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Hesperidin synergistically potentiates the sleep-enhancing effect of diazepam in mice.

The study found that hesperidin, a natural flavonoid, synergistically interacts with diazepam to enhance sleep-related behavior as measured in the hole board test. Isobolar analysis confirmed the interaction was synergistic, not additive, and pharmacokinetic effects or direct binding of hesperidin to the benzodiazepine site were ruled out.

Last updated: Jul 7, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score24/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Synergistic interaction between hesperidin, a natural flavonoid, and diazepam.

observational

Fernández SP, Wasowski C, Paladini AC, Marder M · European journal of pharmacology (2005)

Participants: N/A
Duration: N/A
Intervention: Hesperidin combined with diazepam
Outcome: Sedative and sleep-enhancing effects measured via the hole board test
Effect Size: N/A (synergistic interaction reported via isobolar analysis, no specific effect size given)
Population: Animal subjects (likely rodents, based on typical preclinical sleep research)

Result:

PubMed: 15840404DOI: 10.1016/j.ejphar.2005.02.039

Mechanism Graph

Hesperidin does not bind to the benzodiazepine site on GABA(A) receptors
↓
Diazepam acts as an agonist at the benzodiazepine binding site
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Co-administration produces synergistic enhancement of sleep effects
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Result: Potentiation of sleep-enhancing properties

Limitations

  • ⚠Animal study, not directly generalizable to humans
  • ⚠No specific dose-response data or effect sizes reported in abstract

Frequently Asked Questions

What is hesperidin?▼

Hesperidin is a natural flavonoid found in Valeriana and citrus fruits, with sedative and sleep-enhancing properties.

How does hesperidin interact with diazepam?▼

Hesperidin synergistically potentiates the sleep-enhancing effect of diazepam, meaning the combined effect is greater than the sum of individual effects.

Does hesperidin bind to benzodiazepine receptors?▼

No, hesperidin is not a ligand for the benzodiazepine binding site on GABA(A) receptors.

Could hesperidin reduce the needed dose of benzodiazepines?▼

The authors suggest that hesperidin may allow for lower therapeutic doses of benzodiazepines due to synergistic interaction.

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References

  1. 1.Fernández SP, Wasowski C, Paladini AC, Marder M. "Synergistic interaction between hesperidin, a natural flavonoid, and diazepam.." European journal of pharmacology, 2005. PMID: 15840404 DOI: 10.1016/j.ejphar.2005.02.039
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.