logo logo
The effects of St John's wort extract on heart rate variability, cognitive function and quantitative EEG: a comparison with amitriptyline and placebo in healthy men. Siepmann M,Krause S,Joraschky P,Mück-Weymann M,Kirch W British journal of clinical pharmacology AIMS:To compare the effects of multiple dosing with St John's wort (Hypericum perforatum) extract and amitriptyline on heart rate variability, cognitive function and quantitative EEG (qEEG) with placebo in healthy humans. METHODS:A randomized, double-blind, cross over study of 12 healthy male volunteers. Subjects orally received capsules with 255-285 mg St John's wort extract (900 micro g hypericin content), 25 mg amitriptyline and placebo three times daily for periods of 14 days each with at least 14 days between. The doses of amitriptyline and St John's wort extract are comparable with respect to their antidepressant activity. Compliance was confirmed by coadministration of 10 mg of riboflavin with each capsule and detection of urinary vitamin B2 on treatment day 11 with high performance liquid chromatography. Measurements of heart rate variability, psychometric tests and qEEG were performed before start of medication and repeatedly on the last treatment day. RESULTS:St John's wort extract did not affect heart rate variability (HRV) whereas amitripytline significantly decreased it: the difference in the percentage number of adjacent RR intervals> 50 ms (pNN50) was 8.6 (-2.6, 19.9; mean; 95% confidence interval) between St John's wort extract and placebo and -17.6 (-24.7, -10.4) between amitriptyline and placebo. Neither St John's wort extract nor amitriptyline had an influence on cognitive performance such as choice reaction, psychomotor coordination, short-term memory and responsiveness to distractive stimuli. Amitriptyline but not St John's wort extract decreased self rated activity (P < 0.05). Both drugs caused significant qEEG changes. St John's wort extract increased theta power density. Amitriptyline increased theta as well as fast alpha power density. CONCLUSIONS:Multiple doses of St John's wort extract do not affect heart rate variability nor cognitive function. Chronic administration of amitriptyline causes a decrement of HRV and subjective sedation but it does not impair cognitive performance. 10.1046/j.1365-2125.2002.01658.x
Pharmacological in vivo test to evaluate the bioavailability of some St John's Wort innovative oral preparations. Isacchi B,Galeotti N,Bergonzi M C,Ghelardini C,Bilia A R,Vincieri F F Phytotherapy research : PTR In this study, the optimisation of biopharmaceutical properties of a dried commercial extract of St John's Wort were evaluated employing the in vivo forced swimming test (FST). Three new dosage forms containing beta-cyclodextrin and surfactants (SDS, ASC8) were compared in the FST with the commercial extract. The commercial extract showed antidepressant activity in mice after 60 min at a dosage of 100 mg/kg. The same antidepressant activity appeared in 30 min with a micellar solution of SDS containing the same quantity of extract (100 mg/kg), while with micelles of ASC8 the effect appeared at 15 min and with a dosage of 30 mg/kg. In the case of beta-cyclodextrin the best results were obtained at 30 min, administering 60 mg/kg of the extract. Finally, the influence of the formulations on the water solubility of the constituents of the extract is reported. The tensides dramatically enhanced solubility, in particular that of the more lipophilic compounds, in the case of beta-cyclodextrin this effect was very pronounced for flavonoids and biapigenin, lower for hypericins and practically insignificant for hyperforins. 10.1002/ptr.2586
The antidepressant mechanism of Hypericum perforatum. Mennini Tiziana,Gobbi Marco Life sciences Clinical data indicate that hydroalcoholic extracts of Hypericum perforatum might be as valuable as conventional antidepressants in mild-to-moderate depression, with fewer side effects. One clinical trial using two extracts with different hyperforin contents indicated it as the main active principle responsible for the antidepressant activity. Behavioural models in rodents confirm the antidepressant-like effect of Hypericum extracts and also of pure hyperforin and hypericin. A hydroalcoholic extract lacking hyperforin also lacks the antidepressant-like effect. According to pharmacokinetic data and binding studies, it appears that the antidepressant effect of Hypericum extract is unlikely be due to an interaction of hypericin with central neurotransmitter receptors. The main in vitro effects of hyperforin (at concentrations of 0.1-1 microM) are non-specific presynaptic effects, resulting in the non-selective inhibition of the uptake of many neurotransmitters, and the interaction with dopamine D1 and opioid receptors. However, it is still not clear whether these mechanisms can be activated in vivo, since after administration of Hypericum extract brain concentrations of hyperforin are well below those active in vitro. In the rat, Hypericum extract might indirectly activate sigma receptors in vivo (through the formation of an unknown metabolite or production of an endogenous ligand), suggesting a new target for its antidepressant effects. 10.1016/j.lfs.2004.04.005
Hypericin prolongs action potential duration in hippocampal neurons by acting on K+ channels. Wang Y,Shi X,Qi Z British journal of pharmacology BACKGROUND AND PURPOSE:Synaptic deficiency is generally accepted to be involved in major depression, and accordingly classic antidepressants exert their effects through enhancing synaptic efficiency. Hypericin is one of the major active constituents of extracts of St. John's Wort (Hypericum perforatum L.) with antidepressive actions, but little is known about its therapeutic mechanisms. Our aim was to explore whether hypericin has a modulatory effect on neuronal action potential (AP) duration by acting on voltage-gated ion channels. EXPERIMENTAL APPROACH:We used voltage-clamp and current-clamp techniques in a whole-cell configuration to study primary cultures of neonatal rat hippocampal neurones. We measured the effects of extracellularly applied hypericin on AP duration as well as on voltage-gated Na(+), I(A) and I(K) currents. KEY RESULTS:Extracellularly applied hypericin dose-dependently increased AP duration but barely affected its amplitude. Further analysis revealed that hypericin inhibited both transient I(A) and delayed rectifier I(K) potassium currents. In contrast, hypericin exerted no significant effect on both Na(+) peak current and its decay kinetics. CONCLUSIONS AND IMPLICATIONS:Extracellularly applied hypericin increased AP duration, which might be ascribed to its effect on I(A) and I(K) currents. As a small increase in AP duration could lead to a dramatic increase in synaptic efficiency, our results imply that hypericin might exert its antidepressant effects by enhancing presynaptic efficiency. 10.1111/j.1476-5381.2009.00513.x
About the cover: St. John's wort. Journal of the Society for Integrative Oncology Derived from the aerial parts of the plant, St. John's wort generally is used for depression, seasonal affective disorder, and anxiety. Products currently are standardized based on hypericin content, although the hyperforin and bioflavonoid contents are also believed responsible for activity. St. John's wort is metabolized primarily by the liver. Some studies comparing St. John's wort to standard antidepressants suggest that it may be as effective as imipramine or selective serotonin reuptake inhibitors (SSRIs) to treat mild to moderate depression. Results from another clinical trial indicate that the effectiveness of St. John's wort is comparable to paroxetine, an SSRI, in the treatment of moderate to severe depression and is well tolerated. But a meta-analysis shows that data are inconsistent. Studies also show possible efficacy in the management of anxiety and premenstrual syndrome, although additional research is necessary. St. John's wort can interact with many medications owing to induction of cytochrome P-450 3A4 and other mechanisms. Significant interactions include decreased efficacy of antiretrovirals, cyclosporine, tacrolimus, antiepileptics, irinotecan, and other chemotherapeutic agents. Serotonin syndrome may occur when St. John's wort is combined with sympathomimetics, antidepressants, or triptans. Frequently reported adverse events include nausea, headache, constipation, dizziness, confusion, fatigue, and dry mouth. St. John's wort should be used under medical supervision.
Mechanism of action of St John's wort in depression : what is known? Butterweck Veronika CNS drugs Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature. 10.2165/00023210-200317080-00001
Hypericum perforatum (St John's wort) beyond depression: A therapeutic perspective for pain conditions. Galeotti Nicoletta Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Hypericum perforatum L. (Hypericaceae), popularly called St. John's wort (SJW), has a rich historical background being one of the oldest used and most extensively investigated medicinal herbs. Many bioactivities and applications of SJW are listed in popular and in scientific literature, including antibacterial, antiviral, anti-inflammatory. In the last three decades many studies focused on the antidepressant activity of SJW extracts. However, several studies in recent years also described the antinociceptive and analgesic properties of SJW that validate the traditional uses of the plant in pain conditions. AIM OF THE REVIEW:This review provides up-to-date information on the traditional uses, pre-clinical and clinical evidence on the pain relieving activity of SJW and its active ingredients, and focuses on the possible exploitation of this plant for the management of pain. MATERIALS AND METHODS:Historical ethnobotanical publications from 1597 were reviewed for finding local and traditional uses. The relevant data on the preclinical and clinical effects of SJW were searched using various databases such as PubMed, Science Direct, Scopus, and Google Scholar. Plant taxonomy was validated by the database Plantlist.org. RESULTS:Preclinical animal studies demonstrated the ability of low doses of SJW dry extracts (0.3% hypericins; 3-5% hyperforins) to induce antinociception, to relieve from acute and chronic hyperalgesic states and to augment opioid analgesia. Clinical studies (homeopathic remedies, dry extracts) highlighted dental pain conditions as a promising SJW application. In vivo and in vitro studies showed that the main components responsible for the pain relieving activity are hyperforin and hypericin. SJW analgesia appears at low doses (5-100mg/kg), minimizing the risk of herbal-drug interactions produced by hyperforin, a potent inducer of CYP enzymes. CONCLUSION:Preclinical studies indicate a potential use of SJW in medical pain management. However, clinical research in this field is still scarce and the few studies available on chronic pain produced negative results. Prospective randomized controlled clinical trials performed at low doses are needed to validate its potential efficacy in humans. 10.1016/j.jep.2017.02.016
alleviates CUS-induced depression-like behaviors in mice the gut microbiota-neuroinflammation axis. Frontiers in pharmacology Major depressive disorder is a mental disease with complex pathogenesis and treatment mechanisms involving changes in both the gut microbiota and neuroinflammation. Cuscutae Semen (CS), also known as Chinese Dodder seed, is a medicinal herb that exerts several pharmacological effects. These include neuroprotection, anti-neuroinflammation, the repair of synaptic damage, and the alleviation of oxidative stress. However, whether CuscutaeSemen exerts an antidepressant effect remains unknown. In this study, we evaluated the effect of CS on chronic unpredictable stress (CUS)-induced depression-like behaviors in mice by observing changes in several inflammatory markers, including proinflammatory cytokines, inflammatory proteins, and gliocyte activation. Meanwhile, changes in the gut microbiota were analyzed based on 16 S rRNA sequencing results. Moreover, the effect of CS on the synaptic ultrastructure was detected by transmission electron microscopy. We found that the CS extract was rich in chlorogenic acid and hypericin. And CS relieved depression-like behaviors in mice exposed to CUS. Increased levels of cytokines (IL-1β and TNF-α) and inflammatory proteins (NLRP3, NF-κB, and COX-2) induced by CUS were reversed after CS administration. The number of astrocytes and microglia increased after CUS exposure, whereas they decreased after CS treatment. Meanwhile, CS could change the structure of the gut microbiota and increase the relative abundance of Lactobacillus. Moreover, there was a significant relationship between several Lactobacilli and indicators of depression-like behaviors and inflammation. There was a decrease in postsynaptic density after exposure to CUS, and this change was alleviated after CS treatme. This study found that CS treatment ameliorated CUS-induced depression-like behaviors and synaptic structural defects in mice the gut microbiota-neuroinflammation axis. And chlorogenic acid and hypericin may be the main active substances for CS to exert antidepressant effects. 10.3389/fphar.2023.1107781
St. John's Wort (Hypericum perforatum): clinical effects on depression and other conditions. Miller A L Alternative medicine review : a journal of clinical therapeutic St. John's Wort (Hypericum perforatum), a perennial flowering plant, has been used medicinally for thousands of years, and has most recently been identified as an effective treatment for mild to moderate depression. Clinical studies on the use of this plant for depression have utilized liquid tinctures and standardized solid extracts (0.3% hypericin--300 mg three times a day). Severe depression may also respond to this botanical, although it appears a larger dose is needed (600 mg solid extract three times a day). Hypericum has been favorably compared to numerous antidepressant drugs, the studies having revealed equivalent results and a much more favorable incidence of side effects. Studies have also demonstrated its efficacy in treating seasonal affective disorder. In vitro investigations of Hypericum show antiviral activity, although there is evidence these promising results might not occur in vivo. Traditional actions and uses include enhancement of wound healing, as well as anti-inflammatory and analgesic activity.
Anti-fatigue effect of hypericin in a chronic forced exercise mouse model. Sun Yang,Liang Chen,Zheng Lihua,Liu Lei,Li Zhijin,Yang Guang,Li Yuxin Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Hypericum perforatum L. is a traditional Chinese medicine used to sooth the liver, relieve depression, reduce body temperature, reduce sweating, and stimulate lactation. HP was extracted from Hypericum perforatum L. AIM OF STUDY:The antifatigue effects of hypericin were assessed in a series of experiments. MATERIALS AND METHODS:Six-to eight-week-old male ICR mice were raised in our lab. Mice were subjected to swimming training for 2 h, 6 days/week for 6 weeks. One hour prior to each swimming session, intraperitoneal injection of saline or HP (2 or 4 mg/kg) was performed. RESULTS:Compared with the fatigue model control group, HP was found to significantly increase the swimming time in forced swimming tests. The molecular mechanisms underlying the antifatigue effects were further revealed by analysing energy metabolism, the oxidant-antioxidant system and the inflammatory response. HP normalized changes in BLA, LDH, BUN, and CK, LG in the liver. In addition, multiple assays have confirmed that HP improved the MDA, T-AOC, GSH-PX and SOD activity, and the relevant signalling pathways involved in the antifatigue effects were clarified. Furthermore, HP improves the expression of pro- and anti-inflammatory cytokines in skeletal muscle. CONCLUSION:These results suggested that the anti-chronic fatigue effects of HP are likely achieved by normalizing energy metabolism and attenuating oxidative and inflammatory responses. Consequently, this study supports HP use in the clinic to alleviate chronic fatigue. 10.1016/j.jep.2021.114767
Hypericin-an inhibitor of proteasome function. Pajonk F,Scholber J,Fiebich B Cancer chemotherapy and pharmacology Hypericin is the presumed active moiety within Saint John's wort. Extracts of Saint John's wort are widely used as an effective treatment for depression. Available as "over-the-counter" drugs, they are frequently part of the self-medication of patients undergoing radiation therapy for malignant diseases. In addition to antidepressive properties, hypericin has been shown to be able to induce apoptosis and radiosensitize tumor cells, and to have antiinflammatory and phototoxic skin effects. However, the underlying mechanisms are not clear. In this study, we investigated possible inhibitory effects of hypericin on proteasome function and related pathways. Extracts from U373 human glioma cells were incubated with different concentrations of hypericin. Three proteasome activities were monitored using a fluorogenic peptide assay. Activity of the transcription factor NF-kappaB and protein levels of p65, p50, IkappaBalpha and caspase-3 were investigated by EMSA and Western blotting, respectively. Hypericin caused a dose-dependent and photoactivation-independent inhibition of proteasome function. Hypericin treatment (6.25-50 microM) inhibited NF-kappaB, caused accumulation of phosphorylated IkappaBalpha, decreased p50 protein levels and induced cleavage of p65 protein in U373 cells. These effects were observed in MCF-7 cells only at higher concentrations of hypericin (12.5-50 microM). Additionally, inhibition of NF-kappaB activity in U373 cells by hypericin was prevented by caspase inhibition. Although hypericin clearly inhibits proteasome function, its effect NF-kappaB DNA-binding activity was not exclusively proteasome-dependent. The underlying mechanism might also involve caspase activation, a consequence of proteasome inhibition. 10.1007/s00280-004-0933-8
St. John's wort. Lawvere Silvana,Mahoney Martin C American family physician St. John's wort has been used to treat a variety of conditions. Several brands are standardized for content of hypericin and hyperforin, which are among the most researched active components of St. John's wort. St. John's wort has been found to be superior to placebo and equivalent to standard antidepressants for the treatment of mild to moderate depression. Studies of St. John's wort for the treatment of major depression have had conflicting results. St. John's wort is generally well tolerated, although it may potentially reduce the effectiveness of several pharmaceutical drugs.
Brain-Targeted Black Phosphorus-Based Nanotherapeutic Platform for Enhanced Hypericin Delivery in Depression. Small (Weinheim an der Bergstrasse, Germany) Depression is a significant global health concern that remains inadequately treated due to the limited effectiveness of conventional drug therapies. One potential therapeutic agent, hypericin (HYP), is identified as an effective natural antidepressant. However, its poor water solubility, low bioavailability, and limited ability to penetrate the brain parenchyma have hindered its clinical application. To address these shortcomings and enhance the therapeutic efficacy of HYP, it is loaded onto black phosphorus nanosheets (BP) modified with the neural cell-targeting peptide RVG29 to synthesize a nanoplatform named BP-RVG29@HYP (BRH). This platform served as a nanocarrier for HYP and integrated the advantages of BP with advanced delivery methods and precise targeting strategies. Under the influence of 808 nm near-infrared irradiation (NIR), BRH effectively traversed an in vitro BBB model. In vivo experiments validated these findings, demonstrating that treatment with BRH significantly alleviated depressive-like behaviors and oxidative stress in mice. Importantly, BRH exhibited an excellent safety profile, causing minimal adverse effects, which highlighted its potential as a promising therapeutic agent. In brief, this novel nanocarrier holds great promise in the development of antidepressant drugs and can create new avenues for the treatment of depression. 10.1002/smll.202310608
Potential therapeutic effects of Chinese herbal medicine in postpartum depression: Mechanisms and future directions. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Postpartum depression (PPD) is a common psychiatric disorder in women after childbirth. Per data from epidemiologic studies, PPD affects about 5%-26.32% of postpartum mothers worldwide. Biological factors underlying this condition are multiple and complex and have received extensive inquiries for the roles they play in PPD. Chinese herbal medicine (CHM), which is widely used as a complementary and alternative therapy for neurological disorders, possesses multi-component, multi-target, multi-access, and low side effect therapeutic characteristics. CHM has already shown efficacy in the treatment of PPD, and a lot more research exploring the mechanisms of its potential therapeutic effects is being conducted. AIM OF THE REVIEW:This review provides an in-depth and comprehensive overview of the underlying mechanisms of PPD, as well as samples the progress made in researching the potential role of CHM in treating the disorder. MATERIALS AND METHODS:Literature was searched comprehensively in scholarly electronic databases, including PubMed, Web of Science, Scopus, CNKI and WanFang DATA, using the search terms "postpartum depression", "genetic", "hormone", "immune", "neuroinflammation", "inflammation", "neurotransmitter", "neurogenesis", "brain-gut axis", "traditional Chinese medicine", "Chinese herbal medicine", "herb", and an assorted combination of these terms. RESULTS:PPD is closely associated with genetics, as well as with the hormones, immune inflammatory, and neurotransmitter systems, neurogenesis, and gut microbes, and these biological factors often interact and work together to cause PPD. For example, inflammatory factors could suppress the production of the neurotransmitter serotonin by inducing the regulation of tryptophan-kynurenine in the direction of neurotoxicity. Many CHM constituents improve anxiety- and depression-like behaviors by interfering with the above-mentioned mechanisms and have shown decent efficacy clinically against PPD. For example, Shen-Qi-Jie-Yu-Fang invigorates the neuroendocrine system by boosting the hormone levels of hypothalamic pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axes, regulating the imbalance of Treg/T-helper cells (Th) 17 and Th1/Th2, and modulating neurotransmitter system to play antidepressant roles. The Shenguiren Mixture interferes with the extracellular signal-regulated kinase (ERK) pathway to enhance the number, morphology and apoptosis of neurons in the hippocampus of PPD rats. Other herbal extracts and active ingredients of CHM, such as Paeoniflorin, hypericin, timosaponin B-III and more, also manage depression by remedying the neuroendocrine system and reducing neuroinflammation. CONCLUSIONS:The pathogenesis of PPD is complex and diverse, with the main pathogenesis not clear. Still, CHM constituents, like Shen-Qi-Jie-Yu-Fang, the Shenguiren Mixture, Paeoniflorin, hypericin and other Chinese Medicinal Formulae, active monomers and Crude extracts, treats PPD through multifaceted interventions. Therefore, developing more CHM components for the treatment of PPD is an essential step forward. 10.1016/j.jep.2024.117785
The protective effect of hypericin on postpartum depression rat model by inhibiting the NLRP3 inflammasome activation and regulating glucocorticoid metabolism. Zhai Xuejia,Chen Yan,Han Xuemei,Zhu Ying,Li Xixuan,Zhang Yu,Lu Yongning International immunopharmacology BACKGROUND:St John's Wort (Hypericum perforatum, SJW) is widely used to treat postpartum depression (PPD) because of its high safety. Hypericin (HY) is the main effective component of SJW. The physiological roles of NLRP3 inflammasome activation and glucocorticoid metabolism are closely linked to depression. But, it remains elusive whether HY relieve PPD through targeting NLRP3 inflammasome activation or other mechanism. This study aimed to clarify the therapeutic effects of HY on PPD model rats and its underlying mechanisms in vivo. METHODS:hormone-simulated pregnancy model was used, and behavioral tests was used to assess depressive state. Inflammatory factors in serum were tested by Enzyme-linked immunosorbent assay. RESULTS:Changes in the classic behavioral tests reflected that HY could alleviate the symptoms of PPD as effective as fluoxetine (FLU). Both of HY and FLU could significantly inhibit the protein expression of NLRP3, caspase-1 in hypothalamus and decrease the levels of inflammatory factors (IL-6, IL-1β, TNF - α) in serum. For hormone level determination, HY can not only significantly reduce the level of CORT, but also reverse the activity of 11β - HSD2 enzyme, which is different from FLU. LIMITATIONS:More experiments will be needed to verify the target of HY. CONCLUSION:All those data suggest that HY can effectively relieve PPD by reversing glucocorticoid metabolism, increasing ER expression, and then relieve neuroinflammation. 10.1016/j.intimp.2022.108560
St John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties. Barnes J,Anderson L A,Phillipson J D The Journal of pharmacy and pharmacology The chemical composition of St. John's wort has been well-studied. Documented pharmacological activities, including antidepressant, antiviral, and antibacterial effects, provide supporting evidence for several of the traditional uses stated for St John's wort. Many pharmacological activities appear to be attributable to hypericin and to the flavonoid constituents; hypericin is also reported to be responsible for the photosensitive reactions that have been documented for St. John's wort. With regard to the antidepressant effects of St John's wort, hyperforin, rather than hypericin as originally thought, has emerged as one of the major constituents responsible for antidepressant activity. Further research is required to determine which other constituents contribute to the antidepressant effect. Evidence from randomised controlled trials has confirmed the efficacy of St John's wort extracts over placebo in the treatment of mild-to-moderately severe depression. Other randomised controlled studies have provided some evidence that St John's wort extracts are as effective as some standard antidepressants in mild-to-moderate depression. There is still a need for further trials to assess the efficacy of St John's wort extracts, compared with that of standard antidepressants, particularly newer antidepressant agents, such as the selective serotonin reuptake inhibitors (recent comparative studies with fluoxetine and sertraline have been conducted). Also, there is a need for further studies in well-defined groups of patients, in different types of depression, and conducted over longer periods in order to determine long-term safety. St John's wort does appear to have a more favourable short-term safety profile than do standard antidepressants, a factor that is likely to be important in patients continuing to take medication. Concerns have been raised over interactions between St John's wort and certain prescribed medicines (including warfarin, ciclosporin, theophylline, digoxin, HIV protease inhibitors, anticonvulsants, selective serotonin reuptake inhibitors, triptans, oral contraceptives); advice is that patients taking these medicines should stop taking St John's wort, generally after seeking professional advice as dose adjustment of conventional treatment may be necessary. 10.1211/0022357011775910
Novel antidepressant mechanism of hypericin: Role of connexin 43-based gap junctions. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Hypericin is widely utilized for its precise antidepressant properties, but its exact antidepressant mechanism remains unclear. Gap junctions, which were predominantly expressed in astrocytes in the central nervous system, are concerned with the pathogenesis of depression. However, the role of hypericin in gap junctional dysfunction in depression has rarely been investigated. Here, we found that gap junctions were ultra-structurally broadened in the chronic unpredictable stress (CUS) rat model of depression, while hypericin repaired the dysfunction of gap junctions. Suppression of gap junctions by bilateral injection of carbenoxolone (CBX) in the prefrontal cortex of rats significantly inhibited the restoration of gap junctional dysfunction in depression by hypericin. Meanwhile, hypericin failed to show antidepressant benefits. Furthermore, in corticosterone (CORT)-stimulated primary astrocytes derived from neonatal rats, hypericin dramatically reversed the phosphorylation of connexin 43 (Cx43), normalizing the expression of Cx43 and thereby ameliorating gap junctional dysfunction. Comparatively, CBX inhibited the remission of hypericin on gap junctional intercellular communication function. Gap junctional function might be a novel therapeutic target for hypericin in the treatment of depression and provide potential novel insights into the antidepressant mechanism of other herbal ingredients. 10.1016/j.biopha.2023.115545
A systematic review of St. John's wort for major depressive disorder. Apaydin Eric A,Maher Alicia R,Shanman Roberta,Booth Marika S,Miles Jeremy N V,Sorbero Melony E,Hempel Susanne Systematic reviews BACKGROUND:This systematic review evaluated St. John's wort (SJW) for the treatment of Major Depressive Disorder (MDD). The objectives of this review are to (1) evaluate the efficacy and safety of SJW in adults with MDD compared to placebo and active comparator and (2) evaluate whether the effects vary by severity of MDD. METHODS:We searched PubMed, CINAHL, PsycINFO, CENTRAL, Embase, AMED, MANTIS, Web of Science, and ICTRP and existing reviews to November 2014. Two independent reviewers screened the citations, abstracted the data, and assessed the risk of bias. We included randomized controlled trials (RCTs) examining the effect of at least a 4-week administration of SJW on depression outcomes against placebo or active comparator in adults with MDD. Risk of bias was assessed using the Cochrane Risk of Bias tool and USPSTF criteria. Quality of evidence (QoE) was assessed using the GRADE approach. RESULTS:Thirty-five studies examining 6993 patients met inclusion criteria; eight studies evaluated a hypericum extract that combined 0.3 % hypericin and 1-4 % hyperforin. The herb SJW was associated with more treatment responders than placebo (relative risk [RR] 1.53; 95 % confidence interval [CI] 1.19, 1.97; I(2) 79 %; 18 RCTs; N = 2922, moderate QoE; standardized mean differences [SMD] 0.49; CI 0.23, 0.74; 16 RCTs; I(2) 89 %, N = 2888, moderate QoE). Compared to antidepressants, SJW participants were less likely to experience adverse events (OR 0.67; CI 0.56, 0.81; 11 RCTs; moderate QoE) with no difference in treatment effectiveness (RR 1.01; CI 0.90, 1.14; 17 RCTs, I(2) 52 %, moderate QoE; SMD -0.03; CI -0.21, 0.15; 14 RCTs; I(2) 74 %; N = 2248, moderate QoE) in mild and moderate depression. CONCLUSIONS:SJW monotherapy for mild and moderate depression is superior to placebo in improving depression symptoms and not significantly different from antidepressant medication. However, evidence of heterogeneity and a lack of research on severe depression reduce the quality of the evidence. Adverse events reported in RCTs were comparable to placebo and fewer compared with antidepressants. However, assessments were limited due to poor reporting of adverse events and studies were not designed to assess rare events. Consequently, the findings should be interpreted with caution. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42015016406 . 10.1186/s13643-016-0325-2
Hypericin Ameliorates Depression-like Behaviors via Neurotrophin Signaling Pathway Mediating m6A Epitranscriptome Modification. Molecules (Basel, Switzerland) Hypericin, one of the major antidepressant constituents of St. John's wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms are unknown. Previous clinical studies reported that the mRNA modification N6-methyladenosine (m6A) interferes with the neurobiological mechanism in depressed patients, and it was also found that the antidepressant efficacy of tricyclic antidepressants (TCAs) is related to m6A modifications. Therefore, we hypothesize that the antidepressant effect of hypericin may relate to the m6A modification of epitranscriptomic regulation. We constructed a UCMS mouse depression model and found that hypericin ameliorated depressive-like behavior in UCMS mice. Molecular pharmacology experiments showed that hypericin treatment upregulated the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of UCMS mice. Next, we performed MeRIP-seq and RNA-seq to study m6A modifications and changes in mRNA expression on a genome-wide scale. The genome-wide m6A assay and MeRIP-qPCR results revealed that the m6A modifications of Akt3, Ntrk2, Braf, and Kidins220 mRNA were significantly altered in the hippocampi of UCMS mice after stress stimulation and were reversed by hypericin treatment. Transcriptome assays and qPCR results showed that the Camk4 and Arhgdig genes might be related to the antidepressant efficacy of hypericin. Further gene enrichment results showed that the differential genes were mainly involved in neurotrophic factor signaling pathways. In conclusion, our results show that hypericin upregulates m6A methyltransferase METTL3 and WTAP in the hippocampi of UCMS mice and stabilizes m6A modifications to exert antidepressant effects via the neurotrophin signaling pathway. This suggests that METTL3 and WTAP-mediated changes in m6A modifications may be a potential mechanism for the pathogenesis of depression and the efficacy of antidepressants, and that the neurotrophin signaling pathway plays a key role in this process. 10.3390/molecules28093859
Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis. Ng Qin Xiang,Venkatanarayanan Nandini,Ho Collin Yih Xian Journal of affective disorders INTRODUCTION:St John's wort is a popular herbal remedy recommended by Traditional Chinese Medicine (TCM) practitioners and licensed and widely prescribed for depression in many European countries. However, conflicting data regarding its benefits and risks exist, and the last large meta-analysis on St John's wort use for depression was done in 2008, with no updated meta-analysis available. METHODS:Using the keywords [St John's Wort OR Hypericum perforatum OR hypericin OR hyperforin OR johanniskraut OR] AND [depression OR antidepressant OR SSRI], a preliminary search (without language restriction) on the PubMed, Ovid, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group, Cochrane Field for Complementary Medicine, China National Knowledge Infrastructure and WanFang database yielded 5428 papers between 1-Jan-1960 and 1-May-2016. RESULTS:27 clinical trials with a total of 3808 patients were reviewed, comparing the use of St John's wort and SSRI. In patients with depression, St John's wort demonstrated comparable response (pooled RR 0.983, 95% CI 0.924-1.042, p<0.001) and remission (pooled RR 1.013, 95% CI 0.892-1.134, p<0.001) rate, and significantly lower discontinuation/dropout (pooled OR 0.587, 95% CI 0.478-0.697, p<0.001) rate compared to standard SSRIs. The pooled SMD from baseline HAM-D scores (pooled SMD -0.068, 95% CI -0.127 to 0.021, p<0.001) also support its significant clinical efficacy in ameliorating depressive symptoms. LIMITATIONS:Evidence on the long-term efficacy and safety of St. John's wort is limited as the duration of all available studies ranged from 4 to 12 weeks. It is also unclear if St John's wort would be beneficial for patients with severe depression, high suicidality or suicide risk. CONCLUSION:For patients with mild-to-moderate depression, St John's wort has comparable efficacy and safety when compared to SSRIs. Follow-up studies carried out over a longer duration should be planned to ascertain its benefits. 10.1016/j.jad.2016.12.048
St. John's wort (Hypericum perforatum) and depression: what happens to the neurotransmitter systems? Naunyn-Schmiedeberg's archives of pharmacology St. John's wort (Hypericum perforatum) is a herbaceous plant containing many bioactive molecules including naphthodianthrones, phloroglucinol derivatives, flavonoids, bioflavonoids, proanthocyanidins, and chlorogenic acid. Evidence has shown the therapeutic effects of St. John's wort and especially its two major active components, hyperforin and hypericin, on different psychiatric and mood disorders such as posttraumatic stress disorder (PTSD), attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and anxiety disorders. St. John's wort also induces antidepressant effects. In this review study, we aimed to discuss the role of St. John's wort in modulating depression, with respect to the role of different neurotransmitter systems in the brain. We discussed changes in the neurotransmitter levels in depression, and following use of St. John's wort. It was concluded that changes in the function and level of neurotransmitters in depression are complex. Also, St. John's wort can induce inconsistent effects on neurotransmitter levels. We also found that glutamate and acetylcholine may be the most important neurotransmitters to study in future works, because the function of both neurotransmitters in depression is unclear. In addition, St. John's wort induces a dualistic modulation on the activity of cholinergic signaling, which can be an interesting topic for future studies. 10.1007/s00210-022-02229-z