Antidepressant Properties of St. John’s Wort

The use of Hypericum extracts for the treatment of mild to moderate depression is the most extensive of all the medical uses of St. John’s wort.  

Extracts of St. John's Wort enjoy a reputation as an effective antidepressant.  Standardized extracts of St. John's Wort are sold in pharmacies throughout Europe, and are in fact among the most popular OTC "phytomedicines" sold in European countries. Among the most widely prescribed antidepressants in the United States are Prozac from Eli Lilly and Zoloft from Pfizer.  As people experience adverse side effects from prescription antidepressants, there has been a concomitant rise in the use of SJW and other herbs as natural antidepressants.  Several herbal formulations, sold as natural substitutes for Prozac, are already being marketed.

Mechanisms of Action

The mechanisms of action by which the Hypericum extract acts as an antidepressant are not fully understood.  In vivo studies using mouse or rat brain synaptosomes have indicated that Hypericum extract inhibits the synaptosomal uptake of serotonin, dopamine, and norepinephrine (Castor, 2001).  Most in vivo studies have indicated that Hypericum compounds competitively inhibit subtype A monoamine oxidase (MAO).  Subtype A MAO inhibition, involving dopamine, norepinephrine, and serotonin, is thought to be effective in the treatment of depression.  

Preclinical Studies

XantolDS ProductInformation XantolDS smPreclinical animal studies suggest that Hypericum is effective in three major biochemical systems relevant for antidepressant activity, namely the inhibition of the synaptic re-uptake system for serotonin (5-HT3), noradrenaline (NA) and dopamine (DA).  Hypericum is the only antidepressant capable of inhibiting the re-uptake of 5-HT3, NA and DA with similar potencies. The potencies for monoamine re-inhibition and chronic changes in receptors are also consistent with changes seen with known antidepressants.

Behavioral studies suggest that Hypericum is active in pre-clinical animal models of depression with comparable effects to known antidepressants. Supporting the pre-clinical pharmacology and efficacy, many clinical studies have shown that Hypericum has superior efficacy compared to placebo and comparable efficacy to standard antidepressants in the treatment of mild-to-moderate depression.

Bioactive Constituents

Among the bioactive constituents of St. John’s Wort, hypericin and hyperforin have received the most scientific interest. Hypericin was originally considered the active component in St. John's Wort, and commercial preparations have been standardized to hypericin content. Recent evidence suggests that hyperforin and its analogues play a larger role in the antidepressant pharmacological effects (Castor, 2001). Because hyperforin is an unstable compound and is susceptible to oxidative degradation, its concentration in St. John's Wort, unless stabilized, may vary considerably.  Hypericin does not have any impact on serotonin re-uptake inhibition (Castor, 2001) and appears to be responsible for the photosensitivity of Hypericum extracts (Ilyinskii et al., 2006).

Hyperforin is believed to be the major constituent responsible for antidepressant activity, and it has been shown to inhibit the uptake of 5-HT3, dopamine, and noradrenaline. Hyperforin also has affinity for GABA and glutamate transporters.  Collectively, these pharmacological effects may play a role in the efficacy of St. John's wort in the treatment of mild to moderately severe depressive disorders.


Preclinical and short-term clinical studies demonstrate antidepressant activity of St. John’s Wort extracts.  This activity is more pronounced and consistent with St. John’s Wort products standardized against stable formulations of hyperforin.

The advantage of Hypericum over other antidepressants results from its favorable side-effect profile over prescription antidepressants such as Prozac and Zoloft.  


Drug-drug interactions with St. John’s Wort occur with certain prescription drugs including HIV and heart transplant medications.  St. John’s Wort is thus counter-indicated for certain prescription drugs.  

Also, certain preparations of St. John’s Wort, especially those containing hypericin, can cause phototoxic reactions in light skinned individuals.


  • Castor TP. (2001).  Methods for Making Hypericum Fractions and St. John’s Wort Products. U.S. Patent 6,291,241.
  • Ilyinskii P, Lallos L and Castor TP. (2006). Inactivation of Viral Infections by Chemiluminescence Activated Light-Sensitive Compounds. U.S. Patent No. 7,037, 5334.