St. John's Wort

    Written by:
    Giulia Guerrini, Nick Milazzo

    Fact-checked

    by:

    Nick Milazzo, Natalka Roshak
    Last Updated: June 20, 2024

    St. John’s wort, also known by its Linnean name of Hypericum perforatum (HP), is an anti-depressant herb that is commonly used for its neurological effects. While it appears effective, it is well known to adversely interact with a variety of pharmaceuticals.

    What is St. John’s wort?

    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.

    What are the main benefits of St. John’s wort?

    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]

    What are the main drawbacks of St. John’s wort?

    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]

    Does St. John’s wort interact with any other medication?Can St. John’s wort interact with other supplements?Is St. John’s wort safe during pregnancy?Is St. John’s wort safe during breastfeeding?

    How does St. John’s wort work?

    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]

    Does St. John’s wort have other mechanisms of action?

    What are other names for St. John's Wort?

    Note that St. John's Wort is also known as:

    • St. John's Wort
    • Hypericum Perforatum
    • Klamath Weed
    • Tipton Weed
    • Johanniskraut
    • 圣约翰草 (Guan Ye Lian Qiao)

    Dosage information

    The most common dosage of St. John's wort extract found in studies is 300mg, taken up to three times a day (for a total of 900 mg).[1]

    Frequently asked questions

    What is St. John’s wort?

    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.

    What are the main benefits of St. John’s wort?

    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]

    What are the main drawbacks of St. John’s wort?

    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]

    Does St. John’s wort interact with any other medication?

    Significant antineoplastic drugs, such as irinotecan, should not be used with Hypericum perforatum as the combination reduces the plasma levels of irinotecan and may have an impact on the treatment outcome, as seen in one randomized crossover study.[13]

    St. John’s wort may also cause a higher risk of hypoglycemia when used in combination with tolbutamide.[14]

    HP may also play a role in reducing the plasma concentration of many opioids such as oxycodone, dextromethorphan, and pethidine.[15]

    Hypertensive medications can also be affected. Calcium channel blockers such as nifedipine interact with HP, which induces the metabolism of nifedipine and increases the plasma concentration of dehydronifedipine.[16] Hypericum perforatum also interacts with verapamil by decreasing its bioavailability through the induction of CYP3A4.[17]

    Furthermore, taking theophylline (a bronchodilator) with 300mg of HP resulted in acutely decreased blood concentrations of theophylline through CYP3A4 inhibition.[18] However, when the combination was taken for 15 days, it was found that HP did not play a role in theophylline plasma or urine levels; proper monitoring is recommended when they are given together.[19]

    The interaction between HP and medications metabolized through the CYP pathway is generally considered unsafe due to the potential for significant effects on drug metabolism and efficacy. However, one study has explored the combination of HP with clopidogrel (an anticoagulant medication converted to its active metabolite by CYP enzymes) for people with reduced responsiveness to the drug, aiming to enhance its effect.[20]

    Can St. John’s wort interact with other supplements?

    Taking HP together with red yeast may reduce the effectiveness of the red yeast supplement. Red yeast contains monacolin K, a compound that is identical to the cholesterol-lowering drug lovastatin, a 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor. Lovastatin and other statins (e.g., simvastatin) are metabolized by the enzyme CYP3A4, which is induced by St. John's wort,[21] leading to a decrease in the serum concentration of these drugs. As a result, it is hypothesized that combining HP with red yeast may reduce its effect.[22]

    HP may also interact with 5-hydroxytryptophan (5-HTP) supplements. Both HP and 5-HTP can increase serotonin levels in the brain, and therefore taking them together may increase the risk of serotonin toxicity. This interaction has not yet been verified by in vivo or in vitro studies. However, until more research is conducted, it is generally discouraged to combine HP with 5-HTP unless under medical supervision.

    Is St. John’s wort safe during pregnancy?

    There is limited research available on the safety and toxicity of HP during pregnancy. One in vitro study suggested that the typical dosage of HP prescribed is not toxic. Additionally, the same study indicated that two of the main active compounds in HP, hyperforin and hypericin, exhibited potential toxicity only at much higher doses than what is typically achieved with common supplement usage.[23]

    Another prospective, observational, controlled cohort study, monitored 54 pregnant women who were taking an average daily dosage of 615 mg of HP for depression. The study did not find any congenital malformations in the newborns of these women. It did note a higher rate of spontaneous abortions in the HP group compared to the control group, but this difference was not statistically significant.[24] More extensive studies

    Is St. John’s wort safe during breastfeeding?

    The majority of studies looking at the safety of St. John's wort while breastfeeding have primarily focused on older infants, rather than those in the first 2 months of life when they are more vulnerable to adverse reactions. One study found that breastfed infants whose mothers were taking St. John's wort showed a slightly increased incidence of colic, drowsiness, and lethargy. However, these effects were not severe and did not require any medical attention.[25]

    Another study showed that hypericin and hyperforin in HP are excreted only in limited and non-significant amounts in breast milk.[25]

    Furthermore, conflicting information exists regarding whether HP can reduce serum prolactin levels or maternal milk supply.[25]

    Because HP is sometimes recommended by midwives for postpartum depression, more research must be conducted to thoroughly assess the safety of using HP during lactation.

    How does St. John’s wort work?

    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]

    Does St. John’s wort have other mechanisms of action?

    Some studies have suggested that HP may inhibit monoamine oxidases, a family of enzymes responsible for reducing the levels of monoamine neurotransmitters in the brain (i.e., serotonin, dopamine, norepinephrine). By inhibiting these enzymes, HP may help maintain higher levels of these neurotransmitters, further contributing to its antidepressant effects. However, hypericin and the flavonol fraction of HP appear to inhibit MAOs only at concentrations much higher than those relevant to HP supplementation, therefore this mechanism of action may not be relevant.[11][2]

    HP also appears to interfere with the GABA system in the brain by binding to GABA receptors, which reduces the depressive activity of GABA.[2] More studies are needed to clarify these mechanisms of action, and specifically which compounds in HP are responsible for these effects.

    Furthermore, in vitro and in vivo animal studies showed that HP’s active compounds appear to downregulate β-adrenergic receptors, another potential mechanism of action.[12]

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