The antidepressant mechanism of Hypericum perforatum

Life Sci. 2004 Jul 16;75(9):1021-7. doi: 10.1016/j.lfs.2004.04.005.


Clinical data indicate that hydroalcoholic extracts of Hypericum perforatum might be as valuable as conventional antidepressants in mild-to-moderate depression, with fewer side effects. One clinical trial using two extracts with different hyperforin contents indicated it as the main active principle responsible for the antidepressant activity. Behavioural models in rodents confirm the antidepressant-like effect of Hypericum extracts and also of pure hyperforin and hypericin. A hydroalcoholic extract lacking hyperforin also lacks the antidepressant-like effect. According to pharmacokinetic data and binding studies, it appears that the antidepressant effect of Hypericum extract is unlikely be due to an interaction of hypericin with central neurotransmitter receptors. The main in vitro effects of hyperforin (at concentrations of 0.1-1 microM) are non-specific presynaptic effects, resulting in the non-selective inhibition of the uptake of many neurotransmitters, and the interaction with dopamine D1 and opioid receptors. However, it is still not clear whether these mechanisms can be activated in vivo, since after administration of Hypericum extract brain concentrations of hyperforin are well below those active in vitro. In the rat, Hypericum extract might indirectly activate sigma receptors in vivo (through the formation of an unknown metabolite or production of an endogenous ligand), suggesting a new target for its antidepressant effects.

Publication types

  • Review

MeSH terms

  • Animals
  • Anthracenes
  • Bridged Bicyclo Compounds
  • Depression / drug therapy*
  • Disease Models, Animal
  • Hypericum / chemistry*
  • Neurotransmitter Agents / metabolism
  • Perylene / analogs & derivatives*
  • Perylene / pharmacokinetics
  • Perylene / therapeutic use
  • Phloroglucinol / analogs & derivatives
  • Phytotherapy*
  • Plant Extracts / pharmacokinetics
  • Plant Extracts / therapeutic use
  • Rats
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Opioid / metabolism
  • Terpenes / metabolism
  • Terpenes / pharmacokinetics
  • Terpenes / therapeutic use*


  • Anthracenes
  • Bridged Bicyclo Compounds
  • Neurotransmitter Agents
  • Plant Extracts
  • Receptors, Dopamine D1
  • Receptors, Opioid
  • Terpenes
  • Perylene
  • hypericin
  • Phloroglucinol
  • hyperforin