Etifoxine ball-and-stick.png
Clinical data
AHFS/ International Drug Names
  • Not recommended. Crosses the placental barrier
Routes of
ATC code
Legal status
Legal status
  • US: Unscheduled and not FDA approved
Pharmacokinetic data
Metabolism Hepatic (no CYP450 interactions)
Elimination half-life 2 to 6 hours (etifoxine),[1]
Excretion Renal
CAS Number
PubChem CID
Chemical and physical data
Formula C17H17ClN2O
Molar mass 300.782 g/mol g·mol−1
3D model (JSmol)
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Etifoxine (INN,[2] also known as etafenoxine; trade name Stresam) is an anxiolytic and anticonvulsant drug[3][4] developed by Hoechst in the 1960s.[2] It is sold in approximately 40 countries for anxiety disorders, without the sedation and ataxia associated with benzodiazepine drugs.[5] It has similar anxiolytic effects to benzodiazepine drugs, but is structurally distinct and does not bind to the benzodiazepine receptor.[6] It is as effective as lorazepam as an anxiolytic, but has fewer side effects.[7] Etifoxine is not a scheduled drug in many countries in which it is sold and does not cause dependence or tolerance. Etifoxine is not approved by the U.S. Food and Drug Administration or the European Medicines Agency.

Etifoxine seems to have been mischaracterized in the 1960-70’s as a mild or partial benzodiazepine, because of its lack of typical benzodiazepine side effects, like sedation and ataxia. Thus, it was deemed to be noncompetitive with benzodiazepine drugs of the time, like Valium, and not introduced into world markets. Not until the 2000s was it discovered that etifoxine worked through completely different mechanisms, i.e.. GABA(A) beta subtype selectivity and neurosteroid biosynthesis (purported to work through TSPO). Realization of the MOA has led to its investigation in a number of preclinical studies as an analgesic, anti-inflammatory and neuroprotectant. Recent publications have chronicled its efficacy as a microglia modulator in models of MS and ICH.

The original composition of matter patent for etifoxine expired decades ago, however the S-enantiomer (US8110569 B2) and metabolically stabilized deuterium substituted variants have been recently identified in the patent literature (WO2016154039 A1). The deuterium variants retain the biological activity of etifoxine, but improve the pharmacokinetic profile, allowing less frequent and/or lower dosing than the original.

Side effects[edit]

The most common adverse effect is mild drowsiness at initial dosing. It is not associated with any withdrawal syndromes or dependence, and is not scheduled in France. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines Etifoxine for Pain Patients with Anxiety[8]. A recent (2012) review of etifoxine by the French National Pharmacovigilance Committee determined that etifoxine was safe and continued to provide a favorable alternative to benzodiazepine anxiolytics. Contrary to comments in non-refereed on line journals, the committee found (for a ten-year pharmacovigilance period) that safety concerns were rare or very rare and that the incidence of idiosyncratic hepatic problems were very rare (less than drugs like Lipitor).

Mechanism of action[edit]

Unlike benzodiazepines, etifoxine appears to produce its anxiolytic effects by activating β2 and β3 subunit containing channels of the GABAA receptor complex (a different binding site than benzodiazepines), and by stimulating the production of GABA(A) active neurosteroids that act in conjunction with etifoxine’s direct effects.[9] This difference in binding means that etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites;[10] however, it also means that the effects of etifoxine are not reversed by the benzodiazepine antagonist flumazenil.[11]

Etifoxine has been shown to stimulate the biosynthesis of endogenous neurosteroids, namely 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tetrahydroprogesterone.[12] Several studies have shown that the synthesis of neurosteroids is essential to the pharmacological actions of etifoxine. Inhibitors of neurosteroid biosynthesis reverse the anxiolytic and analgesic actions of etifoxine.


  1. ^ “Stresam PI” (PDF). Adcock Ingram. n.d. Retrieved 2008-08-30.[dead link]
  2. ^ a b U.S. Patent 3,725,404
  3. ^ Kruse HJ, Kuch H (1985). “Etifoxine: evaluation of its anticonvulsant profile in mice in comparison with sodium valproate, phenytoin and clobazam”. Arzneimittelforschung. 35 (1): 133–135.
  4. ^ The Merck Index, 12th Edition. 3910.
  5. ^ Girard C, Liu S, Cadepond F, Adams D, Lacroix C, Verleye M, Gillardin JM, Baulieu EE, Schumacher M, Schweizer-Groyer G (2008). “Etifoxine improves peripheral nerve regeneration and functional recovery”. Proc Natl Acad Sci U S A. 105 (51): 20505–10. Bibcode:2008PNAS..10520505G. doi:10.1073/pnas.0811201106. PMC 2629330. PMID 19075249.
  6. ^ Schlichter R, Rybalchenko V, Poisbeau P, Verleye M, Gillardin J (2000). “Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine”. Neuropharmacology. 39 (9): 1523–35. doi:10.1016/s0028-3908(99)00253-1. PMID 10854897.
  7. ^ Nguyen N, Fakra E, Pradel V, Jouve E, Alquier C, Le Guern ME, Micallef J, Blin O (2006). “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”. Human Psychopharmacology. 21 (3): 139–49. doi:10.1002/hup.757. PMID 16625522.
  8. ^ Choi, Y. M.; Kim, K. H. (2015). “Etifoxine for Pain Patients with Anxiety”. The Korean Journal of Pain. 28 (1): 4–10. doi:10.3344/kjp.2015.28.1.4. PMC 4293506. PMID 25589941.
  9. ^ Hamon A, Morel A, Hue B, Verleye M, Gillardin JM (2003). “The modulatory effects of the anxiolytic etifoxine on GABA(A) receptors are mediated by the beta subunit”. Neuropharmacology. 45 (3): 293–303. doi:10.1016/s0028-3908(03)00187-4. PMID 12871647.
  10. ^ Kruse HJ, Kuch H (1986). “Potentiation of clobazam’s anticonvulsant activity by etifoxine, a non-benzodiazepine tranquilizer, in mice. Comparison studies with sodium valproate”. Arzneimittelforschung. 36 (9): 1320–2. PMID 3098254.
  11. ^ Verleye M, Schlichter R, Gillardin JM (1999). “Interactions of etifoxine with the chloride channel coupled to the GABA(A) receptor complex”. NeuroReport. 10 (15): 3207–10. doi:10.1097/00001756-199910190-00015. PMID 10574561.
  12. ^ do Rego, Jean Luc; Vaudry, David; Vaudry, Hubert (2015). “The Non-Benzodiazepine Anxiolytic Drug Etifoxine Causes a Rapid, Receptor-Independent Stimulation of Neurosteroid Biosynthesis”. PLoS ONE. 10 (3): e0120473. Bibcode:2015PLoSO..1020473D. doi:10.1371/journal.pone.0120473. PMC 4364751. PMID 25785994. Retrieved 24 December 2016.