Hypericum perforatum (HP), commonly known as St. John’s wort, is a plant belonging to the Hypericaceae family with yellow, star-shaped flowers, native to Europe. St. John's wort typically blooms and is harvested towards the end of June, when St. John's feast day is celebrated. Traditionally, the plant was hung from doors on St. John’s feast day to protect against malevolent spirits and to ensure the well-being of both humans and animals.

Hypericin and hyperforin are the two main active metabolites of HP. Additionally, HP contains various other active compounds like flavonoids, as well as several inactive substances.^[2]

In traditional Chinese medicine (TCM) the extract of HP has been used as a herbal remedy to treat depression. It is also recommended for the same purpose in many European countries.

HP appears to be an effective treatment for mild to moderate depression. Several studies have investigated its clinical effects by comparing the Hamilton Depression Rating Scale (HAMD) scores of people taking HP to those of people taking a placebo or commonly prescribed antidepressant drugs. Many of these studies have indicated that HP extracts have a similar clinical response and remission rate to serotonin reuptake inhibitors (SSRIs), while also having a lower rate of treatment discontinuation due to side effects.^[1][3][4]

In comparison to tricyclic antidepressants (TCAs), HP appears to have fewer side effects and a lower dropout rate during treatment.^[4]

Furthermore, one in vitro study using a specific HP extract (containing only 4 compounds) found that that extract of HP increased neuronal plasticity (the ability of neurons and neural elements to adapt to internal or external stimuli such as chronic stress exposure) and neurogenesis (the formation of new neurons). Additionally, the HP extract exhibited anti-inflammatory properties and protected neurons from cytotoxicity induced by glutamate and N-methyl-D-aspartate (NMDA), which is considered a potential factor in depression.^[5]

Studies have shown that HP can interfere with the expression of enzymes of the cytochrome-P (CYP) family^[6] and of P-glycoprotein, both of which play a role in the metabolism of various medications. This can result in altered effects of certain drugs, potentially leading to reduced effectiveness or unexpected outcomes. Common medications whose effect may be decreased by HP include some oral contraceptive pills, warfarin (an anticoagulant drug), cyclosporin (often used as an immunosuppressant in organ transplants),^[7] digoxin (mostly used for atrial fibrillation), proton pump inhibitors (used to reduce stomach acid production), and some statins (cholesterol-lowering drugs).^[1][8]

Furthermore, combining HP with other antidepressants that increase serotonin levels (e.g., SSRIs, MAOIs) may raise the risk of serotonin syndrome (or serotonin toxicity), a potentially life-threatening condition characterized by an excessive accumulation of serotonin in the system. Symptoms of serotonin syndrome include tachycardia, increased blood pressure, dilated pupils, sweating, and elevated body temperatures.^[2] More data is required to verify the level of interaction with such medications.

Although St. John’s wort has been associated with fewer side effects compared to some antidepressant medications, the most common side effects reported with its use include gastrointestinal issues (e.g., abdominal pain or discomfort, nausea, and vomiting), headache, fatigue, sedation, dry mouth, vertigo, dizziness, restlessness, and photosensitivity. More studies are required to further investigate both short-term and long-term side effects of HP and to establish its safety profile when used as an antidepressant.^[9]

St. John’s wort appears to have multiple potential mechanisms of action, some of which have yet to be clarified.

HP (and more specifically one of its main active compounds, hyperforin) can inhibit the reuptake of serotonin, norepinephrine, and dopamine. Although the exact mechanism is still unclear, it seems that HP does not inhibit their reuptake by blocking the presynaptic transporters, as SSRIs do. One hypothesis is that hyperforin instead works by increasing the intracellular concentration of sodium,^[10] resulting in an increased concentration of monoamines available to interact with their postsynaptic receptors. This increased neurotransmitter activity is associated with improved mood and relief of depression symptoms.^[2]

Additionally, both in vivo and in vitro studies have found that HP also works by activating the pregnane-X-receptor (PXR) cytochromes, which play a role in regulating the expression of certain enzymes of the cytochrome P450 system (specifically the CYP3A4 enzyme) and the P-glycoprotein (responsible for transporting drugs and other substances out of cells). The activation of the CYP pathway and/or the P-glycoprotein by HP may contribute to the interactions between HP and other drugs metabolized through these pathways.^[2]