St John’s wort (Hypericum perforatum)
- November 1, 2018
| November 2018 |
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There is far less information about the effectiveness, safety and potential for interactions for complementary and alternative medicines (CAMs) compared to conventional medicines. There is no regulation of their quality or contents in New Zealand. Consider also other risks of CAMs, such as patients choosing them over conventional treatment, and the often substantial cost. Report any possible adverse effects or interactions to CARM: www.nzphvc.otago.ac.nz |
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What is it?St. John’s wort (SJW) is a flowering plant native to Europe, which grows well in New Zealand. It has yellow, star-shaped flowers with five petals (1). SJW contains at least 10 different components (2). Hypericin, pseudohypericin and hyperforin are the main active constituents and all have a half-life around 24 hours (1). There are no standardised preparations available in New Zealand. Plant extracts are not required to have the same quality control as medicines. |
What do people use it for?
In New Zealand, SJW is commonly marketed for mood, stress, tension, worry and irritability. Other promoted uses include menopausal symptoms, premenstrual syndrome and irritable bowel syndrome.
Does it work?
A number of trials have examined the efficacy of SJW in the treatment of depression (2). A Cochrane review concluded that SJW was more effective than placebo in the treatment of mild to moderate depression, and was as effective and better tolerated than standard antidepressants (e.g. tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)). However, efficacy in severe depression remains uncertain (3).
The mechanism of action for SJW’s antidepressant effect is unclear. A variety of mechanisms have been suggested including the inhibition of the reuptake of noradrenaline and serotonin (2,4,5).
For depression a dose of 300 mg three times daily has been used in studies (equating to 2.7 mg hypericin per day)(6). The antidepressant effects shoud be apparent after 4-6 weeks (5).
SJW is possibly effective for improving the vasomotor symptoms of menopause (1,4). It is inconclusive if SJW is effective for anxiety, fatigue, cognitive function, premenstrual syndrome and sleep quality (6). It is ineffective for attention deficit hyperactivity disorder and irritable bowel syndrome (1,4,6).
Is it safe?
Adverse effects include nausea, rash, fatigue, restlessness, insomnia, anxiety and photosensitivity. Like the SSRIs it may be associated with an increased risk of bleeding (1,2).
Should women who are pregnant or breastfeeding take it?
Pregnancy: Consider using an antidepressant with established safety data (e.g. SSRI or TCA). From the limited information available, the use of SJW during pregnancy has not been associated with an increased risk of congenital malformations. A small study has reported individual cases of hypospadias, bilateral hip dislocation and heart septum defects in infants exposed to SJW in utero. Two case reports have described healthy pregnancy and neonatal outcomes following maternal use of SJW (7).
Breastfeeding: Consider using an alternative agent. The data on the safety of SJW in breastfeeding are limited. The weight adjusted maternal dose (WAMD) is 0.9-2.5%. Minor adverse effects such as colic, drowsiness and lethargy have been reported in infants exposed to SJW via breast milk (7).
Does it interact with medicines?
Yes. SJW induces multiple CYP enzymes (CYP3A, 2C19, 2C9 & 1A2) and P-glycoprotein (P-gp) and has been associated with treatment failures due to decreased plasma concentrations of the interacting drugs (see table below). The time to full induction, or recovery from induction following SJW cessation, is approximately 2 weeks. P-glycoprotein substrates are often also CYP3A substrates (8,9).
Pharmacokinetic interactions
| Selected medicines | Elimination | Interaction with St John’s wort |
| Anticoagulants/antiplatelets
warfarin dabigatran etexilate rivaroxaban clopidogrel (prodrug) |
CYP2C8/9 P-gp CYP3A & P-gp CYP2C19 |
Induction of metabolism (CYP2C8/9), may ↓ INR. Induction of P-gp, may ↓[dabigatran] Induction of metabolism (CYP3A) & P-gp, may ↓ INR ↑metabolism to active moiety (CYP2C19), may ↑bleeding |
| Immunosuppressants
e.g. ciclosporin, tacrolimus everolimus, sirolimus |
CYP3A
P-gp |
Induction of metabolism (CYP3A), may ↓efficacy
Induction of P-gp, may ↓ efficacy Risk of transplant rejection |
| HIV protease inhibitors
e.g. indinavir, nelfinavir, nevirapine, ritonavir, saquinavir |
CYP3A
P-gp
|
Induction of metabolism (CYP3A), may ↓efficacy
Induction of P-gp, may ↓ efficacy Risk of HIV treatment failure |
| HIV non-nucleoside reverse transcriptase inhibitors
e.g. efavirenz, nevirapine |
CYP3A | Induction of metabolism (CYP3A), may ↓efficacy
Risk of HIV treatment failure |
| Anticonvulsants
e.g. carbamazepine phenytoin |
CYP3A CYP2C8/9 & 2C19 |
Induction of metabolism (CYP3A), may ↓[carbamazepine] Induction of metabolism (CYP2C8/9, 2C19), may↓[phenytoin] |
| Antiarrhythmics
calcium channel blockers amiodarone digoxin |
CYP3A CYP3A P-gp |
Induction of metabolism (CYP3A), may ↓ efficacy Induction of metabolism (CYP3A), may ↓ efficacy Induction of P-gp, may ↓ [digoxin] |
| Statins
e.g. atorvastatin, simvastatin |
CYP3A | Induction of metabolism (CYP3A), may ↓efficacy |
| Oral contraceptives
e.g. oestradiol, desogestrel, ethinylestradiol, norethisterone |
CYP3A | Induction of metabolism (CYP3A), may ↓ [contraceptive]
Risk of contraceptive failure Additional methods of contraception advised |
| Clozapine | CYP1A2 | Induction of metabolism (CYP1A2), may ↓ [clozapine] |
Abbreviations: ↓ decrease, ↑ increase, [x] concentration of x, INR International Normalised Ratio. This is not an exhaustive list. Stopping, starting and changing brands of SJW may all affect the plasma concentration of other medicines.
Pharmacodynamic interactions
Serotonergic effects: Additive serotonergic adverse effects may occur when SJW is taken in conjunction with other serotonergic medicines e.g. antidepressants, some analgesics (e.g. tramadol) and anti-migraine agents (e.g. sumatriptan, rizatriptan). Signs of serotonin toxicity include confusion, delirium, agitation, restlessness, sweating and tachycardia.
Photosensitising effects: St John’s wort is associated with photosensitivity, which can be additive with other photosensitising agents e.g. tetracyclines and cytotoxic drugs.
Switching
As a general rule of thumb a washout period of one week is reasonable when switching between a prescribed antidepressant and SJW and vice versa.
Key points
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References
- Natural Medicines [Internet]. [cited 2018 Oct 26]. Available from: https://naturalmedicines.therapeuticresearch.com/
- Taylor D, Barnes TE, Young A. The Maudsley Prescribing Guidelines in Psychiatry. 13th ed. Chichester (GB): John Wiley & Sons, Ltd; 2018.
- Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD000448.
- Stockley’s Herbal Medicines Interactions [Internet]. London: The Pharmaceutical Press; [cited 2018 Oct 26]. Available from: https://www.medicinescomplete.com/mc/shmi/current/index.htm
- Procyshyn RM, Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical Handbook of Psychotropic Drugs Online [Internet]. Toronto (ON): Hogrefe Publishing (US); [cited 2018 Oct 26]. Available from: https://chpd.hogrefe.com/main/index.html
- Micromedex® (electronic version) IBM [Internet]. Greenwood Village, Colorado, USA: IBM Watson Health; [cited 2018 Oct 26]. Available from: https://www.micromedexsolutions.com
- Loke YC, Vo-Tran H, Wong, editors. Pregnancy and Breastfeeding Medicines Guide [Internet]. Melbourne (AU): The Royal Women’s Hospital; [cited 2018 Oct 26]. Available from: https://thewomenspbmg.org.au/medicines
- UpToDate® [Internet]. Hudson (OH): Wolters Kluwer Clinical Drug Information Inc. (US); [cited 2018 Oct 26]. Available from: http://www.uptodate.com/
- The Pink Book [Internet]. Christchurch (NZ): Dept. of Clinical Pharmacology, Canterbury District Health Board; [cited 2018 Oct 26]. Available from: http://www.pinkbook.org.nz/index.htm
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