Medicines Q&As
Q&A 214.2
Is there an interaction between St John’s Wort and combined and
progestogen only hormonal contraceptives?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 5th January 2012
Background
St John’s Wort (SJW) is the common name for the plant Hypericum perforatum and is a popular
herbal remedy for the management of mild to moderate depression [1, 2].
SJW has several active constituents including hypericin, hyperforin and adhyperforin. Initially it was
thought that hypericin was responsible for its action; however it is now understood that hyperforin,
adhyperforin and several other related compounds are the primary active constituents [1-3].
In vitro studies have shown that hyperforin is a potent inducer of the cytochrome P450 enzymes,
particularly CYP3A4, CYP1A2 and CYP2C9 as well as affecting the P-glycoprotein cellular transport
system. Small short term studies, in human volunteers have failed to confirm this [4, 5]. SJW
preparations are non-standardised and the exact composition and levels of active constituents,
including hyperforin, varies between different preparations, therefore the overall effectiveness and
level of enzyme induction will vary between preparations [6-9].
In the United Kingdom (UK), hormonal contraceptives are available as combined hormonal
contraceptives (COC), containing both an estrogen, such as ethinylestradiol (EE) and a progestogen,
such as norethisterone, desogestrel or levo-norgestrel or progestogen only contraceptives (POP) [10].
CYP3A4 is the major route for inactivation of most contraceptive steroids, including ethinylestradiol
and most progestogens [1, 6]. The Committee on Safety of Medicines (CSM) has advised that St
John’s Wort (SJW) should not be used with oral contraceptives as there is a risk of contraceptive
failure and unplanned pregnancy [7, 8].
Answer
Most of the available evidence regarding an interaction between SJW and hormonal contraceptives,
relates to women who were taking a combined oral hormonal contraceptive.
There have been several case reports of breakthrough bleeding in women taking regular oral
contraceptives who also took SJW [11-13]. In 1999, 3 cases of breakthrough bleeding were reported
in patients taking ethinylestradiol and desogestrel and were attributed to lowered plasma
ethinylestradiol concentrations caused by SJW [11, 12]. By 2000, the Swedish Medical Products
Agency, had received 8 reports of inter-menstrual bleeding and 1 report of changed menstrual
bleeding in women on oral contraceptive tablets who started taking SJW [12, 13]. An unplanned
pregnancy in a 36 year old woman taking a regular ethinylestradiol plus dienogestrel oral
contraceptive, was reported by Schwarz et al in 2003 [14]. The woman self medicated with up to
1700mg of hypericin extract daily for approximately 3 months prior to conception. Up to June 2011,
the CSM had received 13 reports of unintended pregnancy in patients taking SJW. [15].
Several studies have assessed the effect of SJW extracts on oral contraceptives. The effect of SJW
300mg three times daily (TDS) in 12 healthy premenopausal women receiving a combined oral
contraceptive pill containing norethindrone and ethinylestradiol was assessed over 3 consecutive 28
day menstrual cycles [16]. SJW was associated with increased clearance of norethindrone (8.2 L/h to
9.5L/h, p=0.04) and a reduction in the half life of ethinylestradiol (23.4 to 12.2, p=0.02). Serum
concentrations of follicle stimulating hormone, luteinising hormone and progesterone were not
significantly affected by SJW. Breakthrough bleeding occurred in 17% (2/12 women) on COC alone
vs. 58% (7/12) women when on COC and SJW together [16]. Seventeen women who had received a
low dose oral contraceptive containing ethinylestradiol and desogestrel for one menstrual cycle,
randomly received either 300mg SJW twice daily (BD) or 300mg SJW three times daily (TDS) for one
cycle [17]. The groups were then crossed over. There was no significant change in follicle maturation,
From the NHS Evidence website www.evidence.nhs.uk
1
Medicines Q&As
serum estradiol or progesterone concentrations. More subjects reported intra-cyclic bleeding in the
SJW treatment groups, (77% and 88% in the BD and TDS groups; p<0.001 respectively versus 35%
in the COC alone group). The study authors concluded that there was no evidence of ovulation during
concomitant treatment with SJM, but intra-cyclic bleeding episodes increased which could affect
compliance and lead to unintended pregnancies [17].
In a non-randomised, single blind, sequential trial, 16 healthy women received a low dose COC,
containing ethinylestradiol and norethindrone acetate for 21 days and placebo for 7 days for 2
consecutive 28 day cycles. SJW 300mg three times daily was then taken concomitantly for 2
additional 28 day cycles. The Area under the Curve (AUC) decreased, resulting in a 13-15% reduction
in dose exposure to the oral contraceptives. Breakthrough bleeding occurred in more subjects during
the SJW treatment phase than during the control phase (56% vs. 31%; p=0.05). One patient was
thought to have ovulated during the control phase compared with 6 patients in the SJW cycle. The
study authors concluded that SJW is associated with increased metabolism of norethindrone and
ethinylestradiol, breakthrough bleeding, follicle growth and ovulation [18].
The recommendation of the CSM/MCA and the Faculty of Sexual and Reproductive Health Care
(FSRH) in the UK, is that women taking oral contraceptives (both combined and progestogen-only
pills) should either avoid St John's Wort or they should use an alternative form of contraception,
unaffected by enzyme inducers [e.g. progestogen only injectable, copper bearing intrauterine devices
(Cu-IUDs) or the levonorgestrel containing intrauterine device] [7, 8, 19-22].
Health professionals supplying hormonal contraception should ask women about their current and
previous drug use including prescription, over the counter, herbal, recreational drugs and dietary
supplements [19]. Women using hormonal contraception should be informed about the potential for
interactions with other drugs and the need to seek the advice of a health professional before starting
any new drugs [19].
The FSRH Clinical Effectiveness unit also recommends that, if St John's Wort must be continued, the
following general guidelines for the use of liver enzyme inducers with hormonal contraceptives should
be followed [19-22]:
 Women on short term treatment with SJW (defined arbitrarily as ≤2 months) may continue using
the combined patch, ring or standard strength combined pill, but they should be advised to use
additional contraceptive precautions (e.g. condoms) while taking SJW and for 28 days after
stopping [19].
 To minimise the risk of contraceptive failure the FSRH CEU recommends an extended regimen
(taking CHC continuously for ≥3 weeks until breakthrough bleeding occurs for 3-4 days) or
tricycling (taking 3 pill packets continuously without a break) and a shortened pill/patch or ring free
interval of 4 days. Only monophasic 21 day pill packs are suitable for extended use or tricycling
and the FSRH CEU recommends a minimum COC strength of 30µg EE [19].
 Women who do not wish to use additional contraception or women on long term treatment (>2
months) with an enzyme inducing drug who do not wish to change to another method may be
offered an increased dose of COC containing at least 50µg EE during treatment and for 28 days
after stopping [19].
 An extended or tricycling regimen with reduced pill free interval of 4 days is recommended but
additional contraception is not essential. If breakthrough bleeding occurs, and other causes such
as chlamydia are excluded, the dose of EE can be increased up to a maximum of 70µg, use
additional precautions or switch to a method unaffected by enzyme inducing drugs [19].
 The FRSH CEU also advised that the use of two COCs, extended/tricycling regimens and
shortening the pill free interval are all unlicensed and there is no evidence that such practice is
effective in women on SJW [19].
 There do not appear to have been any clinical pharmacokinetic studies of enzyme inducers,
including SJW, with any of the available oral progestogen only contraceptives [22]. There are
isolated reports of pregnancies in women given these contraceptives with SJW [15, 22]. The
progestogen only pill (POP) or implant may be affected by SJW. Alternative methods of
contraception should be used [19].
 Concomitant use of SJW with progestogen only injectables does not appear to necessitate
additional precautions, dose adjustment or alteration to the dosing /replacement interval [19].
From the NHS Evidence website www.evidence.nhs.uk
2
Medicines Q&As
 Women using a POP or implant with a short term course of SJW could be offered a one-off
injectable progestogen preparation [19].
Summary
 The interaction between oral contraceptives and St John's Wort appears to be established. Its
incidence is not known, but the limited poor quality evidence so far, suggests that breakthrough
bleeding may be a problem. Pregnancy resulting from this interaction has occurred but appears to
be uncommon and it is not known who is most at risk [20, 21].
 Health professionals supplying hormonal contraception should ask women about their current and
previous drug use including prescription, over the counter, herbal, recreational drugs and dietary
supplements [19].
 Women using hormonal contraception should be informed about the potential for interactions with
other drugs and the need to seek the advice of a health professional before starting any new drugs
including herbal of dietary supplements [19].
 The recommendation of the CSM/MCA and the Faculty of Sexual and Reproductive Health Care
(FSRH) in the UK, is that women taking oral contraceptives (both combined and progestogen-only
pills) should either avoid St John's Wort or they should use an alternative form of contraception,
unaffected by enzyme inducers [e.g. progestogen only injectable, copper bearing intrauterine
devices (Cu-IUDs) or the levonorgestrel containing intrauterine device] [7, 8, 19-22].
 If St John's Wort is continued, the general guidelines for the use of liver enzyme inducers with
hormonal contraceptives issued by the FSRH Clinical Effectiveness unit should be followed [1922].
Limitations
This document does not consider the effect of SJW on emergency hormonal contraceptives or on
hormonal contraceptives when used for non-contraceptive indications, such as acne or hirsutism.
References
1)
Jellin J, Gregory P, Batz F, Bonakdar R, editors. Natural Medicines Comprehensive Database. St
John’s Wort. Accessed 24/10/2011 via http://www.naturaldatabase.com.
2) Taylor D, Paton C, Kerwin R. The South London and Maudsley NHS Foundation Trust & Oxleas
NHS Foundation Trust Prescribing Guidelines. 10th ed. London: Informa Healthcare; 2007, p223224.
3) Will-Shahab L, Bauer S, Kunter U et al. St John’s Wort extract (Ze117) does not alter the
pharmacokinetics of a low dose oral contraceptive. European Journal of Clinical Pharmacology
2009; 65: 287-294.
4) Henderson L, Yue QY, Bergquist C et al. St John’s Wort (Hypericum perforatum): drug
interaction and clinical outcomes. British Journal of Clinical Pharmacology 2002; 54: 349-356.
5) Barnes J, Anderson LA et al. St John’s Wort (Hypericum perforatum L.): A review of its
chemistry, pharmacology and clinical properties. Journal of Pharmacy and Pharmacology 2001;
53: 583-600.
6) Mannel M. Drug interactions with St John’s Wort: Mechanisms and Clinical implications. Drug
Safety 2004; 27: 773-797.
7) Committee on Safety of Medicines (UK). Message from Professor. A. Breckenridge (Chairman of
CSM) and Factsheet for HealthCare Professionals. Important interactions between St John’s
Wort preparations and prescribed medicines. February 2000. Available at
http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con019564.pdf.
Accessed 17.10.2011.
8) Committee on Safety of Medicine. Reminder: St Johns Wort (Hypericum perforatum) interactions.
Current Problems in Pharmacovigilance May 2000; 26: 6.
9) Madabushi R, Frank B, Drewelow B et al. Hyperforin in St. John’s Wort drug interactions.
European Journal of Clinical Pharmacology 2006; 62: 225-233.
10) Martin J, editor. British National Formulary 62nd Ed. London: British Medical Association and The
Royal Pharmaceutical Society of Great Britain; 2011. Accessed 17/10/2011 via www.bnf.org.uk
11) Ernst E. Second thoughts about safety of St John’s Wort. Lancet 1999; 354: 2014-2015.
12) Izzo AA. Drug interactions with St John’s Wort (Hypericum perforatum): a review of the clinical
evidence. International Journal of Clinical Pharmacology and Therapeutics 2004; 139-148.
From the NHS Evidence website www.evidence.nhs.uk
3
Medicines Q&As
13) Yue QY, Bergquist C. Safety of St John’s Wort. Lancet 2000; 355: 576-577.
14) Schwarz UI, Buschel B, Kirch W et al. Unwanted pregnancy on self medication with St John’s
Wort despite hormonal contraception. British Journal of Clinical Pharmacology 2003; 55:112-113.
15) Medicines and Healthcare Products Regulatory Agency. Drug Analysis Prints. Hypericum
Accessed 15/10/09 via http://www.mhra.gov.uk/Onlineservices/Medicines/Druganalysisprints.
16) Hall SD, Wang Z, Huang, SM et al. The interaction between St John’s Wort and an oral
contraceptive. Clinical Pharmacology and Therapeutics 2003; 74: 525-535.
17) Pfrunder A, Schiesser M, Gerber S et al. Interaction of St John’s Wort with low dose oral
contraceptive therapy: a randomised controlled trial. British Journal of Clinical Pharmacology
2003; 56: 683-690.
18) Murphy PA, Kern SE, Stanczyk FZ et al. Interaction of St John’s Wort with oral contraceptives:
effects on the pharmacokinetics of norethindrone and ethinylestradiol, ovarian activity and
breakthrough bleeding. Contraception 2005; 71: 402-408
19) FSRH Clinical Effectiveness unit Clinical Guidance: Drug Interactions with Hormonal
Contraception. January 2011 (updated January 2012). Available at
http://www.fsrh.org/pdfs/CEUGuidanceDrugInteractionsHormonal.pdf. Accessed 02/02/2012.
20) Williamson E, Driver S, Baxter K, editors. Stockley’s Herbal Medicines Interactions. St John’s
Wort + Hormonal contraceptives. Revised 14/05/2009. Accessed 15/10/2009 via
www.medicinescomplete.com
21) Baxter K (ed). Stockley’s Drug Interactions online. Combined Hormonal Contraceptives + St
John’s wort (Hypericum perforatum). Accessed 03/11/2011 via www.medicinescomplete.com
22) Baxter K (ed). Stockley’s Drug Interactions online. Progestogen only contraceptives; oral +
enzyme inducers. Accessed 19/01/2012 via www.medicinescomplete.com
Quality Assurance
Prepared by
Victoria Gibson, East Anglia Medicines Information Service.
Date Prepared
5th January 2012
Checked by
Sarah Cavanagh, East Anglia Medicines Information Service
Date of check
2nd February 2012
Search strategy

Embase: St John’s Wort/Hypericum
Estrogen/Progestogen/Gestogen/contracep*/Contraception/Hormonal contraception.

Medline: St John’s Wort/Hypericum +
Estrogen/Progestogen/Gestogen/contracep*/Contraception/Hormonal contraception

IdisWeb: St John's wort/ hypericum + contracep*/estrogen/progesterone

Psychinfo database. St John’s Wort/Hypericum perforatum + contracep*/contraception/Birth
control/estrogen/progestogen/progesterone.

Biomed Central. St John’s wort/hypericum + contracep*/

Cochrane Library. Search term St John’s Wort

Natural Medicines Comprehensive Database: search term: hypericum or St Johns Wort

MHRA website, Nelm website, FDA website: search term. St Johns Wort and Hypericum

BNF, Maudsley Guidelines 10th Ed, Psychotropic drug directory 2010

Yellow card data Search term; Hypericum
From the NHS Evidence website www.evidence.nhs.uk
4