The biologically active compound of Withania somnifera (L.) Dunal, docosanyl ferulate, is endowed with potent anxiolytic properties but devoid of typical benzodiazepine-like side effects

J Psychopharmacol. 2021 Oct;35(10):1277-1284. doi: 10.1177/02698811211008588. Epub 2021 May 3.


Background: Clinical and experimental studies support the therapeutic potential of Withania somnifera (WS) (L.) Dunal on anxiety disorders. This potential is attributable to components present in different plant extracts; however, the individual compound(s) endowed with specific anxiolytic effects and potential modulatory activity of the GABAA receptor complex (GABAAR) have remained unidentified until the recent isolation from a WS methanolic root extract of some GABAAR-active compounds, including the long alkyl-chain ferulic acid ester, docosanyl ferulate (DF).

Aims: This study was designed to assess whether DF (0.05, 0.25 and 2 mg/kg), similarly to diazepam (2 mg/kg), may exert anxiolytic effects, whether these effects may be significantly blocked by the benzodiazepine antagonist flumazenil (10 mg/kg) and whether DF may lack some of the benzodiazepines' typical motor, cognitive and motivational side effects.

Methods: The behavioural paradigms Elevated Plus Maze, Static Rods, Novel Object Recognition, Place Conditioning and potentiation of ethanol-induced Loss of Righting Reflex were applied on male CD-1 mice.

Results: Similarly to diazepam, DF exerts anxiolytic effects that are blocked by flumazenil. Moreover, at the full anxiolytic dose of 2 mg/kg, DF lacks typical benzodiazepine-like side effects on motor and cognitive performances and on place conditioning. Moreover, DF fails to potentiate ethanol's (3 g/kg) depressant activity at the ethanol-induced Loss of Righting Reflex paradigm.

Conclusions: These data point to DF as an effective benzodiazepine-like anxiolytic compound that, in light of its lack of motor, mnemonic and motivational side effects, could be a suitable candidate for the treatment of anxiety disorders.

Keywords: Anxiety; GABAA receptors; Withania somnifera; diazepam; docosanyl ferulate; flumazenil.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Anxiety Agents* / administration & dosage
  • Anti-Anxiety Agents* / pharmacology
  • Behavior, Animal / drug effects
  • Diazepam / pharmacology
  • Dose-Response Relationship, Drug
  • Ethanol / pharmacology
  • Flumazenil / pharmacology
  • Male
  • Maze Learning / drug effects
  • Mice
  • Plant Extracts* / administration & dosage
  • Plant Extracts* / pharmacology
  • Reflex, Righting / drug effects
  • Withania* / chemistry


  • Anti-Anxiety Agents
  • Diazepam
  • Ethanol
  • Flumazenil
  • Plant Extracts
  • docosanyl ferulate