St. John’s Wort: Is it safe as a co-medication?

The safety of St. John’s Wort (Hypericum perforatum) is a very topical question as it is one of the most used medicinal plants worldwide.

In European countries it is available both over the counter and as a prescription medicine and outsells pharmaceutical anti-depressants. Numerous study have shown that it is equivalent in effectiveness to synthetic selective serontoin reuptake inhibitors (SSRIs) in mild to moderate depression but has a better safety profile and is very well tolerated.

Nevertheless, this herb has had a lot of attention due to its alleged ability to interact with pharmaceutical medication. 

 

What are people worried about?

One of the most common concerns that people have is if it is ok to take St. John’s Wort alongside other medication. Considering that millions of people worldwide take St. John’s Wort, reports of actual herb-drug interactions, side effects or unwanted pregnancies are very rare.

Many of the initial and even current concerns raised were based on a specific pharmaceutical type St. John’s Wort preparation containing standardised high levels of hyperforin. Others were raised on theoretical considerations, test tube experiments or on studies that used chemically purified single constituents of St. John’s Wort in vitro instead of testing the whole plant in real people.

Interestingly, the herb-drug interaction issue only became prominent in the late 1990’s, when some German manufacturers artificially stabilised and concentrated the hyperforin content of their St. John’s Wort tablets, as they believed that this active constituent was responsible for the anti-depressant action (Nahrstedt 2010, p.1019).

All other preparations did not show any herb-drug interactions since preparations low in hyperforin have not shown clinically relevant CYP3A induction (Arold et al 2005; Mai et al 2004; Mueller et al 2009; Whitten et al 2006). 

 

What is hyperforin?

Hyperforin is one of the many active phytocompounds produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum (St John's wort). Hyperforin is attributed to provide the main antidepressant effect of St. John's wort. 

High levels of hyperforin can induce cytochrome P450 (CYP) enzymes, a detoxification system which renowned science journal Science nicknamed the ‘garbage disposal’ system of the liver and small intestine. The job of these enzymes is to protect the body against toxins and xenobiotics - a good thing!

However, they also clear out certain synthetic drugs with a narrow therapeutic window faster than intended, which leads to lower blood concentrations of the drug and compromises its efficacy.

 

High-hyperforin versus low-hyperforin

In studies, high-hyperforin extracts were defined as those containing ≥ 10 mg per daily dose and low-hyperforin extracts as those containing ≤ 4 mg hyperforin per daily dose (Arold et al 2005; Whitten et al 2006, p. 514).

Hyperforin is naturally unstable and the amount needed to induce the P450 enzyme pathways (above 4mg) are not found in traditional preparations like medicinal teas and tinctures which are low or free of hyperforin (Meier 2001, pp. 38, 40). A medicinal tea taken as a typical total daily dose of 3.5g of St. John’s Wort as a crude herb preparation yielded a daily total of 0.4mg of hyperforin (Mueller et al 2004, p. 549).

There is also no interaction between a topical formulation, for example a herbal cream or oil containing St. John’s Wort and a pharmaceutical drug.

 

The key to safe co-medication comes down to three things

  1. It is the type of preparation (standardised tablet versus traditional tea or tincture)

  2. The dosage

  3. The concentration of hyperforin that will determine if the St. John’s Wort remedy has a herb-drug interaction potential or not.

Based on scientific studies medicnal teas, fresh plant tinctures and fresh plant juices all deliver low doses of hyperforin and do not interact with pharmaceutical drugs. This means that these preparations are suitable for co-medication with pharmaceutical drugs (Meier 2001, pp. 38, 40; Mueller et al 2004, p.554, 556).

 

Taking St. John's Wort and the contraceptive pill

Because reliable contraception is crucial for the peace of mind of many women, further scientific studies were undertaken to test contraceptive cover in women who took concurrently the pill and St. John’s Wort. They established that St John's Wort preparations do not change key hormonal levels or reduce the effectiveness of the pill, meaning that all women in the trials maintained full protection when taking a low-dose pill and St John's Wort together.

However, a higher rate of breakthrough bleeding was found in the St. John’s Wort groups (Fogle 2006; Hall 2003; Pfunder 2003). Women should always take the full course of their pill as directed, even if breakthrough bleeding occurs. There is no evidence of a mass outbreak of unwanted pregnancies in women taking St John's Wort alongside the contraceptive pill.

 

Medsafe New Zealand's advice

In March of 2014, Medsafe New Zealand confirmed that St John’s Wort preparations, which are low in hyperforin, are unlikely to produce interactions. The Swiss government made the same declaration in 2002 by stating that no warnings on medicinal teas are warranted.

Medsafe also stated that “…most products contain 3% [presumably 3mg?] hyperforin”, however a search highlighted that there seems to be no such standardized preparations in the New Zealand OTC market. If concerned, check with the product manufacturer for the specific level of hyperforin in their formulation. 

 

Traditional preparations of St. John's Wort are suitable as a co-medication with drugs

St John’s Wort is one of the most widely used and researched herbs in the world. As a traditional preparation (medicinal tea, fresh plant tincture or fresh plant juice) it has an excellent safety and efficacy record, including when used as a co-medication with drugs.

Caution: If you are on medication, it is best practice to discuss the introduction of additional medicines under the guidance of your health practitioner, this includes both pharmaceutical and plant medicine.

 

References:

Arold, G., Donath, F., Maurer, A., Diefenbach, K., Bauer, S., Henneicke-von Zepelin, H. H., . . . Roots, I. (2005). No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract. Planta Med, 71(4), 331-337. doi: 10.1055/s-2005-864099

Fogle, R. H., Murphy, P. A., Westhoff, C. L., & Stanczyk, F. Z. (2006). Does St. John's wort interfere with the antiandrogenic effect of oral contraceptive pills? Contraception, (3), 245-248. http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/631/CN-00571631/frame.html doi:10.1016/j.contraception.2006.03.015

Hall, S. D., Wang, Z., Huang, S. M., Hamman, M. A., Vasavada, N., Adigun, A. Q., . . . Gorski, J. C. (2003). The interaction between St John's wort and an oral contraceptive. Clinical Pharmacology & Therapeutics, 74(6), 525-535.

Mai, I., Bauer, S., Perloff, E. S., Johne, A., Uehleke, B., Frank, B., . . . Roots, I. (2004). Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction. Clinical Pharmacology and Therapeutics, 76(4), 330-340.

Meier, B. (2001). Comparing phytopharmaceuticals: the example of St. John’s wort. Advances in Therapy, 18(1), 35-46.

Mueller, S. C., Uehleke, B., Woehling, H., Petzsch, M., Majcher-Peszynska, J., Hehl, E. M., . . . Drewelow, B. (2004). Effect of St John's wort dose and preparations on the pharmacokinetics of digoxin. Clinical Pharmacology and Therapeutics, (6), 546-557. http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/418/CN-00468418/frame.html doi:10.1016/j.clpt.2004.01.014

Mueller, S. C., Majcher-Peszynska, J., Uehleke, B., Klammt, S., Mundkowski, R. G., Miekisch, W., . . . Drewelow, B. (2006). The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose. European Journal of Clinical Pharmacology, 62(1), 29-36.

Mueller, S. C., Majcher-Peszynska, J., Mundkowski, R. G., Uehleke, B., Klammt, S., Sievers, H., . . . Drewelow, B. (2009). No clinically relevant CYP3A induction after St. John's wort with low hyperforin content in healthy volunteers. Eur J Clin Pharmacol, 65(1), 81-87. doi: 10.1007/s00228-008-0554-y

Nahrstedt, A., & Butterweck, V. (2010). Lessons learned from herbal medicinal Products: The example of St. John’s Wort. Journal of Natural Products, 73, 1015-1021.

Pfunder, A., Schiesser, M., Gerber, S., Haschke, M., Bitzer, J., & Drewe, J. (2003). Interaction of St John’s wort with low dose oral contraceptive therapy: a randomised controlled trial. Br J Clin Pharmacol, 56, 683-690.

Whitten, D. L., Myers, S. P., Hawrelak, J. A., & Wohlmuth, H. (2006). The effect of St John's wort extracts on CYP3A: A systematic review of prospective clinical trials. British Journal of Clinical Pharmacology, 62(5), 512-526.