St. John's Wort

The summary of evidence suggests that St. John’s wort has some efficacy in mild to moderate depression but minimal efficacy in the more moderate to severe depression (1,2). A number of compounds that are isolated from St. John’s wort have pharmacological activity (1,2). It is believed that the hyperforin and the related compounds are responsible for the majority of the St. John’s wort’s effect on mood (1). The hyperforin portion of St. John’s wort also has been demonstrated to modulate neurotransmitter levels, including serotonin, norepinephrine and dopamine (1). The effect of this modulation is inhibition of neurotransmitter uptake (1). Other studies have demonstrated that the hypericum extract has weak catechol-o-methyl transferase activity (1). In particular, the hypercium extract LI 160 demonstrated 50% inhibition of the serotonin uptake by rate synaptosomes (1). The standardized LI 1160 extract can decrease the cell surface 5-HT receptors (1). It can also suppress the release of interleukin-6, which creases the release of corticotrophin releasing hormone, which is found in depression (1). There is also some inhibition of binding to the muscarinic cholinergic receptor, 5-HT, and norepinephrine uptake sites, in high doses only (1). There seems to be some MAO-inhibiting ability, but this is mild in nature and is not responsible for the major mechanism of action of St. John’s wort (1).


A 1996 British Medical Journal paper conducted a meta-analysis of 23 clinical trials that were conducted in mainly Europe (20 double-bind, 2 open, and 1 single blind) that involved 1757 patients that had mild to moderate depressive disorders (1,2). These patients were taking St. John’s wort, TCAs and or placebo (1,2). The trials lasted for up to 12 weeks and the doses of the St. John’s wort ranged from 300 to 100 mg daily (1,2). The effect size of the St. John’s wort was significantly superior to placebo and achieved similar levels to TCAs that included amitriptyline and desipramine (1,2). However, the adverse effects were reported as the number of side effects and were not identified (1,2). The limitation against this study was that only small doses of the standard medications were used and study duration is considered to be short (1,2). The Agency for Health Care Policy and Research agreed that St. John’s wort is considered to be more effective when compared to placebo for the short term treatment of mild natured depressive disorders (1,2). There are concerns over the methodological quality of the trials and publication bias that favored the positive trials however (1,2). A systematic review by Cochrane concluded that based on the evidence that is available, St. John’s wort has a modest benefit over placebo for major depression that is similar to the effect of SSRIs and tricyclic antidepressants (1,2). The side effects are less than the conventional SSRI and TCA treatment (1,2).

Time to peak

For single oral doses of 300, 900 and 1800 mg of the Hypericum extract, the median maximal plasma levels were 1.5, 4.1, and 14.2 ng/ml respectively (1). The max plasma concentration of Hypericum was reached 3.5 hours after the oral administration of the 300 mg dose (1).


The systemic bioavailability of hypericin after oral administration is 14% (1). St. John’s wort induces cytochrome P450 enzymes, with a particular emphasize on the CYP3A4 family (3). The hyperfornin activates a regulator (pregnane x receptor) of CYP3A4 transcription and will induce an expression of 3A4 in human liver levels (3). Because of this the levels of the drug may be increased in the blood in the short term (3). Drugs that are affected by St. John’s wort through this action include carbamazepine, cyclosporine, nifedipine, warfarin, theophylline, simvastatin, protease inhibitors and reverse transcriptase inhibitors (3). St. John’s wort is also considered to be an inducer of P-glycoprotein through the pregnane X receptor activation (3). KC is taking diltiazem, which is a P-gylcoprotein substrate (4). P-gylcoprotein is a membrane bound active transport protein that is in a variety of cells (4). It is mostly an efflux transporter and thus this can decrease the serum concentration of diltiazem (4). Monitoring for decreased effects of diltiazem is needed (4).

Side Effects and Interactions

When taking St John’s wort concomitantly with other antidepressants, an increase in side effects such as serotonin syndrome and mania may result (1,4). The concomitant use of 2 or more agents that enhance serotonin activity may increase the concentrations of serotonin to toxic levels (1,4). Serotonin syndrome is characterized by muscle rigidity, fever, increased blood pressure and heart rate, coma, and confusion (1,4). Mania is elevated or irritable mood, with rapid speech or thoughts and decreased need for sleep (1,4). KC is taking an antidepressant in the form of venlafaxine (1,4). Therefore, because of the severity of this interaction, therapy modification is needed (1,4). Furthermore, from a human study, St. John’s wort may cause a significant reduction in the amitriptyline concentration (1,4). This is because the metabolism of TCAs involves CYP enzymes which include 1A2, 2C19, 3A4, and 2D6 (1,4).

The most common side effects of St. John’s wort include dry mouth, diarrhea, nausea, increased sensitivity to sunlight, fatigue, restlessness or anxiety, sexual dysfunction, headache and diarrhea. Infrequent allergic skin reactions have been reported in clinical trials, including rash, itching and pruritus (3). The published studies show that St. John ’s wort is well tolerated at the recommended doses for up to 1-3 months (1).

St. John’s wort should be avoided in patients who have known allergies or hypersensitivities to St. John’s wort or any of its constituents (3,5). It should not be used in HIV/AIDS patients who are taking protease inhibitors or non-nucleoside reverse transcriptase inhibitions because there are reductions in drug concentrations with concomitant St. John’s wort use (3,5). This should be avoided in patients who are own immunnosupressants (cyclosporine) because of reduction in drug levels and possible organ rejections when used concomitant (3,5). This should not be used in patients with suicidal ideation, digoxin (decreased digoxin efficacy), anticoagulants (may decrease anticoagulant effectiveness), and chemotherapeutic agents (may decrease effectiveness of chemotherapeutic agents) (3,5). It should be used cautiously in patients with drugs metabolized by CYP P450 3A4, 2E1 (may decrease drug levels), monoamine oxidase inhibitors or SSRIs (increased risk of serotonin syndrome), oral contraceptives (altered menstrual flow, bleeding and unwanted pregnancies), patients with history of mania or hypomania (biopolar disorder) (case reports of St. John’s wort induced manic episodes observed with standard antidepressant medications), diabetes or taking antidiabetic agnets (potential alteration of glucose metabolism) and renal transplant patients (potential to cause overdosage) (3,5).


  1. St John’s Wort. In: Natural Standard: the authority on integrative medicine [database on the Internet]. Cambridge (MA): Natural Standard; 2008 [cited 4 Mar 2012]. Available from:
  2. Cott JM, Fugh-Berman A. “Is St John's Wort (Hypericum perforatum) an Effective Antidepressant?” J Nerv Ment Dis. 1998. 186(8):500-1.
  3. Zhou, S. F, Lai, X. An update on clinical drug interactions with the herbal antidepressant St. John's wort. Curr.Drug Metab. 2008;9(5):394-409.


This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers

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