Medicinal Plants for the Treatment of Mental Diseases in Pregnancy: An In Vitro Safety Assessment

Abstract

Pregnancy is a critical period for medical care, during which the well-being of woman and fetus must be considered. This is particularly relevant in managing non-psychotic mental disorders since treatment with central nervous system-active drugs and untreated NMDs may have negative effects. Some well-known herbal preparations (phytopharmaceuticals), including St. Johnʼs wort, California poppy, valerian, lavender, and hops, possess antidepressant, sedative, anxiolytic, or antidepressant properties and could be used to treat mental diseases such as depression, restlessness, and anxiety in pregnancy. Our goal was to assess their safety in vitro, focusing on cytotoxicity, induction of apoptosis, genotoxicity, and effects on metabolic properties and differentiation in cells widely used as a placental cell model (BeWo b30 placenta choriocarcinoma cells). The lavender essential oil was inconspicuous in all experiments and showed no detrimental effects. At low-to-high concentrations, no extract markedly affected the chosen safety parameters. At an artificially high concentration of 100 µg/mL, extracts from St. Johnʼs wort, California poppy, valerian, and hops had minimal cytotoxic effects. None of the extracts resulted in genotoxic effects or altered glucose consumption or lactate production, nor did they induce or inhibit BeWo b30 cell differentiation. This study suggests that all tested preparations from St. Johnʼs wort, California poppy, valerian, lavender, and hops, in concentrations up to 30 µg/mL, do not possess any cytotoxic or genotoxic potential and do not compromise placental cell viability, metabolic activity, and differentiation. Empirical and clinical studies during pregnancy are needed to support these in vitro data.

Key words

non-psychotic mental disorders - pregnancy - BeWo cell line - toxicity - Hypericum perforatum - Hypericaceae - Eschscholzia californica - Papaveraceae - Valeriana officinalis - Caprifoliaceae - Lavandula angustifolia - Lamiaceae - Humulus lupulus - Cannabaceae

• References

• 1 Berger A, Bachmann N, Signorell A, Erdin R, Oelhafen S, Reich O, Cignacco E. Perinatal mental disorders in Switzerland: prevalence estimates and use of mental-health services. Swiss Med Wkly 2017; 147: w14417
• 2 Chisolm MS, Payne JL. Management of psychotropic drugs during pregnancy. BMJ 2015; 351: h5918
• 3 Stewart D, Vigod S. Antenatal use of antidepressants and risk of teratogenicity and adverse pregnancy outcomes: selective serotonin reuptake inhibitors (SSRIs). (October 9, 2020). Accessed February 11, 2021 at: https://www.uptodate.com/contents/antenatal-use-of-antidepressants-and-risk-of-teratogenicity-and-adverse-pregnancy-outcomes-selective-serotonin-reuptake-inhibitors-ssris
• 4 Molenaar NM, Kamperman AM, Boyce P, Bergink V. Guidelines on treatment of perinatal depression with antidepressants: an international review. Aust N Z J Psychiatry 2018; 52: 320-327
• 5 Hanley GE, Oberlander TF. The effect of perinatal exposures on the infant: antidepressants and depression. Best Pract Res Clin Obstet Gynaecol 2014; 28: 37-48
• 6 Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry 2010; 67: 1012-1024
• 7 Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiat Serv 2002; 53: 39-49
• 8 Salter S, Brownie S. Treating primary insomnia: the efficacy of valerian and hops. Aust Fam Physician 2010; 39: 433-437
• 9 Dimpfel W, Suter A. Sleep improving effects of a single dose administration of a valerian/hops fluid extract. A double-blind, randomized, placebo-controlled sleep-EEG study in a parallel design using electrohypnograms. Eur J Med Res 2008; 13: 1-5
• 10 Zanoli P, Zavatti M. Pharmacognostic and pharmacological profile of Humulus lupulus L. J Ethnopharmacol 2008; 116: 383-396
• 11 Hattesohl M, Feistel B, Sievers H, Lehnfeld R, Hegger M, Winterhoff H. Extracts of Valeriana officinalis L. s.l. show anxiolytic and antidepressant effects but neither sedative nor myorelaxant properties. Phytomedicine 2008; 15: 2-15
• 12 Holst L, Nordeng H, Haavik S. Use of herbal drugs during early pregnancy in relation to maternal characteristics and pregnancy outcome. Pharmacoepidemiol Drug Saf 2008; 17: 151-159
• 13 Kennedy DA, Lupattelli A, Koren G, Nordeng H. Herbal medicine use in pregnancy: results of a multinational study. BMC Complem Altern M 2013; 13: 355
• 14 Trabace L, Tucci P, Ciuffreda L, Matteo M, Fortunato F, Campolongo P, Trezza V, Cuomo V. “Natural” relief of pregnancy-related symptoms and neonatal outcomes: above all do no harm. J Ethnopharmacol 2015; 174: 396-402
• 15 Schilcher H, Kammerer S, Wegener T. Leitfaden Phytotherapie. München: Urban & Fischer; 2016
• 16 Donelli D, Antonelli M, Bellinazzi C, Gensini GF, Firenzuoli F. Effects of lavender on anxiety: a systematic review and meta-analysis. Phytomedicine 2019; 65: 153099
• 17 Woelk H, Schläfke S. A multi-center, double-blind, randomised study of the Lavender oil preparation Silexan in comparison to Lorazepam for generalized anxiety disorder. Phytomedicine 2010; 17: 94-99
• 18 Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Schläfke S, Dienel A. Lavender oil preparation Silexan is effective in generalized anxiety disorder–a randomized, double-blind comparison to placebo and paroxetine. Int J Neuropsychopharmacol 2014; 17: 859-869
• 19 European Medicines Agency. EMA/HMPC/680372/2013 – European Union herbal monograph on Eschscholzia californica Cham., herba. (January 28, 2015). Accessed June 2, 2021 at: https://www.ema.europa.eu/en/documents/herbal-monograph/final-european-union-herbal-monograph-eschscholzia-californica-cham-herba_en.pdf
• 20 European Medicines Agency. EMA/HMPC/680375/2013–Assessment report on Eschscholzia californica Cham., herba. (January 28, 2015). Accessed June 2, 2021 at: https://www.ema.europa.eu/en/documents/herbal-report/final-assessment-report-eschscholzia-californica-cham-herba_en.pdf
• 21 Rolland A, Fleurentin J, Lanhers MC, Younos C, Misslin R, Mortier F, Pelt JM. Behavioural effects of the American traditional plant Eschscholzia californica: sedative and anxiolytic properties. Planta Med 1991; 57: 212-216
• 22 Rolland A, Fleurentin J, Lanhers M, Misslin R, Mortier F. Neurophysiological effects of an extract of Eschscholzia californica Cham. (Papaveraceae). Phytother Res 2001; 15: 377-381
• 23 Fedurco M, Gregorová J, Šebrlová K, Kantorová J, Peš O, Baur R, Sigel E, Táborská E. Modulatory effects of Eschscholzia californica alkaloids on recombinant GABA_A receptors. Biochem Res Int 2015; 2015: 617620
• 24 Dingermann T, Loew D. Phytopharmakologie: experimentelle und klinische Pharmakologie pflanzlicher Arzneimittel. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH; 2003
• 25 Cui YH, Zheng Y. A meta-analysis on the efficacy and safety of St Johnʼs wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults. Neuropsychiatr Dis Treat 2016; 12: 1715-1723
• 26 Nicolussi S, Drewe J, Butterweck V, Meyer zu Schwabedissen HE. Clinical relevance of St. Johnʼs wort drug interactions revisited. Br J Pharmacol 2020; 177: 1212-1226
• 27 Kolding L, Pedersen LH, Henriksen TB, Olsen J, Grzeskowiak LE. Hypericum perforatum use during pregnancy and pregnancy outcome. Reprod Toxicol 2015; 58: 234-237
• 28 Moretti ME, Maxson A, Hanna F, Koren G. Evaluating the safety of St. Johnʼs Wort in human pregnancy. Reprod Toxicol 2009; 28: 96-99
• 29 Stewart D, Pallivalappila A, Shetty A, Pande B, McLay J. Healthcare professional views and experiences of complementary and alternative therapies in obstetric practice in North East Scotland: a prospective questionnaire survey. BJOG 2014; 121: 1015-1019
• 30 Pallivalappila AR, Stewart D, Shetty A, Pande B, McLay JS. Complementary and alternative medicines use during pregnancy: A systematic review of pregnant women and healthcare professional views and experiences. Evid Based Complement Alternat Med 2013; 2013: 1-10
• 31 Petersen I, McCrea RL, Lupattelli A, Nordeng H. Womenʼs perception of risks of adverse fetal pregnancy outcomes: A large-scale multinational survey. BMJ Open 2015; 5: e007390
• 32 European Medicines Agency. EMA/HMPC/682384/2013–Community herbal monograph on Humulus lupulus L., flos. (May 6, 2014). Accessed June 2, 2021 at: https://www.ema.europa.eu/en/documents/herbal-monograph/final-community-herbal-monograph-humulus-lupulus-l-flos_en.pdf
• 33 European Medicines Agency. EMA/HMPC/150848/2015–European Union herbal monograph on Valeriana officinalis L., radix. (February 2, 2016). Accessed June 2, 2021 at: https://www.ema.europa.eu/en/documents/herbal-monograph/final-european-union-herbal-monograph-valeriana-officinalis-l-radix_en.pdf
• 34 European Medicines Agency. EMA/HMPC/143181/2010–Community herbal monograph on Lavandula angustifolia Miller, aetheroleum. (March 27, 2012). Accessed June 2, 2021 at: https://www.ema.europa.eu/en/documents/herbal-monograph/final-community-herbal-monograph-lavandula-angustifolia-miller-aetheroleum_en.pdf
• 35 European Medicines Agency. EMA/HMPC/101304/2008–Community herbal monograph on Hypericum perforatum L., herba (well-established medicinal use). (November 12, 2009). Accessed June 2, 2021 at: https://www.ema.europa.eu/en/documents/herbal-monograph/final-community-herbal-monograph-hypericum-perforatum-l-herba-well-established-medicinal-use_en.pdf
• 36 Spiess D, Abegg VF, Chauveau A, Treyer A, Reinehr M, Oufir M, Duong E, Potterat O, Hamburger M, Simões-Wüst AP. Placental passage of humulone and protopine in an ex vivo human perfusion system. Planta Med 2021;
• 37 Orendi K, Gauster M, Moser G, Meiri H, Huppertz B. The choriocarcinoma cell line BeWo: Syncytial fusion and expression of syncytium-specific proteins. Reproduction 2010; 140: 759-766
• 38 Medicinal product information search platform (AIPS). Accessed April 9, 2021 at: https://www.swissmedicinfo.ch
• 39 Swiss Federal Statistical Office. Durchschnittliches Körpergewicht (in kg). (February 28, 2019). Accessed February 11, 2021 at: https://www.bfs.admin.ch/bfs/de/home/statistiken/gesundheit.assetdetail.7586025.html
• 40 Da Conceicao AO, Takser L, Lafond J. Effect of St. Johnʼs wort standardized extract and hypericin on in vitro placental calcium transport. J Med Food 2010; 13: 934-942
• 41 Nakamura K, Aizawa K, Yamauchi J, Tanoue A. Hyperforin inhibits cell proliferation and differentiation in mouse embryonic stem cells. Cell Prolif 2013; 46: 529-537
• 42 Schäfer AM, Potterat O, Seibert I, Fertig O, Meyer zu Schwabedissen HE. Hyperforin-induced activation of the pregnane X receptor is influenced by the organic anion-transporting polypeptide 2B1. Mol Pharmacol 2019; 95: 313-323
• 43 Hui-Lian W, Dong-Fang Z, Zhao-Feng L, Yang L, Qian-Rong L, Yu-Zhen W. In vitro study on the genotoxicity of dichloromethane extracts of valerian (DEV) in human endothelial ECV304 cells and the effect of vitamins E and C in attenuating the DEV-induced DNA damages. Toxicol Appl Pharmacol 2003; 188: 36-41
• 44 Al-Majed AA, Al-Yahya AA, Al-Bekairi A, Al-Shabanah O, Qureshi S. Studies on the cytological and biochemical effects of valerian in somatic and germ cells of Swiss albino mice. Food Chem Toxicol 2006; 44: 1830-1837
• 45 Miranda C, Stevens J, Helmrich A, Henderson M, Rodriguez R, Yang YH, Deinzer M, Barnes D, Buhler D. Antiproliferative and cytotoxic effects of prenylated flavonoids from hops (Humulus lupulus) in human cancer cell lines. Food Chem Toxicol 1999; 37: 271-285