National Institute forPublic Health and the Environment Ministryof Health, Welfare and Sport Risk assessment of herbal preparations containing St John’s wort RIVM report 2019-0115 L. de Wit | S. Jeurissen | W. Chen Risk assessment of herbal preparations containing St John's wort RIVM report 2019-0115 RIVM report 2019-0115 Colophon © RIVM 2021 Parts of this publication may be reproduced, provided acknowledgement is given to the: National Institute for Public Health and the Environment, and the title and year of publication are cited. DOI 10.21945/RIVM-2019-0115 L. de Wit (author), RIVM S. Jeurissen (author), RIVM W. Chen (author), RIVM Contact: Lianne de Wit Voeding, Preventie en Zorg\Voedselveiligheid [email protected] This investigation was performed by order, and for the account, of Ministry of Health, Welfare and Sport, within the framework of project 5.1.15. Published by: National Institute for Public Health and the Environment, RIVM P.O. Box 1 | 3720 BA Bilthoven The Netherlands www.rivm.nl/en Page 2 of 148 RIVM report 2019-0115 Synopsis Risk assessment of herbal preparations containing St John's wort People use herbal preparations (food supplements and herbal tea) with St John’s wort, amongst others to feel and sleep better. However, these herbal preparations can reduce the effect of medicines, or enhance their effect. These interactions can have serious health effects. Herbal preparations with St John’s wort, for example, reduce the effect of certain medicines prescribed for fungal or viral infections and for cancer (chemotherapy). The effect of certain consciousness-lowering agents, e.g. sedative medicines, and consciousness-stimulating agents, e.g. antidepressants, is actually enhanced. The use of herbal preparations with St John’s wort may also pose health risks when used alone and not in combination with medicines. For example, the skin can be damaged faster (sunburn) if people sit in the sun after using St John’s wort. Other effects such as dizziness, diarrhea and anxiety have also been reported after the use of herbal preparations containing St. John's wort. It is not known what effects occur after people use these herbal preparations for a long time. There is also insufficient information available to determine whether the use of St John’s wort during pregnancy is safe for the unborn child. Moreover, the composition of herbal preparations containing St John’s wort can vary greatly, and it is often not known what exactly is in it. This makes it difficult to estimate the effects of a product. RIVM draws these conclusions based on a risk assessment on behalf of the Ministry of Health, Welfare and Sport (VWS). RIVM advises consumers to be cautious with the use of herbal preparations containing St John’s wort, and to not use these products in combination with medicines. RIVM advises VWS to draft legislation on the use of St John’s wort in herbal preparations. Keywords: Hypericum perforatum, dietary supplement, botanical, hypericin, hyperforin, herbal preparation Page 3 of 148 RIVM report 2019-0115 Page 4 of 148 RIVM report 2019-0115 Publiekssamenvatting Risicobeoordeling van kruidenpreparaten met sint-janskruid Mensen gebruiken kruidenpreparaten (voedingssupplementen en kruidenthee) met sint-janskruid onder andere om zich beter te voelen en beter te kunnen slapen. Maar deze kruidenpreparaten kunnen de werking van geneesmiddelen verminderen, of juist versterken. Deze wisselwerkingen kunnen ernstige gezondheidseffecten hebben. Kruidenpreparaten met sint-janskruid verminderen bijvoorbeeld de werking van middelen die worden voorgeschreven bij schimmel- of virusinfecties en bij chemotherapie. De werking van bepaalde bewustzijns-verlagende geneesmiddelen, zoals kalmeringsmiddelen, en bewustzijns-stimulerende middelen, bijvoorbeeld antidepressiva, wordt versterkt. Ook zonder de combinatie met geneesmiddelen kan het gebruik van kruidenpreparaten met sint-janskruid schadelijk zijn voor de gezondheid. Zo kan de huid sneller beschadigd raken (zonnebrand) als mensen na het gebruik van sint-janskruid in de zon gaan zitten. Ook worden andere effecten zoals duizeligheid, diarree en angst gemeld na het gebruik van kruidenpreparaten met sint-janskruid. Het is niet bekend welke effecten optreden als mensen deze kruidenpreparaten lang gebruiken. Ook is er onvoldoende informatie om te bepalen of het gebruik van sint-janskruid tijdens de zwangerschap veilig is voor het ongeboren kind. Bovendien verschilt de samenstelling van kruidenpreparaten met sint-janskruid sterk en is vaak niet bekend wat er precies in zit. Dit maakt het moeilijk om de effecten van een product in te schatten. Deze conclusies trekt het RIVM op basis van een risicobeoordeling, in opdracht van VWS. Het RIVM adviseert consumenten om voorzichtig te zijn met het gebruik van kruidenpreparaten met sint-janskruid omdat deze schadelijk kunnen zijn voor de gezondheid. Daarom raadt het RIVM VWS aan om regelgeving over het gebruik van sint-janskruid in kruidenpreparaten op te stellen. Kernwoorden: Hypericum perforatum, voedingssupplement, kruidenpreparaat, hypericine, hyperforine Page 5 of 148 RIVM report 2019-0115 Page 6 of 148 RIVM report 2019-0115 Contents Summary — 9 1 Introduction — 15 1.1 Background — 15 1.2 Information on existing assessments — 15 Scientific Committee on Food — 15 European Medicines Agency — 16 RIVM — 17 1.3 Information on existing legislation — 17 1.4 Reading guide — 18 2 Methodology — 19 3 Identification and characterization — 21 3.1 Identity and nature of the source material — 21 3.2 Manufacturing process — 21 3.3 Chemical composition — 22 3.4 Stability — 25 3.5 Uses and use levels — 25 4 Exposure: extent and duration — 29 4.1 Exposure from food supplements — 29 4.2 Possibility of additional human exposure — 29 5 Biological data — 31 5.1 Introduction — 31 5.2 Toxicokinetics — 31 Absorption — 31 Distribution — 42 Biotransformation — 44 Excretion — 45 Effects on enzymes — 48 Summary on toxicokinetics — 50 5.3 Toxicological studies — 51 Acute toxicity — 51 Short-term and sub-chronic toxicity — 54 Genotoxicity — 56 Chronic toxicity and carcinogenicity — 64 Reproductive and developmental toxicity — 64 Phototoxicity — 70 Human information — 76 Interactions — 81 Summary on toxicological information — 82 5.4 Derivation of toxicological reference value — 85 6 Risk assessment — 87 6.1 Risk assessment — 87 6.2 Sensitive/vulnerable groups — 88 6.3 Uncertainties — 88 Exposure — 88 Page 7 of 148 RIVM report 2019-0115 Toxicity — 88 7 Conclusion and recommendations — 89 Acknowledgements — 91 References — 93 Annex 1 Search strategy St John’s wort — 105 Annex 2 Intake assessment of St John’s wort via plant food supplements — 107 Annex 3 Case studies — 112 Annex 4 Clinical trials — 126 Page 8 of 148 RIVM report 2019-0115 Summary Introduction St John’s wort (Hypericum perforatum L.) is used in food supplements and herbal teas (herbal preparations) that are marketed as mood enhancers and sleep aids, among other things. Hypericin, pseudohypericin and hyperforin are generally thought to be the most relevant constituents for the pharmacological effects of St John’s wort (Linde, 2009). St John’s wort can cause interactions with several prescribed medicines, as described in a previous RIVM report (Tiesjema et al., 2013). These interactions can have serious health effects. Herbal preparations with St John’s wort, for example, reduce the effect of some medicines prescribed for fungal or viral infections and for cancer (chemotherapy). They also reduce the effect of several medicines that suppress the immune system, and are used with tissue transplants. The effect of certain antidepressants (selective serotonin reuptake inhibitors, SSRIs) may be enhanced, which could result in serotonin syndrome. Other aspects of the safety of herbal preparations containing St John’s wort were not addressed in that report. Currently, there are no specific restrictions for the use of St John’s wort in herbal preparations included in the Herbal Preparations Decree of the Dutch Commodities Act. However, a warning on all products containing St John’s wort about possible interactions with medicines will be made a legal requirement.1 The Ministry of Health, Welfare and Sport (VWS) asked RIVM to perform a risk assessment on the safety of herbal preparations containing St John’s wort to investigate whether other restrictions on the use of St John’s wort in herbal preparations are needed besides warning phrases about interactions with medicines. Use of St John’s wort as a herbal medicine St John’s wort is also used in registered herbal medicines to treat mild to moderate depression (Dutch Medicines Evaluation Board (MEB), 2020). Two medicinal products containing St John’s wort are registered in the Netherlands (reference date July 2020). However, only one is still available on the market and can be bought over the counter in pharmacies. This medicinal product has a recommended daily dose of 132 mg dried ethanol (68% v/v) extract, equivalent to 850 – 2600 mg fresh plant. Assuming that the extract contains 0.1 – 0.3% hypericins, this is equivalent to a daily dose of approximately 0.13 – 0.40 mg hypericins per day. In addition, 30 homeopathic products containing St. John’s wort are registered in the Netherlands. Of the homeopathic medicines, 7 contain H. perforatum L. as the only active ingredient and the others contain one or more other active ingredients in addition to St. John’s wort (MEB, 2020). St John’s wort products currently have a dual 1 https://www.rijksoverheid.nl/documenten/kamerstukken/2018/02/12/beantwoording-kamervragen-over-de-