheral nerves. Brain Res Brain Res Rev. 2001 Nov;37(1-3):343-59.

24. Dubrovsky B. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav. 2006 Aug;84(4):644-55. Epub 2006 Sep 7.

25. Pinna G, Costa E, Guidotti A. Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology (Berl). 2006 Jun;186(3): 362-72. Epub 2006 Jan 24.

26. Belelli D, Casula A, Ling A, Lambert JJ. The influence of subunit composition on the interaction of neurosteroids with GABA(A) receptors. Neuropharmacology. 2002 Sep; 43(4):651-61.

27. Poisbeau P, Keller A, Aouad M, et al. Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone. Front Cell Neurosci. 2014 Jun 17;8:174. doi: 10.3389/fncel.2014.00174. eCollection 2014.

28. Juif P, Melchior M, Poisbeau P. Characterization of the fast GABAergic inhibitory action of etifoxine during spinal nociceptive processing in male rats. Neuropharmacology. 2015 Apr;91:117-22. doi: 10.1016/j.neuropharm.2014.12.022. Epub 2014 Dec 26.

29. Aouad M., Petit-Demouliere N., Goumon Y., Poisbeau P. Etifoxine stimulates allopregnanolone synthesis in the spinal cord to produce analgesia in experimental mononeuropathy. Eur J Pain. 2014;18(2):258-68 doi.

30. Aouad M, Zell V, Juif P, et al. Etifoxine analgesia in experimental monoarthritis: a combined action that protects spinal inhibition and limits central inflammatory processes. Pain. 2014 Feb;155(2):403-12. doi: 10.1016/j.pain. 2013.11.003. Epub 2013 Nov 14.

31. Zeilhofer H. Etifoxine (Stresam) for chemotherapy-induced pain? Pain. 2009 Dec 15;147(1-3):9-10. doi: 10.1016/j.pain.2009.09.021. Epub 2009 Oct 12.

32. Aouad M, Charlet A, Rodeau J, Poisbeau P. Reduction and prevention of vincristineinduced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3alpha-reduced neurosteroids. Pain. 2009 Dec 15;147(1-3):54-9. doi: 10.1016/j.pain.2009.08.001. Epub 2009 Sep 27.

33. Kruse H, Kuch H. Potentiation of clobazam's anticonvulsant activity by etifoxine, a non- benzodiazepine tranquilizer, in mice. Comparison studies with sodium valproate. Arzneimittelforschung. 1986 Sep;36(9):1320-2.

34. Kruse H, Kuch H. Etifoxine: evaluation of its anticonvulsant profile in mice in comparison with sodium valproate, phenytoin and clobazam. Arzneimittelforschung. 1985;35(1): 133-5.

35. Girard C, Liu S, Adams D, et al. Axonal regeneration and neuroinflammation: roles for the translocator protein 18 kDa. J Neuroendocrinol. 2012 Jan;24(1):71-81. doi: 10.1111/j.1365-2826.2011.02215.x.

36. Servant D, Graziani P, Moyse D, Parquet P. Treatment of adjustment disorder with anxiety: efficacy and tolerance of etifoxine in a doubleblind controlled study. Encephale. 1998 Nov-Dec; 24(6):569-74.

37. Nguyen N, Fakra E, Pradel V, et al. Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice. Hum Psychopharmacol. 2006 Apr;21(3):139-49.

38. Cottin J, Gouraud A, Jean-Pastor M, et al. Safety profile of etifoxine: A French pharmacovigilance survey. Fundam Clin Pharmacol. 2016 Apr;30(2):147-52. doi: 10.1111/fcp.12169.Epub 2016 Jan 26.

39. Micallef J, Soubrouillard C, Guet F, et al. A double blind parallel group placebo controlled comparison of sedative and mnesic effects of etifoxine and lorazepam in healthy subjects [corrected]. Fundam Clin Pharmacol. 2001 Jun;15(3):209-16.

40. Verleye M, Andre N, Gillardin J. Lack of interaction between etifoxine and CRF1 and CRF2 receptors in rodents. Neurosci Res. 2006 Sep;56(1):53-60.


For citations:

Torshin I.Yu., Gromova O.A., Semenov V.A., Grishina T.R. Systematic analysis of basic and clinical studies of etifoxine. Neurology, Neuropsychiatry, Psychosomatics. 2016;8(3):106-112. (In Russ.)

Views: 531

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)