Every ND has had the notion of drug interaction with St Jon’s wort (SJW) aggressively pounded into their head. And there certainly exists that potential. Likewise, every ND has had the notion that hypericin and hyperforin are the principle active constituents in SJW. As it turns out, this is not true at all.
I began practicing as an ND in 2004, and began focusing on mental health concerns in 2008. In 2012, I was introduced to an herbal combination that contained extracts of St John’s wort, valerian, and passionflower. This herbal combination quickly proved itself to be an invaluable tool in practice, for management of a very broad array of common and at times serious mental health complaints. Quite quickly the question became “can this herbal combination be combined with prescription medications”?
Jonathan Prousky, ND, is an accomplished clinician and the Chief Naturopathic Medical Officer at the Robert Shadd Naturopathic Clinic, the teaching clinic of the Canadian College of Naturopathic Medicine. Dr Prousky introduced me to the herbal combination described above, and we discussed concerns regarding herb-drug interaction with St John’s wort. With available evidence at the time we felt that if less than 4mg of hyperforin and/ or hypericin were administered per day, the possibility of interaction was very minimal. We also had in our possession unpublished data from the manufacturer of the herbal combination stating a hyperforin dose of less than 2% (ranging from 0.076-1.22%), and a hypericin dose of 0.1-0.2%. Furthermore, the document stated that the preparation starts with a hyperforin content of approximately 1.22%, yet the manufacturing process degrades hyperforin, and the finished product ends up with a hyperforin content that approaches detection limit.
Hyperforin has been widely documented as the constituent in SJW responsible for induction of several important P450 enzymes (CYP3A4, CYP2C19, CYP2C9), as well as induction of p- glycoprotein (ABCB1) (P-gp), an ATP- dependent drug efflux pump, capable of reducing bioavailability of a large array of common prescriptions (Chrubasik-Hausmann 2019, Soleymani 2017, Zahner 2019). Finding evidence of SJW interaction with a list of 50+ medications is not difficult, and the consequences of such interactions can be very serious, including death (Soleymani 2017). However, a very large body of literature has clearly demonstrated that this is not the story of relevance. Dose of SJW does not predict whether or not these interactions will occur, or to what magnitude. Of principle importance seems to be the hyperforin content of the preparation (Chrubasik-Hausmann 2019, Mai 2004, Mathijssen 2002, Mueller 2004, Will- Shahab 2009, Zahner 2019). While tremendous focus remains on publicizing horrifying potential for harm when co-administering SJW with a very broad array of medications, the basis for concern has clearly been demonstrated to rest on hyperforin content of the preparation.
Mai and colleagues (2004) demonstrated highly-significant interaction between SJW and cyclosporine when using a high-hyperforin preparation, yet no impact at all on cyclosporine AUC from a SJW preparation with less than 2% hyperforin, even with dosages as large as 2500mg of SJW. Will-Shahab (2009) demonstrated no interaction between low-hyperforin SJW and low-dose oral contraception. Mueller and colleagues (2004) demonstrated no interaction between low-hyperforin SJW and digoxin. Likewise, low-hyperforin SJW was shown to have no impact with co-administration of irinotecan (Mathijssen 2002).
Using a well-validated seven probe drug cocktail (50 mg caffeine tablet (CYP1A2), 75 mg bupropion HCl (CYP2B6), 10 mg flurbiprofen oral solution (CYP2C9), 10 mg omeprazole capsule (CYP2C19), 10 mg dextromethorphan oral solution (CYP2D6), 1 mg midazolam oral solution (CYP3A4), and 25mg fexofenadine oral suspension (P-gp)), Zahner and colleagues (2019) investigated a SJW preparation containing 0.3% hypericin and less than 2% hyperforin. The preparation delivered 0.96mg hyperforin per day. No impact was observed for the first six listed medications, and “weak inhibition” was demonstrated with dextromethorphan.
Chrubasik-Hausmann and colleagues (2019) provide an eloquent review of the subject area. They highlight that greatest concern exists regarding interaction of SJW with drugs metabolized by CYP3A4 and P-gp. The authors conclude:
“This review has highlighted that significant herb–drug interactions with St John’s wort have only occurred with H. perforatum L extracts that result in an adequate hyperforin daily dose (at least > 3 mg) when given to study participants. Low-hyperforin content of H. perforatum L extracts has demonstrated efficacy and safety in the management of people with depression prompting the call to restrict hyperforin content in the daily dosage to avoid the potential for serious herb–drug interactions.”
Armed with an assumption that the herbal combination should be safe to combine, I proceeded very slowly and cautiously. The first ten patients I co-administered the combination with a prescription was limited to individuals receiving only one prescription of any type, specifically an antidepressant, and the patient was mentally stable before prescribing the combination. Patients were warned about the potential for interaction, my basis for thinking it safe was described, and patients were informed of the need for frequent follow-up to ensure lack of interaction. Weekly follow-ups were conducted with these first patients for months. As I clearly gathered case observations of a complete lack of interaction, I slowly became more aggressive with situations in which I would add the herbal combination to various prescription regimes.
This process began in approximately 2012. I now routinely add the herbal combination to quite aggressive prescription regimes. I have administered this herbal combination to at least 100 women utilizing oral contraception. I am yet to see a case of breakthrough bleeding or unwanted pregnancy. Among several hundred patients I have combined this herbal combination with any and all fathomable prescription drugs, I am yet to observe an interaction of any type. I continue to observe caution when combining the combination with warfarin. In a relatively small subset of individuals I have done this with, I insist on INR assessment at least twice per week for the first four weeks of co-administration. Among a modest subset of individuals I have done this with, the combination has not impacted INR among warfarin-medicated individuals.
SJW is broadly considered well-tolerated. Side effects occur in 1-3% of users, and when they do occur are considered mild and transient. The most common side effects are gastrointestinal symptoms, dizziness, confusion, fatigue and/or sedation, skin reactions, restlessness or anxiety, headache, dry mouth and allergic reactions. Photosensitivity may occur, yet is considered very rare. Likewise, very rare reactions may include alopecia, neuropathy, and mania (Oliveira 2016). My clinical observation reveals headache to be the side effect most frequently seen (less than 2% of patients). Rare cases of mild photosensitivity have also occurred (again, less than 2% of patients).
JJ Duguoa, ND, PhD, has established himself as an important authority regarding safety, or lack-thereof, of natural health products through pregnancy and lactation. He has delivered a guest lecture to the second year students at CCNM annually for approaching 10 years, and counting. He proposes SJW and valerian are safe in pregnancy and lactation, with passionflower as “unknown”. In rare cases I have recommended the herbal combination in pregnancy. Typically, these are cases where the patient is already taking the herbal combination, and considering pregnancy or learns of an unexpected pregnancy. We discuss the “unknown” of passionflower, I suggest I think it is safe, yet I clearly state we can not be sure of the safety of the combination through pregnancy. Some of my patients chose to discontinue the combination, some of my patients choose to continue the combination. In the subset of patients who have used this combination through pregnancy, I have yet to observe an adverse birth outcome.
The National Library of Medicine (NLM 2018) addressed use of SJW and breastfeeding. A significant number of case reports and human trials are reviewed. Hyperforin/ hypericin content of SJW preparations was not discussed. Specifically regarding breastfeeding, the report states that hyperocin and hyperforin are “poorly excreted in breastmilk”.
The potential for harm from combining St John’s wort with prescriptions is very real, and can result in catastrophic consequences. If a clinician considers combining St John’s wort with prescriptions it is the absolute responsibility of the prescriber to first confirm the hyperforin and hypericin content of the preparation. Any reputable manufacturer of a St John’s wort extract should have this information readily available, and should be more than willing to share it with the prescriber.
References:
- Chrubasik-Hausmann S, Vlachojannis J, McLachlan AJ. Understanding drug interactions with St John’s wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol. 2019 Jan;71(1):129-138.
- Mai I, Bauer S, Perloff ES, Johne A, Uehleke B, Frank B, Budde K, Roots I. Hyperforin content determines the magnitude of the St John’s wort-cyclosporine drug interaction. Clin Pharmacol Ther. 2004 Oct;76(4):330-40.
- Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst. 2002 Aug 21;94(16):1247-9.
- Mueller SC, Uehleke B, Woehling H, Petzsch M, Majcher-Peszynska J, Hehl EM, Sievers H, Frank B, Riethling AK, Drewelow B. Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxin. Clin Pharmacol Ther. 2004 Jun;75(6):546-57.
- NLM. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. St. John’s Wort. [Updated 2018 Dec 3].
- Oliveira AI, Pinho C, Sarmento B, Dias AC. Neuroprotective Activity of Hypericum perforatum and Its Major Components. Front Plant Sci. 2016 Jul 11;7:1004.
- Soleymani S, Bahramsoltani R, Rahimi R, Abdollahi M. Clinical risks of St John’s Wort (Hypericum perforatum) co-administration. Expert Opin Drug Metab Toxicol. 2017 Oct;13(10):1047-1062.
- Will-Shahab L, Bauer S, Kunter U, Roots I, Brattström A. St John’s wort extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral contraceptive. Eur J Clin Pharmacol. 2009 Mar;65(3):287-94.
- Zahner C, Kruttschnitt E, Uricher J, Lissy M, Hirsch M, Nicolussi S, Krähenbühl S, Drewe J. No Clinically Relevant Interactions of St. John’s Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P-glycoprotein. Clin Pharmacol Ther. 2019 Aug;106(2):432-440.
