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.

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The placental passage of humulone and protopine was investigated with a human ex vivo placental perfusion model. The model was first validated with diazepam and citalopram, 2 compounds known to cross the placental barrier, and antipyrine as a positive control. All compounds were quantified by partially validated U(H)PLC-MS/MS bioanalytical methods. Only a small portion of humulone initially present in the maternal circuit reached the fetal circuit. The humulone concentration in the maternal circuit rapidly decreased, likely due to metabolization in the placenta. Protopine was transferred from the maternal to the fetal circuit, with a steady-state reached after 90 min. None of the study compounds affected placental viability or functionality, as glucose consumption, lactate production, beta-human chorionic gonadotropin, and leptin release remained constant. Histopathological evaluation of all placental specimens showed unremarkable, age-appropriate parenchymal maturation with no pathologic findings.

Nonpsychotic mental diseases (NMDs) affect approximately 15% of pregnant women in the US. Herbal preparations are perceived a safe alternative to placenta-crossing antidepressants or benzodiazepines in the treatment of nonpsychotic mental diseases. But are these drugs really safe for mother and foetus? This question is of great relevance to physicians and patients. Therefore, this study investigates the influence of St. John’s wort, valerian, hops, lavender, and California poppy and their compounds hyperforin and hypericin, protopine, valerenic acid, and valtrate, as well as linalool, on immune modulating effects in vitro. For this purpose a variety of methods was applied to assess the effects on viability and function of human primary lymphocytes. Viability was assessed via spectrometric assessment, flow cytometric detection of cell death markers and comet assay for possible genotoxicity. Functional assessment was conducted via flow cytometric assessment of proliferation, cell cycle and immunophenotyping. For California poppy, lavender, hops, and the compounds protopine and linalool, and valerenic acid, no effect was found on the viability, proliferation, and function of primary human lymphocytes. However, St. John’s wort and valerian inhibited the proliferation of primary human lymphocytes. Hyperforin, hypericin, and valtrate inhibited viability, induced apoptosis, and inhibited cell division. Calculated maximum concentration of compounds in the body fluid, as well as calculated concentrations based on pharmacokinetic data from the literature, were low and supported that the observed effects in vitro would probably have no relevance on patients. In-silico analyses comparing the structure of studied substances with the structure of relevant control substances and known immunosuppressants revealed structural similarities of hyperforin and valerenic acid to the glucocorticoids. Valtrate showed structural similarities to the T cells signaling modulating drugs.

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John’s wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John’s wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin – but not to valerenic acid – is likely to be minimal.

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