The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 3 • July 2015

Surprise! Kappa Opioid Receptors Mediate the Antidepressant-Like Activity of Hesperidin in Mice

Who would have thought it? That hesperidin could exhibit anti-depressant effects in mice subjected to the forced swim test and do so by interacting with the kappa opioid receptor. But that’s one thing about biomedical science—there are always lots of surprises.

The kappa opioid receptor is one of the three currently known opioid receptors, that also includes mu and delta opioid receptors. Hesperidin, a naturally occurring flavonone glycoside, is found in rich quantities in citrus fruits and has been reported to have antioxidant, neuroprotective, and anticancer effects. An earlier paper2 reported that in traditional Mexican medicine, infusion of flowers of the Citrus genera are used as a sedative to treat insomnia. That paper explored this interesting property of Citrus; the authors reported that, in an earlier study, hesperidin in the methanol extract of Citrus sinensis was identified as the sedative active principle of the plant. Others had described the involvement of opioid receptors to the behavioral and antinociceptive (anti-pain) effects of hesperidin.

The immobility period of the mice subjected to the forced swim test (freezing as a result of fear) was significantly reduced by treatment with hesperidin at doses of 0.1, 0.3, and 1 mg/kg. Pretreatment with naloxone (a nonselective opioid receptor antagonist) reversed the antidepressant-like effect of hesperidin, evidence that that effect of hesperidin was mediated by an opioid receptor.

Because of scientific evidence supporting hesperidin’s neuroprotective effects (such as its antidepressant activity in mice subjected to a severe stress), we included hesperidin at a dose of 100 mg per capsule in our special lithium formulation, same as the lowest dose of hesperidin that had antidepressant effects in the mice in this study. If you are a mouse, we suggest you consider the secure feeling you’ll get by taking a hesperidin supplement. If you are a human, we don’t know exactly what dose is going to provide the exact same effects as in the mice, but that hesperidin will activate the kappa opioid receptor seems very likely as there is no evidence to our knowledge that mice and humans differ in this particular respect.

There is much scientific evidence for beneficial effects of hesperidin, such as providing protection against amyloid beta induced neurotoxiciy (as occurs in Alzheimer’s disease),3 reducing neuroinflammation in an animal model of stroke,4 protecting against ischemia-reperfusion injury in rats,5 as just a few examples.


To get the amount of hesperidin contained in a single capsule of our lithium formulation would require drinking 400 ml of raw orange juice. Delicious, but there is a very large amount of natural sugars and calories in all that OJ. Besides, it is a lot more expensive than our lithium formulation. [See “Announcing Durk & Sandy’s New Lithium Formulation” in the May 2014 issue.]

  1. Filho et al. Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. Eur J Pharmacol. 698:286-91 (2013).
  2. Guzman-Gutierrez and Navarrete. Pharmacological exploration of the sedative mechanism of hesperidin identified as the active principle of Citrus sinensis flowers. Planta Med. 75:295-301 (2009).
  3. Wang et al. Protective effects of hesperidin against amyloid-beta induced neurotoxicity through the voltage dependent anion channel 1 (VDAC-1)-mediated mitochondrial apoptotic pathway in PC-12 cells. Neurochem Res. 38:1034-44 (2013).
  4. Raza et al. Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res. 1420:93-105 (2011).
  5. Gaur and Kumar. Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep. 62:635-48 (2010).

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