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]

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.

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

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.

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]