{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:08:47Z","timestamp":1789834127806,"version":"4.0.1"},"reference-count":127,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Depression is a multifactorial disorder shaped by genetic, psychosocial, and biological influences, with hypotheses ranging from monoamine deficiency and neuroplasticity deficits to inflammation and stress-induced dysregulation. St. John\u2019s wort (Hypericum perforatum L.) has long been used as an herbal antidepressant and is supported by clinical evidence for efficacy and safety in mild-to-moderate depression. While its multimodal mechanisms have been linked to neurotransmitter reuptake inhibition, neuroendocrine regulation, and modulation of neuroplasticity, recent findings suggest an additional role at the membrane level. Emerging lipidomic studies highlight that Ze 117, a low-hyperforin H. perforatum extract, counteracts stress- and glucocorticoid-induced increases in membrane fluidity by modulating lipid composition and cholesterol metabolism. These effects normalize receptor mobility and signal transduction, particularly of \u03b21-adrenoceptors, and modulate glycerophospholipid metabolism in both cellular and animal models. Such membrane-stabilizing properties may represent a novel mechanistic pathway complementing classical neurochemical actions. This review revisits the mechanisms of St. John\u2019s wort with a special focus on its impact on membrane lipids, positioning lipidomics as a promising tool for elucidating antidepressant activity. These insights may open avenues toward personalized therapeutic strategies in depression.<\/jats:p>","DOI":"10.3390\/ijms262411925","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T16:11:18Z","timestamp":1765383078000},"page":"11925","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["St. John\u2019s Wort for Depression: From Neurotransmitters to Membrane Plasticity"],"prefix":"10.3390","volume":"26","author":[{"given":"Verena M.","family":"Merk","sequence":"first","affiliation":[{"name":"Medical Department, Max Zeller S\u00f6hne AG, 8590 Romanshorn, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Boonen","sequence":"additional","affiliation":[{"name":"Medical Department, Max Zeller S\u00f6hne AG, 8590 Romanshorn, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7516-8789","authenticated-orcid":false,"given":"Veronika","family":"Butterweck","sequence":"additional","affiliation":[{"name":"Medical Department, Max Zeller S\u00f6hne AG, 8590 Romanshorn, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ajp.2017.01.025","article-title":"The Neurobiology of Depression: An Integrated View","volume":"27","author":"Dean","year":"2017","journal-title":"Asian J. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41392-024-01738-y","article-title":"Major Depressive Disorder: Hypothesis, Mechanism, Prevention and Treatment","volume":"9","author":"Cui","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Filatova, E.V., Shadrina, M.I., and Slominsky, P.A. (2021). Major Depression: One Brain, One Disease, One Set of Intertwined Processes. Cells, 10.","DOI":"10.3390\/cells10061283"},{"key":"ref_4","unstructured":"Freud, S. (1917). Mourning and Melancholia. The Standard Edition of the Complete Psychological Works of Sigmund Freud, Volume Xiv (1914\u20131916): On the History of the Psycho-Analytic Movement, Papers on Metapsychology and Other Works, The Hogarth Press."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1176\/appi.ajp.2008.08050721","article-title":"The Evolution of the Cognitive Model of Depression and Its Neurobiological Correlates","volume":"165","author":"Beck","year":"2008","journal-title":"Am. J. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/0272-7358(82)90013-7","article-title":"Psychosocial Theory and Research on Depression: An Integrative Framework and Review","volume":"2","author":"Billings","year":"1982","journal-title":"Clin. Psychol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1176\/appi.ajp.157.10.1552","article-title":"Genetic Epidemiology of Major Depression: Review and Meta-Analysis","volume":"157","author":"Sullivan","year":"2000","journal-title":"Am. Psychiatr. Publ."},{"key":"ref_8","first-page":"4","article-title":"History and Evolution of the Monoamine Hypothesis of Depression","volume":"61","author":"Hirschfeld","year":"2000","journal-title":"J. Clin. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pastis, I.M., Santos, G., and Paruchuri, A. (2023). Exploring the Role of Inflammation in Major Depressive Disorder: Beyond the Monoamine Hypothesis. Front. Behav. Neurosci., 17.","DOI":"10.3389\/fnbeh.2023.1282242"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/hup.288","article-title":"Expanding the Horizons of Depression: Beyond the Monoamine Hypothesis","volume":"16","author":"Hindmarch","year":"2001","journal-title":"Hum. Psychopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1038\/s41380-022-01520-y","article-title":"Dysregulation of Adult Hippocampal Neuroplasticity in Major Depression: Pathogenesis and Therapeutic Implications","volume":"27","author":"Tartt","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.bbi.2024.08.048","article-title":"The Inflammatory Underpinning of Depression: An Historical Perspective","volume":"122","author":"Yirmiya","year":"2024","journal-title":"Brain Behav. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.neubiorev.2018.09.006","article-title":"The Role of Inflammation in Core Features of Depression: Insights from Paradigms Using Exogenously-Induced Inflammation","volume":"94","author":"Dooley","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1176\/appi.ajp.2015.15020152","article-title":"Inflammation: Depression Fans the Flames and Feasts on the Heat","volume":"172","author":"Derry","year":"2015","journal-title":"Am. J. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nri.2015.5","article-title":"The Role of Inflammation in Depression: From Evolutionary Imperative to Modern Treatment Target","volume":"16","author":"Miller","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41574-019-0228-0","article-title":"The Human Stress Response","volume":"15","author":"Russell","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ortega, V.A., Mercer, E.M., Giesbrecht, G.F., and Arrieta, M.C. (2021). Evolutionary Significance of the Neuroendocrine Stress Axis on Vertebrate Immunity and the Influence of the Microbiome on Early-Life Stress Regulation and Health Outcomes. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.634539"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.tins.2008.06.006","article-title":"The Hpa Axis in Major Depression: Classical Theories and New Developments","volume":"31","author":"Pariante","year":"2008","journal-title":"Trends Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"808643","DOI":"10.1155\/2014\/808643","article-title":"Environmental Control of Adult Neurogenesis: From Hippocampal Homeostasis to Behavior and Disease","volume":"2014","author":"Kuipers","year":"2014","journal-title":"Neural Plast."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s10567-011-0084-5","article-title":"In Search of Hpa Axis Dysregulation in Child and Adolescent Depression","volume":"14","author":"Guerry","year":"2011","journal-title":"Clin. Child. Fam. Psychol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1111\/j.1365-2826.2010.02000.x","article-title":"Nongenomic Actions of Adrenal Steroids in the Central Nervous System","volume":"22","author":"Evanson","year":"2010","journal-title":"J. Neuroendocr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/nsmb.1844","article-title":"Molecular Mechanisms in Signal Transduction at the Membrane","volume":"17","author":"Groves","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nandam, L.S., Brazel, M., Zhou, M., and Jhaveri, D.J. (2019). Cortisol and Major Depressive Disorder-Translating Findings from Humans to Animal Models and Back. Front. Psychiatry, 10.","DOI":"10.3389\/fpsyt.2019.00974"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2014.04.042","article-title":"Alterations in Phospholipidomic Profile in the Brain of Mouse Model of Depression Induced by Chronic Unpredictable Stress","volume":"273","author":"Faria","year":"2014","journal-title":"Neuroscience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1002\/bies.201500070","article-title":"Lipids under Stress\u2014A Lipidomic Approach for the Study of Mood Disorders","volume":"37","author":"Miranda","year":"2015","journal-title":"Bioessays"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100252","DOI":"10.1016\/j.ynstr.2020.100252","article-title":"Neurobiological Effects of Phospholipids in Vitro: Relevance to Stress-Related Disorders","volume":"13","author":"Donoso","year":"2020","journal-title":"Neurobiol. Stress"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, X., and Michaelis, E.K. (2010). Selective Neuronal Vulnerability to Oxidative Stress in the Brain. Front. Aging Neurosci., 2.","DOI":"10.3389\/fnagi.2010.00012"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s41577-021-00618-8","article-title":"Innate Immune Detection of Lipid Oxidation as a Threat Assessment Strategy","volume":"22","author":"Zhivaki","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1038\/s41386-018-0133-6","article-title":"Regulation of Monoamine Transporters and Receptors by Lipid Microdomains: Implications for Depression","volume":"43","author":"Liu","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Blaschek, W. (2015). Wichtl\u2014Teedrogen Und Phytopharmaka, Wissenschaftliche Verlagsgesellschaft.","DOI":"10.52778\/9783804735217"},{"key":"ref_31","unstructured":"Hildebrandt, R., and Gloning, T. (2010). Hildegard Von Bingen: Physica. Liber Subtilitatum Diversarum Naturarum Creaturarum; Textkritische Ausgabe. 2 Bde, De Gruyter."},{"key":"ref_32","unstructured":"Keil, G. (1989). Das Lorscher Arzneibuch; (Handschrift Msc. Med. 1 der Staatsbibliothek Bamberg); Band 2: \u00dcbersetzung von Ulrich Stoll und Gundolf Keil Unter Mitwirkung von Altabt Albert Ohlmeyer, Wissenschaftliche Verlagsgesellschaft."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/s10354-007-0440-8","article-title":"St. John\u2019s Wort: Role of Active Compounds for Its Mechanism of Action and Efficacy","volume":"157","author":"Butterweck","year":"2007","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_34","first-page":"CD000448","article-title":"St John\u2019s Wort for Major Depression","volume":"2008","author":"Linde","year":"2008","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.euroneuro.2010.07.005","article-title":"Efficacy and Tolerability of Hypericum Extract for the Treatment of Mild to Moderate Depression","volume":"20","author":"Kasper","year":"2010","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1046\/j.1365-2125.2003.01716.x","article-title":"Unwanted Pregnancy on Self-Medication with St John\u2019s Wort Despite Hormonal Contraception","volume":"55","author":"Schwarz","year":"2003","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/S0140-6736(05)73227-X","article-title":"Safety of St John\u2019s Wort (Hypericum perforatum)","volume":"355","author":"Yue","year":"2000","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1053\/cp.1999.v66.a101944","article-title":"Pharmacokinetic Interaction of Digoxin with an Herbal Extract from St John\u2019s Wort (Hypericum perforatum)","volume":"66","author":"Johne","year":"1999","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1111\/bph.14936","article-title":"Clinical Relevance of St. John\u2019s Wort Drug Interactions Revisited","volume":"177","author":"Nicolussi","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_40","first-page":"391","article-title":"The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects","volume":"76","author":"Lynch","year":"2007","journal-title":"Am. Fam. Physician"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7500","DOI":"10.1073\/pnas.130155097","article-title":"St. John\u2019s Wort Induces Hepatic Drug Metabolism through Activation of the Pregnane X Receptor","volume":"97","author":"Moore","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/cpt.1392","article-title":"No Clinically Relevant Interactions of St. John\u2019s Wort Extract Ze 117 Low in Hyperforin with Cytochrome P450 Enzymes and P-Glycoprotein","volume":"106","author":"Zahner","year":"2019","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00228-008-0587-2","article-title":"St John\u2019s Wort Extract (Ze 117) Does Not Alter the Pharmacokinetics of a Low-Dose Oral Contraceptive","volume":"65","author":"Bauer","year":"2009","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.clpt.2004.01.014","article-title":"Effect of St John\u2019s Wort Dose and Preparations on the Pharmacokinetics of Digoxin","volume":"75","author":"Mueller","year":"2004","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1124\/mol.118.114066","article-title":"Hyperforin-Induced Activation of the Pregnane X Receptor Is Influenced by the Organic Anion-Transporting Polypeptide 2b1","volume":"95","author":"Schaefer","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1208\/s12248-009-9146-8","article-title":"Herb-Drug Interactions with St John\u2019s Wort (Hypericum perforatum): An Update on Clinical Observations","volume":"11","author":"Borrelli","year":"2009","journal-title":"AAPS J."},{"key":"ref_47","unstructured":"Committee on Herbal Medicinal Products (HMPC) (2022). Assessment Report on Hypericum perforatum L., Herba, Committee on Herbal Medicinal Products (HMPC). EMA\/HMPC\/244315\/2016."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1111\/bcpt.13912","article-title":"Serotonin Syndrome-a Focused Review","volume":"133","author":"Mikkelsen","year":"2023","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S2215-0366(17)30015-9","article-title":"How Do Antidepressants Work? New Perspectives for Refining Future Treatment Approaches","volume":"4","author":"Harmer","year":"2017","journal-title":"Lancet Psychiatry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.neuropharm.2015.10.034","article-title":"Bdnf\u2014A Key Transducer of Antidepressant Effects","volume":"102","author":"Bjorkholm","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.yfrne.2004.04.001","article-title":"Physiology of Bdnf: Focus on Hypothalamic Function","volume":"25","author":"Rage","year":"2004","journal-title":"Front. Neuroendocr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nm.4050","article-title":"Synaptic Plasticity and Depression: New Insights from Stress and Rapid-Acting Antidepressants","volume":"22","author":"Duman","year":"2016","journal-title":"Nat. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s10354-015-0372-7","article-title":"The Mechanisms of Action of St. John\u2019s Wort: An Update","volume":"165","author":"Schmidt","year":"2015","journal-title":"Wien. Med. Wochenschr. (1946)"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0024-3205(98)00299-9","article-title":"Hyperforin as a Possible Antidepressant Component of Hypericum Extracts","volume":"63","author":"Chatterjee","year":"1998","journal-title":"Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1055\/s-2007-979341","article-title":"Hyperforin Represents the Neurotransmitter Reuptake Inhibiting Constituent of Hypericum Extract","volume":"31","author":"Singer","year":"1998","journal-title":"Pharmacopsychiatry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S0006-8993(98)01126-3","article-title":"Hypericum Li 160 Inhibits Uptake of Serotonin and Norepinephrine in Astrocytes","volume":"816","author":"Neary","year":"1999","journal-title":"Brain Res."},{"key":"ref_57","first-page":"1145","article-title":"Pharmacological Profile of Hypericum Extract. Effect on Serotonin Uptake by Postsynaptic Receptors","volume":"45","author":"Perovic","year":"1995","journal-title":"Arzneim. Forsch."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/ptr.2921","article-title":"Hypericum perforatum L. (St John\u2019s Wort) Extract Ze 117 Inhibits Dopamine Re-Uptake in Rat Striatal Brain Slices. An Implication for Use in Smoking Cessation Treatment?","volume":"24","author":"Ruedeberg","year":"2010","journal-title":"Phytother. Res. PTR"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1055\/s-2001-15465","article-title":"Evaluation of Synaptosomal Uptake Inhibition of Most Relevant Constituents of St. John\u2019s Wort","volume":"34","author":"Wonnemann","year":"2001","journal-title":"Pharmacopsychiatry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0022-3565(24)35043-8","article-title":"Hyperforin, a Major Antidepressant Constituent of St. John\u2019s Wort, Inhibits Serotonin Uptake by Elevating Free Intracellular Na+1","volume":"290","author":"Singer","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1007\/s002109900073","article-title":"Hypericum perforatum L. Extract Does Not Inhibit 5-Ht Transporter in Rat Brain Cortex","volume":"360","author":"Gobbi","year":"1999","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0006-8993(01)03394-7","article-title":"Long-Term Effects of St. John\u2019s Wort and Hypericin on Monoamine Levels in Rat Hypothalamus and Hippocampus","volume":"930","author":"Butterweck","year":"2002","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0031-6865(97)00002-2","article-title":"Inhibition of Benzodiazepine Binding in Vitro by Amentoflavone, a Constituent of Various Species of Hypericum","volume":"72","author":"Baureithel","year":"1997","journal-title":"Pharm. Acta Helv."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1055\/s-2007-979529","article-title":"In Vitro Receptor Binding and Enzyme Inhibition by Hypericum perforatum Extract","volume":"30","author":"Cott","year":"1997","journal-title":"Pharmacopsychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s00213-002-1073-7","article-title":"In Vitro Receptor Screening of Pure Constituents of St. John\u2019s Wort Reveals Novel Interactions with a Number of Gpcrs","volume":"162","author":"Butterweck","year":"2002","journal-title":"Psychopharmacology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1055\/s-2001-15458","article-title":"In Vitro Binding Studies with Two Hypericum perforatum Extracts--Hyperforin, Hypericin and Biapigenin--on 5-Ht6, 5-Ht7, Gaba(a)\/Benzodiazepine, Sigma, Npy-Y1\/Y2 Receptors and Dopamine Transporters","volume":"34","author":"Gobbi","year":"2001","journal-title":"Pharmacopsychiatry"},{"key":"ref_67","first-page":"17","article-title":"Johanniskraut: In-Vitro Studie \u00dcber Hypericum-Extrakt (Li 160), Hypericin Und K\u00e4mpferol Als Antidepressiva","volume":"136","year":"1996","journal-title":"Dtsch. Apoth. Ztg."},{"key":"ref_68","first-page":"207","article-title":"Effect of Hypericum Extract (Li 160) on Neurotransmitter Receptor Binding and Synaptosomal Uptake Systems","volume":"28","author":"Rolli","year":"1995","journal-title":"Pharmacopsychiatry"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S137","DOI":"10.1055\/s-2001-15475","article-title":"Neurochemical Studies with St. John\u2019s Wort in Vitro","volume":"34","author":"Simmen","year":"2001","journal-title":"Pharmacopsychiatry"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/S0031-9422(00)00305-8","article-title":"Bisanthraquinone Glycosides of Hypericum perforatum with Binding Inhibition to Crh-1 Receptors","volume":"55","author":"Wirz","year":"2000","journal-title":"Phytochemistry"},{"key":"ref_71","first-page":"237","article-title":"Effects of Hypericum Extracts on Glutaminergic and Gabaergic Receptor Systems","volume":"30","author":"Wonnemann","year":"1997","journal-title":"Pharmacopsychiatry"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1055\/s-2001-15452","article-title":"St. John\u2019s Wort Extract Ze 117 (Hypericum perforatum) Inhibits Norepinephrine and Serotonin Uptake into Rat Brain Slices and Reduces \u00df-Adrenoceptor Numbers on Cultured Rat Brain Cells","volume":"34","author":"Kientsch","year":"2001","journal-title":"Pharmacopsychiatry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.lfs.2003.07.027","article-title":"Extracts of St. John\u2019s Wort and Various Constituents Affect Beta-Adrenergic Binding in Rat Frontal Cortex","volume":"74","author":"Simbrey","year":"2004","journal-title":"Life Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1055\/s-2007-979528","article-title":"Effects of Hypericum Extract (Li 160) in Biochemical Models of Antidepressant Activity","volume":"30","author":"Rolli","year":"1997","journal-title":"Pharmacopsychiatry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/sj.mp.4000937","article-title":"St John\u2019s Wort, Hypericin, and Imipramine: A Comparative Analysis of Mrna Levels in Brain Areas Involved in Hpa Axis Control Following Short-Term and Long-Term Administration in Normal and Stressed Rats","volume":"6","author":"Butterweck","year":"2001","journal-title":"Mol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1590\/1516-4446-2017-2271","article-title":"Hypericum perforatum Chronic Treatment Affects Cognitive Parameters and Brain Neurotrophic Factor Levels","volume":"40","author":"Valvassori","year":"2018","journal-title":"Braz. J. Psychiatry"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1038\/sj.npp.1300253","article-title":"Hyperforin-Containing Extracts of St John\u2019s Wort Fail to Alter Gene Transcription in Brain Areas Involved in Hpa Axis Control in a Long-Term Treatment Regimen in Rats","volume":"28","author":"Butterweck","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1055\/a-0581-5286","article-title":"Hyperforin and Miquelianin from St. john\u2019s Wort Attenuate Gene Expression in Neuronal Cells after Dexamethasone-Induced Stress","volume":"84","author":"Verjee","year":"2018","journal-title":"Planta Med."},{"key":"ref_79","first-page":"101","article-title":"Is the Hpa Axis as Target for Depression Outdated, or Is There a New Hope? Front","volume":"10","author":"Menke","year":"2019","journal-title":"Psychiatry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1177\/089198879400700116","article-title":"Modulation of Cytokine Expression by Hypericum Extract","volume":"7","author":"Thiele","year":"1994","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Bonaterra, G.A., Schwendler, A., Huther, J., Schwarzbach, H., Schwarz, A., Kolb, C., Abdel-Aziz, H., and Kinscherf, R. (2017). Neurotrophic, Cytoprotective, and Anti-Inflammatory Effects of St. John\u2019s Wort Extract on Differentiated Mouse Hippocampal Ht-22 Neurons. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00955"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00592-013-0518-2","article-title":"St. John\u2019s Wort Extract and Hyperforin Protect Rat and Human Pancreatic Islets against Cytokine Toxicity","volume":"51","author":"Novelli","year":"2014","journal-title":"Acta Diabetol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1002\/ptr.5350","article-title":"Hypericum perforatum Reduces Paracetamol-Induced Hepatotoxicity and Lethality in Mice by Modulating Inflammation and Oxidative Stress","volume":"29","author":"Hohmann","year":"2015","journal-title":"Phytother. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00213-010-2032-3","article-title":"Profiling of Hypothalamic and Hippocampal Gene Expression in Chronically Stressed Rats Treated with St. John\u2019s Wort Extract (Stw 3-Vi) and Fluoxetine","volume":"213","author":"Jungke","year":"2011","journal-title":"Psychopharmacology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.1038\/s41380-022-01804-3","article-title":"Analysis of Hyperforin (St. John\u2019s Wort) Action at Trpc6 Channel Leads to the Development of a New Class of Antidepressant Drugs","volume":"27","author":"Zheng","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1055\/s-2007-979531","article-title":"Effects of the Total Extract and Fractions of Hypericum perforatum in Animal Assays for Antidepressant Activity","volume":"30","author":"Butterweck","year":"1997","journal-title":"Pharmacopsychiatry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1055\/s-2006-957437","article-title":"Solubilized Hypericin and Pseudohypericin from Hypericum perforatum Exert Antidepressant Activity in the Forced Swimming Test","volume":"64","author":"Butterweck","year":"1998","journal-title":"Planta Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1055\/s-2000-11119","article-title":"Flavonoids from Hypericum perforatum Show Antidepressant Activity in the Forced Swimming Test","volume":"66","author":"Butterweck","year":"2000","journal-title":"Planta Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S0924-977X(99)00005-X","article-title":"Comparison of Hypericum Extracts with Imipramine and Fluoxetine in Animal Models of Depression and Alcoholism","volume":"9","author":"Maurel","year":"1999","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1055\/s-2007-979342","article-title":"Activity Profiles of Two Hyperforin-Containing Hypericum Extracts in Behavioral Models","volume":"31","author":"Bhattacharya","year":"1998","journal-title":"Pharmacopsychiatry"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1097\/00008877-199501000-00010","article-title":"Imipramine and Fluoxetine Prevent the Stress-Induced Escape Deficits in Rats through a Distinct Mechanism of Action","volume":"6","author":"Gambarana","year":"1995","journal-title":"Behav. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1046\/j.1471-4159.1999.0722039.x","article-title":"A Chronic Stress That Impairs Reactivity in Rats Also Decreases Dopaminergic Transmission in the Nucleus Accumbens: A Microdialysis Study","volume":"72","author":"Gambarana","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_93","first-page":"296","article-title":"St. John\u2019s Wort Flavonoids and Their Metabolites Show Antidepressant Activity and Accumulate in Brain after Multiple Oral Doses","volume":"63","author":"Paulke","year":"2008","journal-title":"Pharmazie"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5632","DOI":"10.1038\/srep05632","article-title":"Antidepressant-Like Activity of Adhyperforin, a Novel Constituent of Hypericum perforatum L.","volume":"4","author":"Tian","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_95","first-page":"63","article-title":"Serotonergic Mediation Effects of St John\u2019s Wort in Rats Subjected to Swim Stress","volume":"21","author":"Bano","year":"2008","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_96","first-page":"131","article-title":"Antidepressant-Like Effects of Two Commercially Available Products of Hypericum perforatum in the Forced Swim Test: A Long-Term Study","volume":"4","author":"Saavedra","year":"2010","journal-title":"J. Med. Plant Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.3109\/13880209.2015.1127979","article-title":"The Protective Effect of Hypericum Connatum on Stress-Induced Escape Deficit in Rat Is Related to Its Flavonoid Content","volume":"54","author":"Scheggi","year":"2016","journal-title":"Pharm. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s00210-007-0236-9","article-title":"Alleviation by Hypericum perforatum of the Stress-Induced Impairment of Spatial Working Memory in Rats","volume":"376","author":"Trofimiuk","year":"2008","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s00210-011-0604-3","article-title":"St. John\u2019s Wort May Relieve Negative Effects of Stress on Spatial Working Memory by Changing Synaptic Plasticity","volume":"383","author":"Trofimiuk","year":"2011","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.ejphar.2008.03.021","article-title":"Antidepressant-Like Effect of Rutin Isolated from the Ethanolic Extract from Schinus molle L. In Mice: Evidence for the Involvement of the Serotonergic and Noradrenergic Systems","volume":"587","author":"Machado","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.bbalip.2014.12.014","article-title":"Brain Membrane Lipids in Major Depression and Anxiety Disorders","volume":"1851","author":"Reichel","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nature10742","article-title":"Molecular Recognition of a Single Sphingolipid Species by a Protein\u2019s Transmembrane Domain","volume":"481","author":"Contreras","year":"2012","journal-title":"Nature"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6252","DOI":"10.1038\/s41467-024-50299-9","article-title":"Spatially and Temporally Probing Distinctive Glycerophospholipid Alterations in Alzheimer\u2019s Disease Mouse Brain Via High-Resolution Ion Mobility-Enabled Sn-Position Resolved Lipidomics","volume":"15","author":"Xu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nrm2330","article-title":"Membrane Lipids: Where They Are and How They Behave","volume":"9","author":"Voelker","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"109555","DOI":"10.1016\/j.abb.2023.109555","article-title":"The Role of Polyunsaturated Fatty Acids in Neuronal Signaling in Depression and Cognitive Processes","volume":"737","author":"Stachowicz","year":"2023","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_106","first-page":"746","article-title":"Dysregulation of Cholesterol Balance in the Brain: Contribution to Neurodegenerative Diseases","volume":"5","author":"Vance","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1021\/acschemneuro.3c00823","article-title":"Serotonin Signaling through Lipid Membranes","volume":"15","author":"Kalinichenko","year":"2024","journal-title":"ACS Chem. Neurosci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"12651","DOI":"10.1038\/s41598-020-69454-5","article-title":"Cholesterol Modulates Presynaptic and Postsynaptic Properties of Excitatory Synaptic Transmission","volume":"10","author":"Korinek","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/j.febslet.2009.12.010","article-title":"Sphingolipids and Gangliosides of the Nervous System in Membrane Function and Dysfunction","volume":"584","author":"Sipione","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1172\/JCI0216390","article-title":"Cholesterol, Lipid Rafts, and Disease","volume":"110","author":"Simons","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1042\/bj20021528","article-title":"Ceramide: Second Messenger or Modulator of Membrane Structure and Dynamics?","volume":"369","author":"Veldman","year":"2003","journal-title":"Biochem. J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/mp.2015.14","article-title":"The Impact of Chronic Stress on the Rat Brain Lipidome","volume":"21","author":"Oliveira","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"28","DOI":"10.5483\/BMBRep.2020.53.1.278","article-title":"Sphingolipids in Neuroinflammation: A Potential Target for Diagnosis and Therapy","volume":"53","author":"Lee","year":"2019","journal-title":"BMB Rep."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41398-019-0478-6","article-title":"Differential Lipid Composition and Regulation Along the Hippocampal Longitudinal Axis","volume":"9","author":"Miranda","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1176\/jnp.23.2.jnp215","article-title":"Elevated Plasma Ceramides in Depression","volume":"23","author":"Rao","year":"2011","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.brainresbull.2022.08.008","article-title":"Plasmalogen in the Brain: Effects on Cognitive Functions and Behaviors Attributable to Its Properties","volume":"188","author":"Udagawa","year":"2022","journal-title":"Brain Res. Bull."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.biopsych.2010.03.018","article-title":"A Meta-Analytic Review of Polyunsaturated Fatty Acid Compositions in Patients with Depression","volume":"68","author":"Lin","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0009-3084(03)00101-4","article-title":"Docosahexaenoic Acid: Membrane Properties of a Unique Fatty Acid","volume":"126","author":"Stillwell","year":"2003","journal-title":"Chem. Phys. Lipids"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"110817","DOI":"10.1016\/j.exger.2019.110817","article-title":"Aging Membranes: Unexplored Functions for Lipids in the Lifespan of the Central Nervous System","volume":"131","author":"Budin","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.phymed.2018.06.013","article-title":"St John\u2019s Wort Extract Influences Membrane Fluidity and Composition of Phosphatidylcholine and Phosphatidylethanolamine in Rat C6 Glioblastoma Cells","volume":"54","author":"Keksel","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"114006","DOI":"10.1016\/j.biopha.2022.114006","article-title":"Effect of St. John\u2019s Wort Extract Ze 117 on the Lateral Mobility of Beta(1)-Adrenergic Receptors in C6 Cells","volume":"157","author":"Bussmann","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s10020-023-00644-3","article-title":"Impact of St. John\u2019s Wort Extract Ze 117 on Stress Induced Changes in the Lipidome of Pbmc","volume":"29","author":"Bussmann","year":"2023","journal-title":"Mol. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"9878","DOI":"10.1038\/s41598-024-60562-0","article-title":"St. John\u2019s Wort Extract Ze 117 Alters the Membrane Fluidity of C6 Glioma Cells by Influencing Cellular Cholesterol Metabolism","volume":"14","author":"Bremer","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Bussmann, H., Bremer, S., Hernier, A.M., Drewe, J., H\u00e4berlein, H., Franken, S., Freytag, V., Boonen, G., and Butterweck, V. (2024). St. John\u2019s Wort Extract Ze 117 and Escitalopram Alter Plasma and Hippocampal Lipidome in a Rat Model of Chronic-Stress-Induced Depression. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312667"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.cell.2019.04.018","article-title":"The Lateral Organization and Mobility of Plasma Membrane Components","volume":"177","author":"Jacobson","year":"2019","journal-title":"Cell"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s12013-017-0792-7","article-title":"High Cholesterol\/Low Cholesterol: Effects in Biological Membranes: A Review","volume":"75","author":"Subczynski","year":"2017","journal-title":"Cell Biochem. Biophys."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Pinto, B., Conde, T., Domingues, I., and Domingues, M.R. (2022). Adaptation of Lipid Profiling in Depression Disease and Treatment: A Critical Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042032"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/11925\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T05:27:53Z","timestamp":1765517273000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/11925"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":127,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262411925"],"URL":"https:\/\/doi.org\/10.3390\/ijms262411925","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]}}}