Clinical trials using St John’s wort

St John’s wort (Hypericum perforatum) extracts (SJW) have shown it to be effective in treating moderate depression (Linde, et al. 2005) and more recently to be effective for major depressive disorders (Linde, et al. 2009) (Rahimi, et al. 2009). One Cochrane review examined 29 clinical trials (5489 patients) carried out between 1998 and 2008 (Linde, et al. 2009), and the other analysed 17 trails (Rahimi, et al. 2009). SJW was as effective as SSRI’s and had fewer side effects. These findings were for alcoholic extracts (50-80%) from dried plant material, with daily dosages of 500-1200 mg and a ratio of raw material to extract of 3-7:1. (Linde, et al. 2009).   

Drug interactions :hypericin and hyperforin

SJW extracts contain more than 27 phytochemicals, including hypericin and hyperforin, flavonoids, volatile oil, plant acids, amino acids, vitamin C, tannins, and carotenoids (Di Carlo, et al. 2001).  

SJW with high levels of hyperforin (most preparations sold commercially) can cause rapid clearance of many drugs from the blood, resulting in decreased plasma concentrations. Hyperforin induces expression of the P450 family of enzymes (includes cytochromes CYP3A4 , CYP2C9, CYP1A2), responsible for clearance of many drugs via the liver (Wang, et al. 2004). Drug-substrate binding affected includes digoxin (binds P-gp), simvastatin (binds CYP3A4) and cyclosporine (binds both P-gp and CYP3A4) (Izzo 2004). The P450 family of enzymes act in the liver to catalyse the oxidation of organic compounds (Izzo 2004; Di, Li et al. 2008) (Zhou and Lai 2008). These transporters are induced by SJW, increasing the rate of drug clearance, thus decreasing the effective plasma levels of these drugs (see Buttermick 2009, for a table listing interactions).

“Data for the extract ZE 117, marketed as Remotiv, indicate low amounts of hyperforin (0.2% compared with 5% in most commercial preparations). Three clinical trials performed using ZE 117 SJW extract with low hyperforin showed that the efficacy of this SJW extract was superior to placebo and as effective as imipramine and fluoxetine, thus showing that high hyperforin levels were not needed for the anti-depressive efficacy of SJW."

No drug interaction has been reported with products that have low contents of hyperforin.”

From, “St. John’s Wort: Quality Issues and Active Compounds”, Veronika Butterweck, 539-40370_ch01_3P.indd, 2009 in Botanical Medicine: From Bench to Bedside, Chapter 4, pp 69-91, Edited by R. Cooper and F. Kronenberg

SJW and selective serotonin re-uptake inhibitors (SSRIs),   

Since SJW binds to the same receptors as selective serotonin re-uptake inhibitors (SSRIs), SJW increases the effects of these drugs when they are taken together. Serotonin (5-hydroxytrytamine) is a derivative of tryptophan, and is widely distributed in the body, especially in platelets and the intestinal wall. It plays a role in inflammatory responses and is a neurotransmitter, with levels in brain influencing moods. SSRI and SJW both prolong serotonin effects in the brain, improving moods and stabilising mood swings (Kubera, et al. 2001). SSRI plus SJW can result in serotonin overdose, causing skin flushes/rash, allergic responses, fluid retention, agitation and nausea (Upfal 2002 p293) (Izzo 2004). 


SJW is a widely used medicinal herb with well documented antidepressant properties (Linde, et al. 2005; Rahimi, et al 2009, Linde, et al. 2009). Thus concomitant use of SJW and SSRIs poses a significant risk, with readily available SJW often bought over the counter. Both medical and herbal practitioners need to be well aware of this risk and to inform their patients of additive effects. The review by Butterwick gives an excellent summary of the clinical findings on SJW.


Butterweck, V. 2009. 'St. John’s Wort: Quality Issues and Active Compounds', 539-40370_ch01_3P.indd, in Botanical Medicine: From Bench to Bedside,Edited by R. Cooper and F. Kronenberg, Chapter 4, pp 69-91,

Di Carlo, G., Borrelli, F., et al. 2001. 'St John's wort; prozac from the plant kingdom.' Trends in Pharmacological Sciences Vol.22, no.6: pp 292-297.

Di, Y., Li, C., et al. 2008. 'Clinical drugs that interact with St John's wort and implication in drug development ' Current Pharmaceutical Design Vol.14, no.17: pp 1723-1742.  

Izzo, A. A. and Ernst, E. 2009. 'Interactions between herbal medicines and prescribed drugs: an updated systematic review.' Drugs Vol.69, no.13: pp 1777-1798.

Kubera, M., Lin, A.-H., et al. 2001. 'Anti-Inflammatory Effects of Antidepressants Through Suppression of the Interferon-[gamma]/Interleukin-10 Production Ratio.' Journal of Clinical Psychopharmacology Vol.21, no.2: pp 199-206.

Linde, K., Berner, M., et al. 2009. 'St John's wort for major depression (Review).' Cochrane Database Systemic Review,  Vol.4: pp 1-55

Linde, K., Mulrow, C., et al. 2005. 'St John's wort for depression.' Cochrane Database Systemic Review Vol.2: pp 1-60

Mai, I., Bauer, S., et al. 2004. 'Hyperforin content determines the magnitude of the St John's wort-cyclosprine drug interaction.' Clinical Pharmacology and Therapeutics Vol.76, no.4: pp 330-340.

Rahimi, R., Nikfar, S., et al. 2009. 'Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: A meta-analysis.' Progress in Neuro-Psychopharmacology & Biological Psychiatry: pp 118-127.

Upfal, J. 2002. The Australian Drug Guide. Schwartz Publishing Pty Ltd. Melbourne, Australia,

Wang, E., Barecki-Roach, M., et al. 2004. 'Quantitative characterisation of direct P-glycoprotein inhibition by St John's wort consituents hypericin and hyperforin.' Journal of Pharmacy and Pharmacology Vol.56: pp 123-138.

Zhou, S. and Lai, X. 2008. 'An update on clinical drug interactions with herbal antidepressant St. John's wort. ' Current Drug Metabolism Vol.9, no.5: pp 394-409.







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