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Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial

There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cel...

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Long-term assessment of the NHS hybrid closed-loop real-world study on glycaemic outcomes, time-in-range, and quality of life in children and young people with type 1 diabetes

Hybrid closed-loop (HCL) systems seamlessly interface continuous glucose monitoring (CGM) with insulin pumps, employing specialised algorithms and user-initiated automated insulin delivery. This study aimed to...

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer

Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the inter...

Very short sleep duration reveals a proteomic fingerprint that is selectively associated with incident diabetes mellitus but not with incident coronary heart disease: a cohort study

The molecular pathways linking short and long sleep duration with incident diabetes mellitus (iDM) and incident coronary heart disease (iCHD) are not known. We aimed to identify circulating protein patterns as...

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety ...

Impact of perioperative low-molecular-weight heparin therapy on clinical events of elderly patients with prior coronary stents implanted > 12 months undergoing non-cardiac surgery: a randomized, placebo-controlled trial

Little is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. ...

A Pfs48/45-based vaccine to block Plasmodium falciparum transmission: phase 1, open-label, clinical trial

The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibod...

Impact of COVID-19 pandemic on depression incidence and healthcare service use among patients with depression: an interrupted time-series analysis from a 9-year population-based study

Most studies on the impact of the COVID-19 pandemic on depression burden focused on the earlier pandemic phase specific to lockdowns, but the longer-term impact of the pandemic is less well-studied. In this po...

Undiagnosed type 2 diabetes is common – intensified screening of established risk groups is imperative in Sweden: the SDPP cohort

Undiagnosed type 2 diabetes (T2D) is a global problem. Current strategies for diagnosis in Sweden include screening individuals within primary healthcare who are of high risk, such as those with hypertension, ...

Variability in the prevalence of depression among adults with chronic pain: UK Biobank analysis through clinical prediction models

The prevalence of depression among people with chronic pain remains unclear due to the heterogeneity of study samples and definitions of depression. We aimed to identify sources of variation in the prevalence ...

Prevalence and differences in the co-administration of drugs known to interact: an analysis of three distinct and large populations

The co-administration of drugs known to interact greatly impacts morbidity, mortality, and health economics. This study aims to examine the drug–drug interaction (DDI) phenomenon with a large-scale longitudina...

Anti-PD-1 antibody in combination with radiotherapy as first-line therapy for unresectable intrahepatic cholangiocarcinoma

Unresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination wi...

Characterising smoking and nicotine use behaviours among women of reproductive age: a 10-year population study in England

Tobacco smoking affects women’s fertility and is associated with substantial risks of adverse pregnancy outcomes. This study explored trends by socioeconomic position in patterns of smoking, use of non-combust...

Lipid metabolic reprogramming mediated by circulating Nrg4 alleviates metabolic dysfunction-associated steatotic liver disease during the early recovery phase after sleeve gastrectomy

The metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms unde...

Quantifying the impact of hospital catchment area definitions on hospital admissions forecasts: COVID-19 in England, September 2020–April 2021

Defining healthcare facility catchment areas is a key step in predicting future healthcare demand in epidemic settings. Forecasts of hospitalisations can be informed by leading indicators measured at the commu...

COVID-19 inequalities in England: a mathematical modelling study of transmission risk and clinical vulnerability by socioeconomic status

The COVID-19 pandemic resulted in major inequalities in infection and disease burden between areas of varying socioeconomic deprivation in many countries, including England. Areas of higher deprivation tend to...

Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis

To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved.

Association and biological pathways between lung function and incident depression: a prospective cohort study of 280,032 participants

Lung health is increasingly recognized as an essential factor in mental health. However, prospective evidence on lung function with incident depression remains to be determined. The study aimed to examine the ...

What is quality in long covid care? Lessons from a national quality improvement collaborative and multi-site ethnography

Long covid (post covid-19 condition) is a complex condition with diverse manifestations, uncertain prognosis and wide variation in current approaches to management. There have been calls for formal quality sta...

Olfactory bulb anomalies in KBG syndrome mouse model and patients

ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cor...

Identification and support of autistic individuals within the UK Criminal Justice System: a practical approach based upon professional consensus with input from lived experience

Autism spectrum disorder (hereafter referred to as autism) is characterised by difficulties with (i) social communication, social interaction, and (ii) restricted and repetitive interests and behaviours. Estim...

The effects of telehealth-delivered mindfulness meditation, cognitive therapy, and behavioral activation for chronic low back pain: a randomized clinical trial

Chronic low back pain (CLBP) is a significant problem affecting millions of people worldwide. Three widely implemented psychological techniques used for CLBP management are cognitive therapy (CT), mindfulness ...

Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study

The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research su...

PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer

Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibit...

Cervical lymph node metastasis prediction from papillary thyroid carcinoma US videos: a prospective multicenter study

Prediction of lymph node metastasis (LNM) is critical for individualized management of papillary thyroid carcinoma (PTC) patients to avoid unnecessary overtreatment as well as undesired under-treatment. Artifi...

Characterizing the polygenic overlap and shared loci between rheumatoid arthritis and cardiovascular diseases

Despite substantial research revealing that patients with rheumatoid arthritis (RA) have excessive morbidity and mortality of cardiovascular disease (CVD), the mechanism underlying this association has not bee...

Patterns of comorbidities in patients with atrial fibrillation and impact on management and long-term prognosis: an analysis from the Prospective Global GLORIA-AF Registry

Clinical complexity, as the interaction between ageing, frailty, multimorbidity and polypharmacy, is an increasing concern in patients with AF. There remains uncertainty regarding how combinations of comorbidi...

Canadians’ use of cannabis for therapeutic purposes since legalization of recreational cannabis: a cross-sectional analysis by medical authorization status

There has been a precipitous decline in authorizations for medical cannabis since non-medical cannabis was legalized in Canada in 2018. This study examines the demographic and health- and medical cannabis-rela...

Interventions on gender equity in the workplace: a scoping review

Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interve...

Real-world performance of indobufen versus aspirin after percutaneous coronary intervention: insights from the ASPIRATION registry

Indobufen is widely used in patients with aspirin intolerance in East Asia. The OPTION trial launched by our cardiac center examined the performance of indobufen based dual antiplatelet therapy (DAPT) after pe...

Blood leukocytes as a non-invasive diagnostic tool for thyroid nodules: a prospective cohort study

Thyroid nodule (TN) patients in China are subject to overdiagnosis and overtreatment. The implementation of existing technologies such as thyroid ultrasonography has indeed contributed to the improved diagnost...

Childhood urbanicity is associated with emotional episodic memory-related striatal function and common variation in NTRK2

Childhoods in urban or rural environments may differentially affect the risk of neuropsychiatric disorders, possibly through memory processing and neural response to emotional stimuli. Genetic factors may not ...

Inpatient-level care at home delivered by virtual wards and hospital at home: a systematic review and meta-analysis of complex interventions and their components

Technology-enabled inpatient-level care at home services, such as virtual wards and hospital at home, are being rapidly implemented. This is the first systematic review to link the components of these service ...

A practical evidence-based approach to management of type 2 diabetes in children and young people (CYP): UK consensus

Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and glo...

Comparing the clinical practice and prescribing safety of locum and permanent doctors: observational study of primary care consultations in England

Temporary doctors, known as locums, are a key component of the medical workforce in the NHS but evidence on differences in quality and safety between locum and permanent doctors is limited. We aimed to examine...

SARS-CoV-2, influenza A/B and respiratory syncytial virus positivity and association with influenza-like illness and self-reported symptoms, over the 2022/23 winter season in the UK: a longitudinal surveillance cohort

Syndromic surveillance often relies on patients presenting to healthcare. Community cohorts, although more challenging to recruit, could provide additional population-wide insights, particularly with SARS-CoV-...

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China

Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhib...

Association between genetic risk and adherence to healthy lifestyle for developing age-related hearing loss

Previous studies have shown that lifestyle/environmental factors could accelerate the development of age-related hearing loss (ARHL). However, there has not yet been a study investigating the joint association...

Associations between maternal pre-pregnancy BMI and infant striatal mean diffusivity

It is well-established that parental obesity is a strong risk factor for offspring obesity. Further, a converging body of evidence now suggests that maternal weight profiles may affect the developing offspring...

Evaluation of a hospital-initiated tobacco dependence treatment service: uptake, smoking cessation, readmission and mortality

The National Health Service in England aims to implement tobacco dependency treatment services in all hospitals by 2024. We aimed to assess the uptake of a new service, adapted from the Ottawa Model of Smoking...

Delivering synaptic protein mRNAs via extracellular vesicles ameliorates cognitive impairment in a mouse model of Alzheimer’s disease

Synaptic dysfunction with reduced synaptic protein levels is a core feature of Alzheimer’s disease (AD). Synaptic proteins play a central role in memory processing, learning, and AD pathogenesis. Evidence sugg...

Association between inflammatory bowel disease and cancer risk: evidence triangulation from genetic correlation, Mendelian randomization, and colocalization analyses across East Asian and European populations

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), has been associated with several cancer risks in observational studies, but the observed associations have bee...

Medication non-adherence and self-inflicted violence behaviors among 185,800 patients with schizophrenia in the community: a 12-year cohort study

Despite the importance of medication adherence in treatment effectiveness, little is known about the association between medication non-adherence and self-inflicted violence behaviors. We aimed to assess wheth...

Childhood maltreatment and health in the UK Biobank: triangulation of outcome-wide and polygenic risk score analyses

Childhood maltreatment is common globally and impacts morbidity, mortality, and well-being. Our understanding of its impact is constrained by key substantive and methodological limitations of extant research, ...

Sleep alterations as a function of 88 health indicators

Alterations in sleep have been described in multiple health conditions and as a function of several medication effects. However, evidence generally stems from small univariate studies. Here, we apply a large-s...

Sarcopenic obesity is part of obesity paradox in dementia development: evidence from a population-based cohort study

Sarcopenic obesity, a clinical and functional condition characterized by the coexistence of obesity and sarcopenia, has not been investigated in relation to dementia risk and its onset.

Sex-specific associations between sodium and potassium intake and overall and cause-specific mortality: a large prospective U.S. cohort study, systematic review, and updated meta-analysis of cohort studies

The impact of sodium intake on cardiovascular disease (CVD) health and mortality has been studied for decades, including the well-established association with blood pressure. However, non-linear patterns, dose...

Progress with the Learning Health System 2.0: a rapid review of Learning Health Systems’ responses to pandemics and climate change

Pandemics and climate change each challenge health systems through increasing numbers and new types of patients. To adapt to these challenges, leading health systems have embraced a Learning Health System (LHS...

Regional disparities and risk factors of mortality among patients at high risk of sudden cardiac death in emerging countries: a nonrandomized controlled trial

Comprehensive data on patients at high risk of sudden cardiac death (SCD) in emerging countries are lacking. The aim was to deepen our understanding of the SCD phenotype and identify risk factors for death amo...

Association of in utero HIV exposure with child brain structure and language development: a South African birth cohort study

There is a growing population of children with in utero HIV exposure who are at risk of poor neurodevelopmental outcomes despite avoiding HIV infection. However, the underlying neurobiological pathways are not...

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Last Reviewed: February 5, 2024

Current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments

Sandra salm.

1 Institute of Pharmaceutical Biology, Goethe University, Frankfurt, Germany

2 Institute of General Practice, Goethe University, Frankfurt, Germany

Jochen Rutz

3 Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany

Marjan van den Akker

4 Department of Family Medicine, Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands

5 Department of Public Health and Primary Care, Academic Centre of General Practice, KU Leuven, Leuven, Belgium

Roman A. Blaheta

Beatrice e. bachmeier.

Marilena Gilca , Carol Davila University of Medicine and Pharmacy, Romania

Associated Data

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding author.

Herbal medicines are becoming increasingly popular among patients because they are well tolerated and do not exert severe side effects. Nevertheless, they receive little consideration in therapeutic settings. The present article reviews the current state of research on the clinical benefits of herbal medicines on five indication groups, psychosomatic disorders, gynecological complaints, gastrointestinal disorders, urinary and upper respiratory tract infections. The study search was based on the database PubMed and concentrated on herbal medicines legally approved in Europe. After applying defined inclusion and exclusion criteria, 141 articles were selected: 59 for psychosomatic disorders (100% randomized controlled trials; RCTs), 20 for gynecological complaints (56% RCTs), 19 for gastrointestinal disorders (68% RCTs), 16 for urinary tract infections (UTI, 63% RCTs) and 24 for upper respiratory tract infections (URTI) (79% RCTs). For the majority of the studies, therapeutic benefits were evaluated by patient reported outcome measures (PROs). For psychosomatic disorders, gynecological complaints and URTI more than 80% of the study outcomes were positive, whereas the clinical benefit of herbal medicines for the treatment of UTI and gastrointestinal disorders was lower with 55%. The critical appraisal of the articles shows that there is a lack of high-quality studies and, with regard to gastrointestinal disorders, the clinical benefits of herbal medicines as a stand-alone form of therapy are unclear. According to the current state of knowledge, scientific evidence has still to be improved to allow integration of herbal medicines into guidelines and standard treatment regimens for the indications reviewed here. In addition to clinical data, real world data and outcome measures can add significant value to pave the way for herbal medicines into future therapeutic applications.

1 Introduction

Plant derived drugs have been used since humans have started treating physical and mental illnesses. They are part of Traditional Medicine in different cultures all over the world ( Yuan et al., 2016 ). Since then, medicine and treatment procedures have evolved and while in Traditional Medicine a holistic approach of life focusing on health and its maintenance was common philosophy, present Modern Medicine has a clear emphasis on unravelling the changes leading to disease and eradiating it ( Fries, 2019 ). Traditional medicine has a rigorous algorithm of identifying the root of the disease, which is based on traditional concepts, which, unfortunately, are considered obsolete nowadays, despite their practical longevity (e.g., acupuncture, ayurveda). The problem is that this traditional medical epistemology is not fully understood and science has limited tools to “translate” it into modern terms.

With the success of synthetic drugs along with the design of targeted therapies interfering specifically with the respective disease-related signaling pathways, herbal medicines have been eliminated from modern rational treatment strategies. The most important obstacles for the use in novel therapy strategies is that markers to measure clinical efficacy of herbal medicine have not been developed so far. Markers of efficacy of herbal drugs could also be useful to distinguish between patients who could benefit from a therapy with herbal medicines from those who will not. First preclinical studies already indicate that those markers or “signatures” (e.g., mRNA, miRNA) could be found in the future ( Bachmeier et al., 2007 ; Bachmeier et al., 2008 ; Bachmeier et al., 2009 ; Bachmeier et al., 2010 ; Killian et al., 2012 ; Kronski et al., 2014 ).

In the last years, more and more patients report on the perceived efficacy of herbal drugs and praise the absence of undesired side effects and the good tolerability.

The following section provides insights into the standard therapies of selected ailments for which herbal medicines may be a rational alternative.

1.1 Indications suitable for treatment with herbal medicines

Herbal medicines are in particular suitable for the treatment of non-life-threatening conditions for which knowledge from traditional use is available pointing to their clinical benefits in treating the respective ailment ( Wachtel-Galor and Benzie, 2011 ). This applies especially to psychosomatic disorders, gynecological complaints, and upper respiratory tract infections. However also for other diseases like gastrointestinal diseases, urinary tract infections herbal medicines have been clinically applied and—as we will show in this review—with some success.

Standard Care of psychosomatic disorders comprises the application of synthetic psychotropic drugs and psychotherapy ( Laux, 2021 ). Psychotropic drugs are used not only for the treatment of depressive disorders and anxiety, but also for sleep disorders, excitation and chronic pain ( Gründer and Benkert, 2012 ). However undesired adverse events having negative impact on quality of life can occur like, e.g., weight gain, sexual dysfunction, sedation, headache and tremor ( Grunze et al., 2017 ). In addition their use, in particular benzodiazepines, can lead to addiction and drug abuse ( Soyka and Mann, 2018 ) and interactions with other medication has to be taken into consideration especially in older multimorbid patients ( Burkhardt and Wehling, 2010 ). About 23% of all over 70-year-old people have psychosomatic disorders with about 40% requiring therapy ( Haupt and Vollmar, 2008 ). In this context herbal medicines represent an interesting alternative to avoid the above-mentioned problems with standard synthetic drugs. However, they do not belong to standard therapy-options and therefore are underrepresented in therapy-guidelines ( Bittel et al., 2022 ). Nevertheless they play an important role in self-medication of patients ( Stange, 2014 ) probably due to their favorable ratio between benefit and side-effects.

Gynecological complaints include, e.g., menopausal and premenstrual symptoms. According to the German medical guideline for post- and perimenopause, vasomotor symptoms of the peri- and post-menopause such as hot flushes and sweating should be treated with hormone therapy for menopause (hormone replacement therapy; HRT), if not contraindicated ( AWMF, 2020 ). The side effects of HRT include edema, joint pain, psychological symptoms or even thrombosis and breast cancer ( Maclennan et al., 2004 ). Herbal medicines, on the other hand, are characterized by a low risk of adverse events which increases patients’ adherence and in consequence prevents therapy discontinuations ( AWMF, 2020 ). Premenstrual syndrome (PMS) is characterized by recurring physical and psychological symptoms in the days before menstruation. There are currently no medical guidelines in German-speaking countries for the treatment of PMS. Systematic reviews on hormonal treatments (oral contraceptives, progesterone and estrogen) ( Ford et al., 2006 ; Lopez et al., 2007 ; Naheed et al., 2013 ; Kwan and Onwude, 2015 ) and acupuncture/acupressure ( Armour et al., 2018 ) point to ambiguous evidence. Treatment with serotonin reuptake inhibitors was shown to be effective but was associated with frequent side effects, e.g., nausea and asthenia ( Marjoribanks et al., 2013 ).

Gastrointestinal diseases include several conditions like irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disease (hepatitis), and functional dyspepsia (FD).

Beside dietary changes, stress management and psychotherapy, severe cases of IBS and IBD require additional medication to reduce inflammation or to slow down the intestinal irritations. However patients often complain about the side effects of medical treatment like, e.g., dizziness or weight gain (particularly caused by steroids), or undesired fatigue, headache, and/or tiredness associated with the intake of methotrexate ( Feagan et al., 1995 ). Common types of hepatitis are viral hepatitis B and C. Antiviral therapy represents the treatment of choice to fight the virus caused disease. However, poor tolerability and significant adverse effects that include, for example, headaches, dizziness, depression, and irritability often lead to treatment discontinuation, further decreasing response rates ( Cornberg et al., 2002 ). FD is a common gastrointestinal disorder treated by proton pump inhibitors (PPI) or H2 receptor antagonist, and/or treatment with tricyclic antidepressants or prokinetic agents. As in all cases, adverse side effects may occur ranging from dizziness to the development of diabetes mellitus type 2 ( Yuan et al., 2021 ).

Urinary tract infections (UTI) with estimated 150 million cases worldwide each year reflect the most common outpatient infections ( Zavala-Cerna et al., 2020 ). Women are more susceptible than men with a lifetime incidence of 50%–60%. Application of antibiotics represents the standard treatment regimen to overcome the infection. However, serious side effects, predominantly exerted on the digestive system, may outweigh the benefits of this drug class. Most importantly, routine use of antibiotics bears the risk to trigger the selection of resistant strains. Hence, avoiding antibiotic treatment of UTI has gained high priority among the urologic community ( Jung et al., 2023 ). Lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) requires a medical therapy which aims to reduce the BPH-related complications. A range of synthetic drugs is available to treat this condition. However, these have a range of side effects, including postural hypotension, dizziness, asthenia, abnormal ejaculation, intraoperative floppy iris syndrome (α1-blocker), or decreased libido, gynecomastia, and erectile dysfunction (5α-reductase inhibitors) ( Cheng et al., 2020 ). Due to this, patients often discontinue treatment.

The most common acute upper respiratory infections include bronchitis, rhinosinusitis and common cold. Common cold or acute viral rhinosinusitis is triggered by a viral infection/inflammation of the nose and by definition has a duration up to 10 days. According to Jaume and co-workers ( Jaume et al., 2020 ) the recommended therapy (mainly symptomatic) contains of paracetamol, NSAIDs, second-generation antihistamines to reduce symptoms the first 2 days; nasal decongestants with small effect in nasal congestion in adults; combination of analgesics and nasal decongestants; ipratropium bromide for reducing rhinorrhea; probiotics; zinc when administered the first 24 h after the onset of symptoms; nasal saline irrigations; and some herbal medicines. About 5% of adults have an episode of acute bronchitis each year. An estimated 90% of these seek medical advice for the same ( Saust et al., 2018 ). Acute bronchitis is caused by infection of the large airways commonly due to viruses and is usually self-limiting. Bacterial infection is uncommon. Still, often antibiotics are prescribed, despite lacking effectiveness ( Tanner and Karen Roddis, 2018 ). Most medical guidelines advice a “wait-and-see” policy, the use of antihistamines and cough medicines is discouraged.

1.2 Objectives

In the last decade we experienced a renaissance of herbal medicines with a rising demand especially for the treatment of the before-mentioned indications. This implicates that there is an urgent need for a scientific progress towards a rational phytotherapy, which will combine the benefits of “Modern Medicine” with the “Traditional Knowledge” on the therapeutic benefits of herbal medicines.

In order to create a basis of knowledge to build upon novel interdisciplinary research ideas towards the establishment of herbal medicines into rational therapeutic strategies, we extracted information from clinical studies. Thereby we aimed to get an overview on.

• - which herbal medicines have been studied so far for which ailment
• - which outcomes have been studied
• - what quality level (level of evidence) the published studies have

Answering these questions, we create a comprehensive critical picture of the current knowledge on clinical efficacy and benefits as well as on failures and possible adverse events. Based on the results of these studies we give recommendations for practitioners and patients.

2.1 Search strategy and selection of scientific reports

Information on the therapeutic use of herbal medicines in different ailments was collected from scientifically published articles by conducting a search in the database PubMed for each of the five indication groups according to the following inclusion and exclusion criteria.

2.1.1 Inclusion criteria

• 1. Herbal Medicine
• a.Psychosomatic symptoms (depressive disorder, sleeping disorders/insomnia, anxiety, cognitive impairment)
• b.Gynecological complaints (climactic symptoms, menstrual symptoms, premenstrual syndrome)
• c.Gastrointestinal disorders/dyspepsia
• d.Urinary tract infections
• e.Upper respiratory tract infections
• 3. Clinical Trial
• Exclusion criteria
• a. Reports in languages other than German or English language
• b. No full-text available
• c. Study protocols
• d. Traditional medicine (e.g., Traditional Chinese Medicine, Ayurveda, etc. ),
• e. Aroma therapy
• f. Dietary supplements
• g. Self-made extracts and preparations
• h. Adjuvant treatment with herbal medicine
• i. Herbal medicines without market access in the EU
• j. In vivo / in vitro studies (pre-clinical studies)
• k. Homeopathy
• l. Acupuncture/acupressure
• m. Children and youth (under the age of 18 years)
• n. Healthy volunteers
• o. Primary preventive interventions (incl. Pre-post-operative complaints)
• p. Predominant comorbidities
• q. Case studies/case reports
• r. Televised, internet-based or web-based trials

Reasons for exclusion criteria:

a, b: Authors should be able to read and understand the full text; c: clinical results should have been obtained from a study; d, e, f, g, h, i: selected in order to filter all available information on legally approved (in Europe in particular in Germany) herbal medicines or the respective standardized extract (HMPC Monographs of the European Medical Agency - EMA) only; j: preclinical evidence should be excluded; k, l: alternative naturopathic therapy forms should be excluded; m: children should be excluded due to different drug metabolism; n, o: healthy volunteers should be excluded in order to obtain information on clinical therapeutic benefits; p: predominant comorbidities should be excluded because they can affect the efficacy of the herbal drug in particular when co-administered with other drugs; q; clinical benefits from single cases are difficult to generalize; r: excluded for methodological reasons, e.g., data interpretation.

2.2 Data extraction and quality assessment of scientific reports

To get an overview on the characteristics of all included articles, a table was created for each indication group containing information on the publication, the study design, the population and treatment duration, the indication and the primary outcome, the herbal medicine and comparison treatment (comparator) as well as the results. Furthermore, we performed a quality assessment of the collected reports according to the following scoring method.

• • 1 point for an observational study or a pre-post observational comparison
• • 2 points for a clinical trial
• • 3 points for a randomized controlled trial plus 1 additional point for blinding

Thereby, a score between 1 and 4 was obtained indicating the quality for all scientific reports; respectively publications with the highest level of evidence (RCT + blinded) had a scoring value of four points (see Figures 1 – 5 ).

Numbers of studies and outcomes.

3.1 Psychosomatic disorders

A search for publications with the terms “psychosomatic disorder” and “herbal medicine” yielded only 64 results. Therefore, the search was extended with more specific terms (see inclusion criteria) yielding in 4.440 hits for depressive disorder, 1.907 hits for sleeping disorders, 2.380 hits for anxiety and 1.374 hits for cognitive impairment including Alzheimer’s disease. After eliminating all publications according to the exclusion criteria 59 publications remained. Among those, 39 studies were related to depressive disorders, 4 to sleeping disorders, 6 to anxiety and 10 to cognitive impairment and Alzheimer’s disease (neurological disorders). Most of them were double blind randomized controlled trials (quality group 4). For the treatment of depressive disorders predominantly Hypericum perforatum L (St. John’s Wort; SJW) was used and only few studies examined the clinical benefits of Rhodiola rosea L (Rosewood). Valeriana officinalis L (Valerian Root) and Humulus lupulus L (Hops) extracts were preferred for the treatment of sleeping disorders, while for anxietyextracts of Lavandula angustifolia (Lavender) were studied. Extracts of Ginkgo biloba L (Maidenhair Tree) were used in clinical studies with patients having neurological disorders (cognitive impairment and Alzheimer’s disease). Supplementary Table S1 provides an overview of the studies, their characteristics and results (see also Figure 1 ).

3.1.1 Depressive disorders

The use of herbal medicines in depressive disorders is well examined and in particular the clinical benefits of SJW are well supported by clinical studies of high quality. All 37 selected studies on the use of SJW in depressive disorders ranging from mild to severe forms have been double-blind randomized controlled trials (quality group 4). Study duration was predominantly between 4 and 8 weeks and only few studies examined the effects for longer time periods of up to 6 months. The majority of the studies reported positive therapeutic effects concerning Hamilton depression rating scale (HAMD) as primary outcome parameter and only 5 of them ( Shelton et al., 2001 ; Davidson et al., 2002 ; Bjerkenstedt et al., 2005 ; Moreno et al., 2006 ; Rapaport et al., 2011 ) did not demonstrate superiority as compared to placebo or pre-post.

In six studies (published predominantly before the year 2000) comparing SJW with tricyclic anti-depressive drugs the clinical benefits of the herbal drug in respect to placebo or in pre-post comparison was at least equal to the synthetic drug no matter if it was imipramine ( Vorbach et al., 1994 ; Vorbach et al., 1997 ; Philipp et al., 1999 ; Woelk, 2000 ), maprotiline ( Harrer et al., 1994 ) or amitriptyline ( Wheatley, 1997 ). However, with regards to tolerability, SJW was clearly superior to any of the tricyclic antidepressants.

The more recent studies compared the efficacy of SJW with the selective serotonin reuptake inhibitors (SSRI) paroxetine, sertraline, citalopram and fluoxetine. In most of the 18 studies the therapeutic benefits of SJW were at least equal to those of the SSRIs ( Harrer et al., 1999 ; Berger et al., 2000 ; Brenner et al., 2000 ; Friede et al., 2001 ; van Gurp et al., 2002 ; Bjerkenstedt et al., 2005 ; Gastpar et al., 2005 ; Szegedi et al., 2005 ; Anghelescu et al., 2006 ; Gastpar et al., 2006 ; Sarris et al., 2012 ). In two studies SJW was even superior to fluoxetine ( Fava et al., 2005 ) or paroxetine ( Seifritz et al., 2016 ) in reducing depressive symptoms. In one study the responders of a previous study were included in a further RCT testing the efficacy of SJW against citalopram. Here the numbers of patients with relapse was lower in the SJW group as compared to citalopram ( Singer et al., 2011 ). The results of one study indicated that SJW was less efficacious than both fluoxetine and placebo, however in this study the group on SJW had the lowest remission rates ( Moreno et al., 2006 ). In two studies no statistical differences in HAMD scores between SJW, placebo and citalopram ( Rapaport et al., 2011 ) or sertraline ( Davidson et al., 2002 ) could be found with adverse effects in the SJW and the SSRI groups.

In most of the above-mentioned studies, comparing the efficacy of SJW to standard therapy, a placebo group was included. However, in 13 studies SJW was tested exclusively against placebo whereby two of these studies examined the efficacy of different dosages of SJW extract ( Laakmann et al., 1998 ; Kasper et al., 2006 ). In these studies, the higher concentrations had the better clinical benefits. In a continuation study of the effect of SJW in long term treatment a higher dosage (1,200 mg/d) was not superior to the lower one (600 mg/d) ( Kasper et al., 2007 ). Interestingly the higher dosages were still well tolerated although mild adverse events related to gastrointestinal disorders were observed in a small portion of the patients ( Kasper et al., 2006 ). In only one of our selected studies SJW was not effective in comparison to placebo for the treatment of major depression but safe and well tolerated ( Shelton et al., 2001 ). In all other studies SJW was superior to placebo no matter if given in low ( Laakmann et al., 1998 ; Lecrubier et al., 2002 ; Randlov et al., 2006 ), medium ( Kasper et al., 2006 ; Kasper et al., 2007 ; Mannel et al., 2010 ) or in high ( Hansgen et al., 1994 ; Harrer et al., 1994 ; Sommer and Harrer, 1994 ; Kalb et al., 2001 ; Uebelhack et al., 2004 ; Kasper et al., 2006 ; Kasper et al., 2007 ; Kasper et al., 2008 ) dosages.

For the efficacy of Rhodiola rosea in treatment of depressive disorders only few studies were performed so far. Therefore, a clear conclusion cannot be drawn, especially as the outcomes are not homogenous. While one study investigating the efficacy of R. rosea against placebo and the SSRI sertraline reported on a statistically not-significant inferiority of the herbal medicine ( Mao et al., 2015 ) another study demonstrated clinical benefits concerning the symptoms of depression, insomnia, emotional instability and somatization against placebo. In this study two dosages of R. rosea were tested and the higher dose (680 mg/d) showed even positive effects on self-esteem ( Darbinyan et al., 2007 ).

3.1.2 Sleeping disorder

Interestingly the search for qualitatively high clinical studies (according to our inclusion and exclusion criteria) revealed only few studies. The majority of them investigated the efficacy of valerian alone ( Donath et al., 2000 ) or in combination with hops ( Koetter et al., 2007 ) compared to placebo ( Donath et al., 2000 ; Koetter et al., 2007 ) or to oxazepam ( Dorn, 2000 ; Ziegler et al., 2002 ). All studies reported clinical benefits, however while the one research group reported that valerian alone was efficacious against insomnia ( Donath et al., 2000 ) the other group reported on clinical benefits only in combination with hops ( Koetter et al., 2007 ). Both study designs were placebo-controlled. In comparison to oxazepam valerian was not inferior and both therapy options improved sleep quality (SF-B) in a similar fashion ( Dorn, 2000 ; Ziegler et al., 2002 ).

3.1.3 Anxiety

Herbal Medicines with lavender extracts were clinically studied for the treatment of anxiety. Between 2010 and 2019 six qualitatively high studies performed in Germany, Austria and Switzerland reported on the beneficial effects of lavender against symptoms of anxiety with improvements on the Hamilton anxiety rating (HAMA) scale as primary outcome ( Kasper et al., 2010 ; Woelk and Schlafke, 2010 ; Kasper et al., 2014 ; Kasper et al., 2015 ; Kasper et al., 2016 ; Seifritz et al., 2019 ) and all studies used the same extract (WS1265). Four of the 6 studies were performed by the same group, however the study design differed. In these studies the efficacy of lavender was either compared to placebo ( Anghelescu et al., 2006 ; Kasper et al., 2010 ; Kasper et al., 2016 ; Seifritz et al., 2016 ) and/or to paroxetine ( Kasper et al., 2014 ) and lorazepam ( Woelk and Schlafke, 2010 ). Overall, the lavender preparation was regarded as efficacious and safe.

3.1.4 Neurological disorders (cognitive impairment and Alzheimer)

We selected 10 studies investigating the efficacy of ginkgo biloba extract in the treatment of cognitive impairment and Alzheimer’s Disease (AD) with 8 of them testing against placebo ( Le Bars et al., 1997 ; Le Bars et al., 2002 ; Le Bars, 2003 ; van Dongen et al., 2003 ; Schneider et al., 2005 ; Napryeyenko et al., 2007 ; Gavrilova et al., 2014 ; Gschwind et al., 2017 ), one against rivastigmine ( Nasab et al., 2012 ) and one against donepezil ( Mazza et al., 2006 ). In three of the studies two different ginkgo extracts did not show superiority over placebo regarding the primary outcome. In detail 5 of the studies showed that extracts of ginkgo biloba lead to a decrease in NPI composite score ( Gavrilova et al., 2014 ) improved significantly ADAS-Gog and GERRI ( Le Bars et al., 1997 ; Le Bars et al., 2002 ; Le Bars, 2003 ), or the SKT test battery ( Napryeyenko et al., 2007 ) as outcome parameters. In three studies ginkgo extracts did not show superiority over placebo regarding the primary outcome parameters ADAS-cog ( Schneider et al., 2005 ), gait analyses ( Gschwind et al., 2017 ) or SKT test-battery ( van Dongen et al., 2003 ), whereby in one of these studies the primary outcome parameter ADAS-cog also declined in the placebo group rendering the results of the study inconclusive ( Schneider et al., 2005 ). With respect to the AD conventional medication rivastigmine, ginkgo biloba extract was inferior regarding the primary outcome parameters MMSE and SKT test-battery ( Nasab et al., 2012 ). Finally one study in which gingko biloba was more efficacious than placebo and equal to the second generation cholinesterase inhibitor donepezil ( Mazza et al., 2006 ) was heavily criticized by two other groups ( Corrao et al., 2007 ; Korczyn, 2007 ), making it difficult to estimate if the use of ginkgo containing herbal medicines are justified for the treatment of mild to moderate AD.

3.2 Gynecological complaints

Of 383 search hits, 20 articles met the inclusion criteria. Eleven studies were related to menopausal symptoms and nine to PMS. Most were double-blind randomized controlled trials or observational studies ( Figure 2 ). The studies on menopausal symptoms reported mainly positive results and the results concerning PMS were exclusively positive ( Figure 2 ). The tested phytopharmaceuticals contained Cimicifuga racemosa (L.) (Black cohosh) (10 studies) and Salvia officinalis (Sage) (1 study) for the treatment of menopausal symptoms and Vitex agnus-castus L (VAC, Chaste tree) (8 studies) and SJW (1 study) for PMS. Supplementary Table S2 provides an overview of the study characteristics and results.

3.2.1 Menopausal symptoms

In studies examining the clinical benefits of black cohosh for the treatment of menopausal symptoms, sample sizes ranged from n = 62 to n = 6,141. Treatment duration was between 12 weeks and 9 months. The herbal drug dosages ranged from 20 to 127.3 mg.

In comparison to HRT, the benefit-risk-balance points to significant non-inferiority and superiority of black cohosh ( Bai et al., 2007 ). In three other studies menopausal complaints improved overall, but differences between black cohosh and HRT were not significant ( Wuttke et al., 2003 ; Nappi et al., 2005 ; Friederichsen et al., 2020 ). The combination of black cohosh with SJW significantly reduced menopausal complaints and was superior to transdermal estradiol ( Briese et al., 2007 ). Independent of a high or low dose, menopausal complaints decreased significantly ( Liske et al., 2002 ; Drewe et al., 2013 ). Adverse events rates were lower in the low dose group ( Drewe et al., 2013 ) or similar to the high dose group ( Liske et al., 2002 ). Menopausal symptoms decreased significantly more for black cohosh compared to placebo ( Osmers et al., 2005 ). In another study with 62 participants, the difference between the symptom scores just approached significance ( Wuttke et al., 2003 ). Interestingly, this also applies to the comparison of conjugated estrogens and placebo. Adverse events rates did not differ significantly between black cohosh and placebo ( Wuttke et al., 2003 ; Osmers et al., 2005 ). Significant and clinically relevant reductions in menopausal symptoms ( Vermes et al., 2005 ) or higher quality of life ( Julia Molla et al., 2009 ) were observed after treatment with black cohosh compared to therapy start. Sage taken for 8 weeks significantly decreased the number of menopausal hot flushes from week to week ( Bommer et al., 2011 ). Observed treatment-related adverse events were mild and occurred in only one person. However, no comparison was made to another treatment or placebo.

3.2.2 Premenstrual syndrome

Eight studies dealt with the treatment of PMS with VAC. The sample sizes ranged from n = 43 to n = 1,634. Treatment duration was three cycles; Berger et al. (2000) added three subsequent cycles without treatment. The administered dosages ranged from 1.6 to 20 mg extract.

Results of studies comparing VAC with pyridoxine or placebo were similar. PMS symptom reduction was significantly more pronounced for VAC compared to pyridoxine ( Lauritzen et al., 1997 ) or placebo ( Schellenberg, 2001 ; Bachert et al., 2009 ; Barrett et al., 2010 ; Schellenberg et al., 2012 ). Rates of adverse events were similar between groups in each study ( Loch et al., 2000 ; Schellenberg, 2001 ; Barrett et al., 2010 ; Schellenberg et al., 2012 ). Schellenberg et al. (2012) compared a VAC reference dose to a lower and higher dose; the results were in favor for the reference dose compared to the low dose. No significant differences between the high and reference dose emerged. The number of participants with adverse events was slightly elevated for the high dose. In single-arm studies, symptoms of PMS significantly decreased after three cycles of VAC treatment ( Berger et al., 2000 ; Loch et al., 2000 ; Momoeda et al., 2014 ). Only mild PMS-like adverse events were observed. Berger et al. demonstrated a gradual symptom return after therapy completion ( Berger et al., 2000 ). PMS symptoms were significantly higher compared to the end of the treatment, but still 20% lower than at baseline.

A clinical study testing the efficacy of SJW in treating mild PMS ( Canning et al., 2010 ) demonstrated significant improvements in physical (e.g., food craving) and behavioral (e.g., confusion) symptoms compared to placebo. The effect on mood (e.g., irritability) and pain (e.g., cramps) was not significant.

3.3 Gastrointestinal disorders

A search for publications with the search terms “gastrointestinal disorder” and “herbal medicine” yielded a total of 19 results after applying the exclusion criteria. Of these, eight studies were related to hepatic disorders, three publications dealt with IBD, two studies focused on IBS, and six studies had been done on FD. Most of them were done in a double-blinded randomized controlled manner ( n = 12) ( Figure 3 ). Silybum marianum (L.) Gaertn (Silymarin, milk thistle) was used in patients suffering from a hepatic disease. Patients with IBD were treated with Artemisia absinthium L (wormwood) or Potentilla erecta (tormentil). The standardized extract STW 5 containing Iberis amara (bitter candytuft), Glycyrrhiza glabra L (Liquorice), Carum carvi L (caraway), Mentha × piperita (peppermint), Melissa officinalis L (lemon balm) , Matricaria chamomilla (chamomile) , Angelica archangelica (wild celery), Chelidonium majus (greater celandine) and milk thistle has been applied in IBS and FD. The same has been done with the standardized extract STW 5-II which in contrast to STW 5 is free of wild celery, greater celandine, and milk thistle. SJW has been used to treat patients suffering from IBS. A combination of the standardized extracts WS 1340 (peppermint oil) and WS 1520 (caraway oil) was used for patients with FD. Supplementary Table S3 and Figure 3 provide an overview of the study characteristics and results.

3.3.1 Hepatic disease

Trials on steatohepatitis, cirrhosis and different kinds of hepatitis ( n = 18) included patient cohorts ranging from 14 to 200 participants, all of them aged >18 years. Patients were treated with silymarin orally or intravenously ( Pares et al., 1998 ; Tanamly et al., 2004 ; Ferenci et al., 2008 ; Hawke et al., 2010 ; Fried et al., 2012 ; Adeyemo et al., 2013 ; Fathalah et al., 2017 ; Tanwar et al., 2017 ) with dosages ranging from 280 to 2,100 mg/day or 5–20 mg/kg/day, respectively. Six studies compared the HM group to a placebo group ( Pares et al., 1998 ; Tanamly et al., 2004 ; Hawke et al., 2010 ; Fried et al., 2012 ; Adeyemo et al., 2013 ; Tanwar et al., 2017 ). Silymarin did not reduce virus titers and/or serum alanine transaminase (ALT) in patients with Hepatitis C and non-alcoholic Steatohepatitis C, compared to placebo ( Adeyemo et al., 2013 ). The same observation has been made by others ( Hawke et al., 2010 ). Furthermore, the integration of silymarin into a PEGylated (Peg)-interferon based regimen did not improve the outcome of HCV patients in terms of HCV RNA suppression and Enhanced Liver Fibrosis score performance ( Tanamly et al., 2004 ). There was also no effect of silymarin on HCV patients who were previously unsuccessfully treated with interferon (multicenter, double-blind, placebo-controlled trial) ( Fried et al., 2012 ). Although HCV-patients reported to “feel better” after 12 months of silymarin therapy in a further study, symptoms and quality of life (QOL) scores did not differ between the silymarin and the placebo group ( Tanamly et al., 2004 ). Treatment with silymarin was also well tolerated over a period of 2 years. However, the course of liver cirrhosis in this patient cohort has not been improved ( Pares et al., 1998 ). Contrasting these results, dose escalating studies on HCV cirrhotic patients revealed positive effects of silymarin or silibinin (also milk thistle), in a way that high-dosed silymarin (1,050 mg/day) improved QOL and biochemical parameters of chronic HCV-decompensated cirrhotic patients with no serious adverse events ( Ferenci et al., 2008 ; Fathalah et al., 2017 ) compared to low-dosed silymarin (420 mg/day). Notably, silibinin exerted a dose-dependent antiviral effect on Peg-interferon/ribavirin non-responders ( Ferenci et al., 2008 ; Fathalah et al., 2017 ).

3.3.2 Inflammatory bowel disease (IBD)

Between 2007 and 2009, three clinical trials on CD or IBD have been conducted, two in Germany (quality groups 1 and 2) and one in the United States (quality group 4) ( Huber et al., 2007 ; Omer et al., 2007 ; Krebs et al., 2010 ). Patients were treated with wormwood or tormentil for 3–10 weeks. A total of 30 patients were treated with wormwood or placebo ( Omer et al., 2007 ; Krebs et al., 2010 ). In this context, wormwood decreased tumor necrosis factor alpha levels and the CD activity index score, whilst scores for IBD questionnaire and Hamilton depression scale have been improved, compared to the controls ( Omer et al., 2007 ; Krebs et al., 2010 ). Daily intake of tormentil reduced clinical activity index scores in all patients, however, during the wash out phase scores increased again. Tormentil has been proven to be safe for ulcerative colitis patients in dosages up to 3,000 mg/day ( Huber et al., 2007 ).

3.3.3 Irritable bowel syndrome (IBS)

Symptoms of IBS were treated with STW 5 and STW 5-II or SJW (both studies were quality group 4) ( Madisch et al., 2004b ; Saito et al., 2010 ). The clinical trial carried out by Madisch et al. compared the effects of the treatment group with those of bitter candytuft mono-extract and placebo. STW 5 and STW 5-II (60 drops/day over 4 weeks) significantly reduced the total abdominal pain and the IBS score compared to placebo and bitter candytuft mono-extract ( Madisch et al., 2004b ). The study carried out by Saito and others investigated the clinical efficacy of SJW pointing to a lower effect as compared to placebo ( Saito et al., 2010 ).

3.3.4 Functional dyspepsia (FD)

Six studies on patients suffering from FD were performed, including treatment with either a WS 1520/WS 1340 combination ( n = 3) ( Madisch et al., 1999 ; Rich et al., 2017 ; Storr and Stracke, 2022 ) or with STW 5 ( von Arnim et al., 2007 ) and/or STW 5-II ( n = 3) ( Rösch et al., 2002 ; Madisch et al., 2004a ). WS 1340/WS 1520 was documented to be a “valuable” ( Storr and Stracke, 2022 ) or an “effective” therapeutic regimen ( Rich et al., 2017 ), as it relieved pain and improved disease-specific QOL, compared to placebo. The primary outcome of WS 1340/WS 1520 was also proven to be comparable to the prokinetic agent cisapride ( Madisch et al., 1999 ).

It is to be noted that the use of cisapride has meanwhile be restricted by the EMA due to the risk of potentially life-threatening cardiac arrhythmia [ https://www.ema.europa.eu/en/medicines/human/referrals/cisapride ].

Similar results have been presented in the STW 5 and STW 5-II trials. The gastrointestinal symptom score was significantly lowered when compared to the placebo group ( Madisch et al., 2004a ; von Arnim et al., 2007 ), with a therapeutic response comparable to cisapride ( Rösch et al., 2002 ).

3.4 Urinary tract infection (UTI) and lower urinary tract symptoms (LUTS)

Initial search on herbal drugs in urologic clinical trials pointed to 263 manuscripts published between 1983 and 2022. Narrowing the search to “herbal medicine” (HM) 18 relevant publications were identified. One publication was nearly identical to another one and, therefore, has not been taken care of in this chapter, one article only reviewed former trials (16 publications remaining). All of them were related to lower urinary tract infection (UTI), or acute uncomplicated cystitis, respectively. Four different HM have been applied, either compared to placebo or guideline-based treatment ( n = 12).

3.4.1 Urinary tract infections (UTI)

Several studies investigated the standardized herbal extract BNO 1045 which contains Centaurium erythraea Rafin, herba (Centaury); Levisticum officinale Koch, radix (Lovage); and Rosmarinus officinalis L., folium (Rosemary). In two studies, the clinical benefits of BNO 1045 in preventing UTI in high-risk women undergoing urodynamic studies (UDS) ( Miotla et al., 2018 ) or urogynecological surgeries ( Wawrysiuk et al., 2022 ) was evaluated. High-risk women were defined as: age over 70, elevated postvoid residual urine>100 mL, recurrent UTI, pelvic organ prolapse (POP) ≥II in POP-Q scale, and neurogenic bladder. No statistical differences in UTI incidence were found between patients receiving antibiotics or BNO 1045. No superiority of antibiotics over BNO 1045 has been confirmed as well in a subsequent prospective study on postoperative UTI after midurethral sling surgery (MUS) ( Rechberger et al., 2020 ). In another study, an herbal mixture based on D-mannose, Arctostaphylos uva-ursi, Betula pendula, and Berberis aristata was compared to BNO 1045 in reducing symptoms of UTI after MUS ( Rechberger et al., 2022 ). The rationale was based on the EAU 2022 guidelines which recommended D-mannose as prophylaxis of UTI. In this context, BNO 1045 was proven to be similar effective, compared to the herbal mixture. The use of BNO 1045 has been documented here to be a potential and valuable alternative to antibiotics for UTI prevention. All four trials have been carried out in the same institution involving the same main investigators which were (partially) associated with the manufacturer of BNO 1045.

A randomized, double-blind, multicenter Phase III clinical trials compared the efficacy and of BNO 1045 to antibiotics concerning symptoms and recurrence rates in women with uncomplicated UTI. Based on the endpoints “UTI-recurrence” and “additional antibiotics use”, BNO 1045 was proven to be non-inferior to antibiotic treatment ( Wagenlehner et al., 2018 ). In a retrospective cohort study, data from outpatients in Germany with at least one diagnosis of acute cystitis or UTI and a prescription of either BNO 1045 or standard antibiotics were analyzed ( Holler et al., 2021 ). Compared to antibiotics, BNO 1045 was associated with significantly fewer recurrence rates of UTI and with reduced additional antibiotic prescription. BNO 1045 was propagated to be an effective and safe symptomatic treatment option for acute cystitis or UTI.

In an open-labeled, randomized, controlled trail the effect of BNO 1045 to prevent recurrences of cystitis in younger women was evaluated ( Sabadash and Shulyak, 2017 ). All patients received an antibacterial therapy, the test group was additionally treated with BNO 1045. The integration of BNO 1045 prevented bacteriuria and recurrent cystitis episodes more frequently (primary outcome), compared to the control group without BNO 1045. This may indicate superiority of the combination therapy. However, interpretation of the results of the study is limited due to the lack of blinding on both sides - patients and physicians. A further study without any involvement of the manufacturer (no conflicts of interest noted) included younger women with acute uncomplicated cystitis. All patients received the same therapy, the nonsteroidal anti-inflammatory drug ketoprofen in combination with BNO 1045 ( Kulchavenya, 2018 ). Quite interestingly, although the majority of the patients responded well to the therapy, the investigators also observed patients who only slightly responded, or did not respond to treatment at all. The authors concluded that uncomplicated cystitis might be cured by BNO 1045 instead of antibiotics which may be required only in minor cases. Still, the data seems to be over-interpreted, since patients were treated with both ketoprofen and BNO 1045 which does not allow to conclude to one drug alone.

Aside from BNO 1045, further herbal medicines have been investigated in clinical studies. Tablets with a standardized herbal extract containing Armoraciae rusticanae radix (Horseradish root) (80 mg) and Tropaeoli majoris herba (Nasturtium) (200 mg) have been applied to patients suffering from chronically recurrent UTI symptoms, with the result that recurrent UTI symptoms were less, compared to the placebo group ( Albrecht et al., 2007 ). However, a subsequent trial failed to demonstrate non-inferiority of this extract to antibiotics due to a poor recruitment rate ( Stange et al., 2017 ). Actually, no respective clinical trials with sufficient statistical power are underway.

3.4.2 Lower urinary tract symptoms LUTS

Clinical studies have also been conducted with an herbal medicine containing the standardized extracts WS 1473 Sabal serrulata Schult.f (Sabal fruit) (160 mg) and WS1031 Urtica dioica L (Urtica root) (120 mg). All studies were related to the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). The study protocols (placebo-controlled, double-blind, multicentric) were similar in all trials with the International Prostate Symptom Score (I-PSS), quality of life index, uroflow and sonographic parameters as the outcome measures for treatment efficacy. In one study ( Lopatkin et al., 2005 ) patients were randomized to either the herbal medicine (WS 1473 and WS1031) (treatment group) or placebo (control group) while in another study patients received either WS 1473 and 1031 or the α1-adrenoceptor antagonist tamsulosin ( Engelmann et al., 2011 ). A further study was based on the previous mentioned study ( Lopatkin et al., 2005 ), whereby all patients were offered participation in a further 48-week follow-up with WS 1473/1031 ( Lopatkin et al., 2007 ). Independent on the study design, it was concluded that WS 1473/1031 is superior to the placebo, and not inferior to tamsulosin in the treatment of LUTS. In a later re-evaluation of the data sets, WS 1473/1031 was shown to significantly improve nocturnal voiding frequency compared to placebo, with similar effects compared to tamsulosin or the 5α-reductase inhibitor finasteride ( Oelke et al., 2014 ). No further studies have been enrolled since then. However, a database search in 2022 including 3,000 private practices in Germany revealed a significant association between WS 1473/1031 prescription and reduced incidence of urinary incontinence and urinary retention compared to tamsulosin and tamsulosin/dutasteride (5α-reductase blocker), as well as reduced incidence of erectile dysfunction compared to dutasteride ( Madersbacher et al., 2023 ). In all four studies the manufacturer of the extract was involved.

One observational study was investigating the effectiveness of a standardized herbal extract containing a combination of Cucurbita pepo L (Marrow), Rhus aromatica bark (Fragrant sumac), and hops, in women with overactive bladder ( Gauruder-Burmester et al., 2019 ). Of the 113 patients included, nearly the half (61 patients) used concomitant medications (e.g., antihypertensive, levothyroxine, lipid/cholesterol lowering agents, low dose ASS, NSAIDS) within the frame of a routine clinical setting. Considering the noninterventional character of this study, the herbal combination was demonstrated to improve overactive bladder symptoms and quality of life. A controlled study has not yet been initiated.

3.5 Upper respiratory tract infections (URTI)

The search on herbal medicines for the indication Upper Respiratory Infections revealed 24 publications.

The most common indications studied for the effectiveness of herbal medications were sinusitis, viral acute Rhisosinusitis (ARS) and common cold (N = 13), bronchitis (N = 8), and less frequently on acute cough (N = 2) and Acute lower and upper tract respiratory infections (N = 1) and chronic rhinosinusitis (N = 1). Most of them (N = 18) were double-blind randomized placebo-controlled trials, there were also randomized controlled trials that compared herbal medication to other herbal medication (N = 2) or to antibiotics (N = 1). Other study designs involved prospective cohorts (N = 3) and one retrospective cohort.

3.5.1 Sinusitis/common cold and chronic rhinosinusitis

Studies on treatment of acute sinusitis and acute rhinosinusitis used a follow-up period between 7 and 14 days, with the (adapted) Sinusitis Severity Score (SSS) (N = 2), the Major Symptom Score (MSS) (N = 4), the Total Symptom Score (N = 1) and facial pain relief (N = 1) as primary endpoints. All studies reported significantly improvement of the intervention group over the placebo or control group.

The treatment of acute sinusitis and acute rhinosinusitis with Eps 7630 (standardized root extract of Pelargonium sidoides DC (Pelargonium) was studied in two double blind randomised placebo controlled trials ( Bachert et al., 2009 ; Dejaco et al., 2019 ) and in one prospective ( Perić et al., 2020 ), randomized, open-label, non-inferiority study comparing study medication to Amoxicillin All three studies reported a significant superiority resp. Non-inferiority for Eps 7630. The use of the standardized herbal extract BNO 1016 ( Primulae flos (Primrose), Gentiana lutea Ruiz and Pav. Ex G.Don (Yellow gentian), Rumicis herba (Sorrel), Sambuci flos (Elderflower) and verbenae herba (Vervain) was tested in two randomised placebo controlled trials ( Jund et al., 2015 ), one of which was blinded ( Jund et al., 2015 ). Both studies showed stronger impact on the symptom score for BNO 1016 compared to placebo. One more study tested BNO 1016 in a multicenter, prospective, open-label study comparing its effect to intranasal fluticasone furoate, with patients in both groups showing improvement ( Passali et al., 2015 ). ELOM-080 (standardized herbal drug preparation containing specially destilled oils from Eucalyptus (Eucalypt) and Citrus ×sinensis (Sweet orange) and Myrtus (Myrtle) and Citrus limon (L.) Osbeck (Lemon oil)) was evaluated once in a double blind randomised placebo controlled trial ( Federspil et al., 1997 ) and once in a prospective, non-interventional parallel-group trial where the control group received BNO 1016 ( Gottschlich et al., 2018 ). In both studies BNO 1016 showed superior results.

The use of extracts containing Echinacea for the treatment of common cold was positively tested in two studies, reporting on total number of facial tissues used in three to 7 days after intervention start ( Naser et al., 2005 ) and on the Total Daily Symptom Scores (TDSS) after 7 days ( Goel et al., 2004 ). No statistically significant differences were observed between treatment groups for the total symptom score (SS) after 14 days. In two other studies testing capsules/pills containing Echinacea angustifolia root and Echinacea purpurea root and E. purpurea herb there was no statistically significant difference between the intervention and placebo group concerning severity and duration of self-reported symptoms ( Barrett et al., 2002 ) or global severity ( Barrett et al., 2010 ).

In a double blind randomised placebo controlled trial BNO 1016 was tested for the treatment of chronic rhinosinusitis. The results reveal that the herbal drug was not superior over placebo regarding the Major Symptom Score (MSS) in week 8 and week 12 ( Palm et al., 2017 ).

3.5.2 Bronchitis

For bronchitis, nine studies were included, of which six were double-blind randomized placebo-controlled trials, testing EPs 7630 (N = 5) ( Matthys et al., 2003 ; Chuchalin et al., 2005 ; Matthys and Heger, 2007 ; Matthys et al., 2010 ; Kähler et al., 2019 ) or ELOM-080 (N = 1) ( Gillissen et al., 2013 ). The prospective observational studies included a standardized syrup of Hedera helix L (Ivy leaves) (N = 1) ( Fazio et al., 2009 ), pills with ethanolic Ivy-leaves dry extracts (N = 1) ( Hecker et al., 2002 ) and EPs 7630 (N = 1) ( Matthys and Heger, 2007 ).

Using a follow-up period of 7 days to 4 weeks, all but one (double-blinded placebo controlled trial) ( Matthys et al., 2003 ) reported positive effects of the study medication on either Bronchitis Severity Scores, change of symptoms and coughing frequency.

3.5.3 Acute cough

The treatment of acute cough with EA-575 (standardized extract from H. helix L.) was tested against placebo in one double blind randomized placebo controlled trial and reported a significantly better improvement of cough severity (CS) assessed by Visual Analogue Scale (VAS) in the intervention group after 1 week as compared to placebo ( Schaefer et al., 2016 ).

3.5.4 Acute lower and upper tract respiratory infections

We included one retrospective cohort study comparing people with acute lower and upper tract respiratory infections who were prescribed a phytopharmaceutical to those who were not prescribed such drugs. They found that extract EPs 7630 (description see 3.5.1) (odds ratio (OR) 0.49 [95% CI: 0.43–0.57]) and thyme extract (OR 0.62 [0.49–0.76]) compared to no phytopharmaceutical prescription exhibited the strongest decrease in antibiotics prescriptions among patients treated by general practitioners ( Martin et al., 2020 ).

4 Discussion

The aim of this review is to depict the current evidence for the therapeutic efficacy of herbal medicines. Therefore, we conducted a literature search with defined inclusion and exclusion criteria in particular to select information from clinical studies with high levels of evidence and legally approved (in Europe) herbal medicines. Certainly, life-threatening disease are not suitable for the treatment with herbal medicines. This is the reason why we limited our perspective on psychosomatic disorders, gynecological complaints, gastrointestinal disorders and common infectious diseases of the urinary and the upper respiratory tract. Additionally, we concentrated on clinical trials with adult patients. It is to be emphasized that respective studies using herbal drugs have also been done in children with psychosomatic diseases ( Verlaet et al., 2017 ; Schloss et al., 2021 ), IBS ( Menon et al., 2023 ), gastrointestinal disorders ( Michael et al., 2022 ), UTIs ( Ching, 2022 ), and URIs ( Mancak Karakus et al., 2023 ) to mention only some examples.

The use of herbal medicines in the treatment of psychosomatic disorders is widespread and accordingly a high number of clinical studies was available for our analysis. In our literature search, the term “psychosomatic disorders” has been chosen. This term has not been clearly defined but is related to diseases which involve both physical and psychological illness. In other words, the respective symptoms are caused by mental processes and not directly by a physical disorder. The hits we got are based on this “terminology”. In contrast, the term “mental illnesses” which also includes psychological or behavioral manifestations is strictly defined as “health conditions with changes in emotion, thinking or behavior” ( Stein et al., 2021 ). However, even this definition is problematic, since there are concerns about specific conditions, the discrimination between independent biological entities or value-laden social constructs, and the defined indicators of dysfunction ( Stein et al., 2021 ). Independent on these concerns, we did not apply this search term. Therefore, we cannot exclude that (very few) articles have not been discovered with our search strategy.

For the treatment of depressive disorders, St. John’s wort is well-established and the studies we selected were predominantly positive regarding improvement of symptoms. Concurrently, SJW is well tolerated and in the majority of the studies at least equal to conventional medication like tricyclic anti-depressants and selective serotonin reuptake inhibitors, which exhibit in part notable adverse events impacting patients’ quality of life of ( Voican et al., 2014 ; Jakobsen et al., 2017 ).

In contrast evidence for insomnia and anxiety was thinner. It would be worthwhile to study the use of herbal drugs as alternative medication for the treatment of sleeping disorders, as for elderly people or long term use conventional hypnotics are not always the best option ( Wortelboer et al., 2002 ; Cheng et al., 2020 ). All the studies we included were using valerian root extract alone or in combination with Humulus lupulus extract and showed positive effects on sleep without notable side effects. The few studies we selected for anxiety demonstrated efficacy of lavender extract (Lavandula angustifolia) and also here we had a homogenous picture of good efficacy along with good tolerability.

Several years ago, consistent beneficial effects of Ginkgo biloba for patients with cerebral insufficiency were proven in a systematic review ( Kleijnen and Knipschild, 1992 ). However, the methodologic quality of many trials was considered to be poor. Moreover, the studies entailed a heterogeneous collection of target health problems, ranging from overt dementia to noncognitive manifestations of brain dysfunction, such as vertigo and tinnitus. More recently, the results of several new Ginkgo biloba trials have been published, most of them focusing on dementia, and showing positive effects. Probably the most talked about is the trial of the North American EGb Study Group, which was published in the JAMA in 1997 and showed a modest improvement of the cognitive performance and the social functioning of the demented patients involved ( Le Bars et al., 1997 ), which is well in line with the studies we have collected.

In addition, menopausal symptoms and premenstrual syndrome are suitable for treatment with herbal medicines. In the here collected studies, no overall negative effects were observed and adverse events did not occur more frequently than in the comparison groups. A consistent picture emerged when comparing herbal treatment with synthetic drugs or placebo: while herbal drugs and treatment with, e.g., HRT or pyridoxine showed equal efficacy, herbal treatment was in general superior to placebo administration, except for one study.

Effective treatment of menopausal symptoms with black cohosh is supported with multiple study designs. Regardless of the study quality, there are no contradictory results.

The evidence for the treatment of PMS with VAC initially appears similar to that of black cohosh for menopausal symptoms. However, the sample sizes have been insufficient and there was a complete lack of comparisons of VAC with other therapies. Also of interest are the hints on the importance of the dose and continuous administration. A higher dosage did not have a higher efficacy compared to the standard dosage, but slightly more participants experienced adverse events ( Momoeda et al., 2014 ). This suggests a preference for the standard dosage of VAC. Continuous use of VAC is recommended, as it has been shown that symptoms increase significantly, even if they are still lower than before therapy ( Bachert et al., 2009 ).

However, further research is needed for both gynecological indications. Only one study each on sage for menopausal symptoms and SJW for premenstrual symptoms was found ( Lauritzen et al., 1997 ; Lauritzen et al., 1997 ; Adeyemo et al., 2013 ). The trend-setting results point to positive effects which have to be confirmed.

For gastrointestinal disorders herbal drugs were, at least partially, shown to be similar efficacious as the standard treatment. Selected, non-toxic plant derived natural compounds may, therefore, replace synthesized drugs which are associated with undesired negative side effects and the therapeutic potential of the compounds may depend on both the plant extract and the type of disease to be treated. Indeed, SJW was not efficacious in treating IBS, whereas WS 1340/WS 1520 and STW 5 and STW 5-II showed efficacy in both IBS and FD. Considering the broad spectrum of gastrointestinal complaints, therapy of severe liver disease may require more effort than treatment of moderate dyspepsia and, hence, herbal medicine may not replace standard therapy.

As no standard therapy has so far been established for FD ( Madisch et al., 2018 ) and IBS ( Lacy et al., 2021 ) the design of clinical studies is difficult, making it impossible to compare the phytodrug group with a “reference” cohort, and to finally assess the value of the phytodrugs.

Particular attention should be given to STW 5 containing greater celandine which has been related to liver and biliary tract disorders ( Zielińska et al., 2018 ). Therefore, careful preclinical examination of potential toxic properties of a compound of question is necessary before starting clinical trials.

Overall, most of the studies were well designed (multicenter, double-blind, placebo-controlled trials) with large cohorts. Considering the low side effects and often significant improvements, it might be useful to conduct further studies to either gain more detailed information about herbal medicine or to transfer the knowledge to diseases with a similar cluster of symptoms, so that distinct ailments might particularly benefit from herbal medicine ( Chey et al., 2015 ).

With respect to urinary tract infections (UTI), herbal medicines have been proven to be similar effective as antibiotics. Undoubtedly, the data encourages further research on herbal medicines as alternatives to antibiotics in acute lower uncomplicated UTI ( Wagenlehner et al., 2018 ). The use of herbal medicines has also been considered to be a good and safe alternative to perioperative antibiotic prophylaxis ( Miotla et al., 2018 ). However, whether herbal medicines may reduce or even replace antibiotics in future guideline-based regimen requires more prospective studies conducted on large groups of participants ( Wawrysiuk et al., 2022 ).

It is important to note in this context that one study discriminated between HM responders and non-responders ( Kulchavenya, 2018 ). This phenomenon is highly important, since it indicates that the application of HM in general might be restricted to a subset of patients. Unfortunately, no ongoing trials have been enrolled in this matter, and none of the publications cited here discussed the problem of acquired or innate resistance, at least from a theoretical point of view.

LUTS caused by BPH was treated differently than UTI, since the complications of BPH, namely, urinary incontinence, polyuria, urinary retention, and erectile dysfunction, have to be targeted. The clinical trials published so far point to the benefit of herbal medicines in reducing BPH symptoms. However, it is not clear yet whether the integration of herbal medicines may allow to reduce or even to avoid the use of standard medical therapeutics in this case.

Overall, several clinical studies conducted in the last years document a beneficial role of herbal medicines in the treatment of UTI and LUTS.

Upper Respiratory Infections (URIs) are a frequent cause of troublesome symptoms, that might be appropriately treated with herbal medicine. Most studies included in this paper evaluated herbal medicines for the treatment of acute bronchitis or common cold and acute sinusitis or rhinosinusitis.

The majority of the studies we included for the treatment of acute bronchitis tested P. sidoides against placebo and reported a statistically significant decrease of bronchitis symptoms and/severity. This is in line with the results of a systematic review and meta-analysis ( Agbabiaka et al., 2008 ), although a more recent systematic review judged that the evidence was of low quality ( Timmer et al., 2013 ). Evidence for other herbal medicines in the treatment of acute bronchitis was scarce.

For the treatment of common cold we found some indications of effectiveness of P. sidoides , Eucalyptus, sweet orange, myrtle and lemon oil (ELOM-080) and for Gentianae radix, Primulae flos, Sambuci flos, Rumicis herba and verbenae herba (BNO 1016). A recent systematic review with network meta-analysis, showed very little solid evidence of herbal medicine versus placebo for common cold, with only P. sidoides and Andrographis paniculata showing a reliable decrease of symptoms. Better results were found for herbal medicine versus placebo concerning health related quality of life (HRQoL) (in particular Spicae aetheroleum ) and for symptoms (Cineole and P. sidoides ) ( Hoang et al., 2023 ). A further systematic review reported on the efficacy of P. sidoides (liquid and tablet preparation) for the treatment of acute bronchitis, showing a positive results with, however, low evidence quality ( Timmer et al., 2013 ).

Although herbal medicines are considered to be safe in principle, this might not always be the case. Some herbal compounds are suspected to be carcinogenic and/or hepatotoxic. Herbal products have also been shown to inhibit and/or induce drug-metabolizing enzymes ( Moreira et al., 2014 ). This has to be taken into account, since herbal medicines are often used in combination with conventional drugs. In this context, preparations with SJW may reduce the efficacy of chemotherapy and of anticoagulants but enhance the one of certain consciousness-lowering agents (e.g., sedative medicines, antidepressants) ( Nicolussi et al., 2020 ; Scholz et al., 2021 ). Due to potential liver toxicity of chelidonium majus, preparations containing more than 2.5 mg daily dose of whole chelidonium alkaloids had to be withdrawn, and for all preparations with lower daily doses, their instruction leaflet must include warnings on liver toxicity ( Rosien, 2019 ). Therefore, the drug’s safety must always be carefully investigated and guaranteed by the producers and the regulatory authorities.

The analysis of the outcomes in the selected disorders reflects that herbal medicines are most efficacious for the treatment of URTI ( Figure 5 ), followed by gynecological complaints ( Figure 2 ) and psychosomatic disorders ( Figure 1 ). For the treatment of urological diseases ( Figure 4 ) in particular UTI and LUTS, we could select only 16 studies according to our strict inclusion/exclusion criteria and therefore more studies of high quality have to be performed to gain a better insight into the efficacy of herbal drugs for these ailments. Gastrointestinal diseases hold a special position as only the added value of the phytodrugs to the conventional therapy was tested. In addition, the number of studies we selected was small ( Figure 3 ), making it difficult to judge the efficacy of herbal drugs for this indication.

This report on the current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments has some limitations.

• 1. The literature search had to be restricted to Pubmed, because other relevant databases like e.g., EMBASE or CINAHL have not been accessible to the authors.
• 2. Further limitations are the small cohorts in some of the studies
• 3. Or that the results/outcomes of some studies have been re-analyzed from previous studies.
• 4. A general obstacle of data interpretation is that for some indications, in particular for gastrointestinal diseases, herbal medicines are predominantly co-administered with standard therapy, which makes it difficult to estimate the clinical benefit of the phytodrug alone.

5 Perspective

Our literature research gives insights into applied herbal medicines for selected indications, the study outcomes and their quality. Based on our results, we (the authors) provide an overview for patients and healthcare practitioners which extracts can be recommended for the treatment if which disorder/complaint ( Supplementary Table S1 ).

In this context we recommend in particular H. perforatum L. for depressive disorder, V. agnus castus L. for menstrual complaints, Cimicifica racemose (L.) for menopausal symptoms, a combination of I. amara L., M. chamomilla L., Mentha × piperita L., C. carvi L., G. glabra L. and M. officinalis L., for functional dyspepsia, a combination of C. erythraea , Levisticum officinale W.D.J.Koch and Rosmarinus officinalis L. for uncomlicated urinary tract infections, P. sidoides DC. for bronchitis and sinusitis and finally H. helix for cough ( Supplementary Table S1 ). These recommendations are based on studies with the highest levels of evidence (RCTs).

However, evidence for efficacy of herbal medicines is still not satisfying in order to integrate them in conventional medicine guidelines and standard treatment regimen, which is the reason why statutory health insurances do not reimburse the costs. In fact, herbal medicines are highly popular and accepted among patients, since their application is safe since they do not exert severe side-effects. Especially when conventional medical therapies fail due to undesired side effects having a negative impact on the quality of life, patients are willing to purchase herbal medicines at their own expense. Often doctors do not know about the self-medication activities of their patients and in consequence cannot monitor the treatment with herbal medicines and possible interactions with other drugs.

The discrepancy between available results from clinical research and the use of herbal medicines under everyday conditions shows that we need to perform more interdisciplinary research studies in the future in order to collect scientific sound evidence on their benefits. Clinical research can provide information on the efficacy of phytodrugs and the importance of genetic dispositions and metabolism as well as possible interactions with other medicines. For effectiveness under everyday conditions (from bedside to practice), methods of health services research are necessary. With the help of these, the outcomes of herbal medicines can be recorded from different perspectives, in particular those of the patients (patient-reported outcomes (PROs)). For longitudinal observations, analyses of health insurance and sales volume data are also relevant, using prescriptions and the over-the-counter sales to get a picture on the needs of the patients and the acceptance of phytotherapy by healthcare practitioners. In order to pave the way for the integration of herbal medicines into therapy guidelines and regimens, findings from clinical studies should be carefully evaluated for their transferability to everyday healthcare within the scope of health services research. This way could lead to novel rational efficacious therapy strategies with less side-effects and better compliance of the patients.

Data availability statement

Author contributions.

SS: Investigation, Formal analysis, Writing–Original Draft. JR: Investigation, Formal analysis, Writing–Original Draft, Visualization. MA: Methodology, Investigation, Formal analysis, Writing–Original Draft. RB: Investigation, Formal analysis, Writing–Original Draft. BB: Conceptualization, Methodology, Investigation, Formal analysis, Writing–Original Draft, Supervision. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1234701/full#supplementary-material

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Taking Multiple Medications? You May Need to Scale Back.

Many people in the United States are taking five or more prescription drugs. That can lead to serious complications.

By Knvul Sheikh

Around one in five adults between the ages of 40 to 79 is taking five or more prescription drugs, according to data from the Centers for Disease Control and Prevention. And the older patients are, the more likely it is they’re taking even more medications.

But taking many medicines simultaneously, known among medical experts as polypharmacy, increases people’s risk of experiencing severe side effects and drug interactions, said Dr. Nina Blachman, an associate professor of medicine and geriatrics at the N.Y.U. Grossman School of Medicine.

Studies show that taking multiple medications is associated with a faster decline in memory in some patients with mild cognitive impairment, and with a greater risk of falls among people with balance problems or weakened muscles. And certain combinations of drugs can lead to excessive bleeding, dangerously low blood sugar or other serious complications that lead to hundreds of older adults being hospitalized every day. While medicines can be critical for improving our quality of life, it is important to understand how people end up taking too many drugs unnecessarily and when to ask for help trimming your prescription list.

How prescriptions can pile up

As people age, they develop more health issues such as diabetes, heart disease, arthritis and high blood pressure, and “end up on more and more medications,” Dr. Blachman said. Many are never taken off the drugs they’ve been prescribed for years, even if they no longer need them or if there are newer formulations available that can treat different symptoms simultaneously.

Patients sometimes also see a variety of medical providers, each of whom may prescribe medication without necessarily communicating with one another.

Sometimes medical professionals may prescribe drugs to treat the side effects of another medication, in what doctors refer to as a “prescription cascade.” For example, people who take certain over-the-counter pain medicines called nonsteroidal anti-inflammatory drugs may experience an increase in blood pressure, which doctors may misdiagnose as a new ailment and prescribe calcium channel blockers as a treatment. But in some people, these blood pressure drugs can lead to ankle swelling, which may then lead to a prescription for a diuretic to reduce fluid buildup in the body.

“So you just end up chasing side effects of one medication after the next,” Dr. Blachman said.

Older patients may also be more likely to develop new or worse side effects to drugs because kidney and liver function can decline with age, making the body less able to filter out some medications, said Barbara Farrell, a scientist with the Bruyere Research Institute in Ottawa. This can lead to patients being prescribed even more medications to treat those side effects.

While polypharmacy is most common in older people, younger adults and even children, particularly those with complicated chronic conditions like epilepsy, learning disorders or mental health issues, can also end up on many medications.

To further complicate matters, pharmacists and doctors don’t always know how or when to safely help patients come off drugs, Dr. Farrell said. But in recent years, she and other experts have pushed for more guidelines on tapering or stopping prescription drugs.

How to review your medications and cut back where you can

Ideally, doctors and pharmacists should do what’s called medication reconciliation each time you see them, said Kuldip Patel, the senior associate chief pharmacy officer at Duke University Hospital in North Carolina. To do this, his team reviews the list of medications people are taking whenever they are admitted to or discharged from the hospital. But that doesn’t always happen in every medical setting, he said.

Experts suggest asking a primary care doctor or pharmacist to do a full medication review at least once a year. Many pharmacies offer such evaluations under free medication therapy management programs. Make a list of your medicines — including supplements and over-the-counter drugs — or grab all of your pill bottles and take them with you to the appointment, Dr. Patel said.

But perhaps the best time to speak up about prescription use is before you start a new drug. Ask your doctor questions such as “Am I experiencing a symptom that could be a side effect of a drug I’m taking?” or “Can I try to manage this symptom with lifestyle changes first?”

When you do need a medication, check if you can start with a lower dose, Dr. Farrell said. Remind the doctor of medications you are taking and ask how the new drug will interact with them.

Lastly, ask how long you’ll need to take a medication and work on a plan with your doctor to stop taking it if needed. You should understand how your provider plans to help you taper off the drug, what withdrawal symptoms to watch for and how to make sure the issue you were being treated for doesn’t return. “These are questions people should be asking even in their teens and 20s when they’re being started on some of these medications,” Dr. Farrell said. “Then hopefully someday we’ll be able to prevent people from getting to the point where they’re taking 25 medications all together.”

An earlier version of this story misstated the title of Dr. Nina Blachman. She is an associate professor of medicine and geriatrics, not an assistant professor.

How we handle corrections

Knvul Sheikh is a Times reporter covering chronic and infectious diseases and other aspects of personal health. More about Knvul Sheikh

What to Know About Diabetes

Diabetes, a condition in which the body has trouble regulating blood sugar, is increasingly common among americans..

Over 37 million Americans have some form of diabetes. Scientists say that medical care  won’t be enough to halt the spread of the disease: Sweeping societal changes are needed .

Insulin resistance can be a precursor to diabetes and pre-diabetes. Here is what to know about the condition and how to know if you have it .

For people with Type 1 diabetes, which often strikes in adolescence, staying healthy can be exhausting . A treatment that can delay the disease’s onset offers some hope .

People who regularly eat red meat may have a higher risk of Type 2 diabetes later in life , according to a new study. Those who often consume processed meats have an even greater risk.

Healthy practices can delay and prevent Type 2 diabetes. Something as simple as going for a 15-minute walk after a meal  could help ward off the disease.

People are claiming that the diabetes medication Ozempic helped them lose weight quickly and easily — but experts say it’s not a miracle drug .

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Carolyn M. Mazure, PhD, Chair of the White House Initiative on Women’s Health Research

Dr. carolyn m. mazure.

Dr. Carolyn M. Mazure, chair of the White House Initiative on Women's Health Research, in front of the White House in November. Photo by Erin Scott, Official White House Photographer.

In November, President Joe Biden launched the White House Initiative on Women’s Health Research. This effort is led by First Lady Dr. Jill Biden in close collaboration with the White House Gender Policy Council. It is chaired by Carolyn M. Mazure, PhD, founder and director of Yale School of Medicine’s Women’s Health Research at Yale. Mazure is the Norma Weinberg Spungen and Joan Lebson Bildner Professor in Women's Health Research and a professor of psychiatry and psychology at Yale.

Historically, research on women’s health has been chronically underfunded, with often significant consequences for women’s health and health care. The White House Initiative seeks to increase and improve women’s health research and shed light on conditions that are specific to women, disproportionately affect women, or affect women differently.

“I have always believed in the power of research to save lives and to ensure that Americans get the high-quality health care they need,” President Biden said in a White House press release . “That’s why today, we’re establishing a new White House Initiative on Women’s Health Research so that my Administration—from the National Institutes of Health to the Department of Defense—does everything we can to drive innovation in women’s health and close research gaps.”

“Every woman I know has a story about leaving her doctor’s office with more questions than answers,” First Lady Jill Biden added . “Our new White House Initiative on Women’s Health Research will help change that by identifying bold solutions to uncover the answers that every woman and her family deserves.”

For 25 years, Mazure’s nationally recognized center, Women’s Health Research at Yale , has been leading innovative and interdisciplinary research on women’s health and on the influence of sex and gender on health outcomes.

“I’ve had the opportunity to see women’s health research become a recognized field of study that spans all health conditions experienced by women, its exponential growth in published data, innovations in care, and new careers in women’s health research,” says Mazure.

Nevertheless, women remain at higher risk for chronic disease and disability, for acute and chronic pain syndromes, and to die following heart attack. Women are also at higher risk for adverse effects of treatments and for co-occurring conditions. Mazure continues, “There is a tremendous need for science to move forward in supporting research that targets the health of women to improve outcomes.”

The Initiative’s Early Days

The White House Initiative on Women’s Health Research is pioneering the next generation of women’s health discoveries. The first step in the Initiative was to engage agencies across the federal government to generate concrete recommendations within 45 days from the signing of the Presidential Memorandum that will advance women’s health research. They are also deciding on priority areas of focus with these agencies and exploring new public-private partnerships that would spur further research.

“This initiative elevates the importance of women’s health research in the nation, which is really extraordinary,” says Mazure. “We have outstanding opportunities to make the progress that we need.”

Visiting Los Angeles, Chicago & Atlanta

In December, Mazure, the First Lady, and long-time women’s health advocate Maria Shriver, among others, visited Cedars-Sinai Medical Center in Los Angeles and toured facilities specializing in cardiovascular disease research. “We cannot answer questions of how to treat women medically if the research doesn’t match up,” said Shriver .

The Initiative’s work continued, with a January visit to the University of Illinois-Chicago campus to hear about research on menopausal symptoms and the way scientists can monitor women’s hot flashes and the effect on their brains. “Every woman will be affected by menopause; yet there’s a stunning lack of information about how to manage and treat its symptoms. UIC is working to change that,” said Dr. Biden who was accompanied by actress and women’s health advocate Halle Berry.

In February, the team visited SteelSky Ventures’ Atlanta headquarters, a venture capital firm that focuses on investing in women’s health and femtech. There, Mazure facilitated a roundtable discussion focused on public-private partnerships.

During her opening remarks, Dr. Biden underscored , “We have a clear goal: to fundamentally change how we approach and fund women’s health research. Together, we will build a future where…health care meets the needs of everyone.”

“It was tremendous to hear from this panel and learn about innovations in research, in collaboration with community and corporate efforts, all centered on improving the health of women. New public-private partnerships can spark the innovation needed to improve the health of all women,” said Mazure.

A Transformational Investment in Women’s Health Research

At the end of February, an unprecedented announcement was made: $100 million in federal funding over the next year was committed to forward women’s health research. This marked the Initiative’s first deliverable and comes from the Advanced Research Projects Agency for Health, or ARPA-H, within the Department of Health and Human Services. The announcement officially launched ARPA-H’s “Sprint for Women’s Health.”

“Somewhere … may be the idea that will cure cancer, cure heart disease, cure Alzheimer’s. Heart health, brain health, chronic diseases – you might just have the answers if we only dissolve the barriers standing in your way,” said Dr. Biden . “Together, through our White House Initiative on Women’s Health Research, we will write new stories about women’s health care. We will accelerate your ideas and change women’s lives. We will build a health care system that puts women and their lived experiences at its center.”

“In just 100 days from the start of the Initiative, it is tremendously meaningful to be able to announce this investment in women’s health research,” said Mazure. “This kind of commitment, spurred by the First Lady and the Presidential Memorandum, will generate research to improve women’s lives.”

Major Action During Women’s History Month

During a Women’s History Month reception at the White House on March 18, President Biden signed an Executive Order “Advancing Women’s Health Research and Innovation,” solidifying women’s health research as a priority for the federal government.

“With the Executive Order I’m about to sign, I’m directing the most comprehensive set of executive actions ever taken to improve women’s health…And I’m going to ensure women’s health is integrated and prioritized across the entire federal government,” said President Biden during the event .

The new Executive Order integrates women’s health across the federal research portfolio, prioritizes investments in women’s health research, galvanizes new research on women’s midlife health, and directs the federal government to assess unmet needs in relation to women’s health.

Federal agencies also announced new actions they are taking as members of the initiative in five key areas. These areas include prioritizing and increasing investments in women’s health research; fostering innovation and discovery in women’s health; expanding and leveraging data collection and analysis related to women’s health; strengthening coordination, infrastructure, and training to support women’s health research; and improving women’s health across the lifespan.

“For too long women’s health research has been underfunded and understudied,” said Mazure. “We have made great progress in the last two decades, yet we still need to know much more about how to effectively prevent, diagnose, and treat a wide array of health conditions in women.”

“Today, as we celebrate Women’s History Month, let’s write a new future for ourselves, and for the girls and women who will follow. A future where women leave doctors’ offices with more answers than questions,” said Dr. Biden .

Featured in this article

• Carolyn M. Mazure, PhD Norma Weinberg Spungen and Joan Lebson Bildner Professor in Women's Health Research and Professor of Psychiatry and of Psychology

Automated machine learning robot unlocks new potential for genetics research

This technology will save labs time and money while enabling large-scale experiments.

University of Minnesota Twin Cities researchers have constructed a robot that uses machine learning to fully automate a complicated microinjection process used in genetic research.

In their experiments, the researchers were able to use this automated robot to manipulate the genetics of multicellular organisms, including fruit fly and zebrafish embryos. The technology will save labs time and money while enabling them to more easily conduct new, large-scale genetic experiments that were not possible previously using manual techniques

The research is featured on the cover of the April 2024 issue of GENETICS , a peer-reviewed, open access, scientific journal. The work was co-led by two University of Minnesota mechanical engineering graduate students Andrew Alegria and Amey Joshi. The team is also working to commercialize this technology to make it widely available through the University of Minnesota start-up company, Objective Biotechnology.

Microinjection is a method for introducing cells, genetic material, or other agents directly into embryos, cells, or tissues using a very fine pipette. The researchers have trained the robot to detect embryos that are one-hundredth the size of a grain of rice. After detection, the machine can calculate a path and automate the process of the injections.

"This new process is more robust and reproducible than manual injections," said Suhasa Kodandaramaiah, a University of Minnesota mechanical engineering associate professor and senior author of the study. "With this model, individual laboratories will be able to think of new experiments that you couldn't do without this type of technology."

Typically, this type of research requires highly skilled technicians to perform the microinjection, which many laboratories do not have. This new technology could expand the ability to perform large experiments in labs, while reducing time and costs.

"This is very exciting for the world of genetics. Writing and reading DNA have drastically improved in recent years, but having this technology will increase our ability to perform large-scale genetic experiments in a wide range of organisms," said Daryl Gohl, a co-author of the study, the group leader of the University of Minnesota Genomics Center's Innovation Lab and research assistant professor in the Department of Genetics, Cell Biology, and Development.

Not only can this technology be used in genetic experiments, but it can also help to preserve endangered species through cryopreservation, a preservation technique conducted at ultra-low temperatures.

"You can use this robot to inject nanoparticles into cells and tissues that helps in cryopreservation and in the process of rewarming afterwards," Kodandaramaiah explained.

Other team members highlighted other applications for the technology that could have even more impact.

"We hope that this technology could eventually be used for in vitro fertilization, where you could detect those eggs on the microscale level," said Andrew Alegria, co-lead author on the paper and University of Minnesota mechanical engineering graduate research assistant in the Biosensing and Biorobotics Lab.

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Story Source:

Materials provided by University of Minnesota . Note: Content may be edited for style and length.

Journal Reference :

• Andrew D Alegria, Amey S Joshi, Jorge Blanco Mendana, Kanav Khosla, Kieran T Smith, Benjamin Auch, Margaret Donovan, John Bischof, Daryl M Gohl, Suhasa B Kodandaramaiah. High-throughput genetic manipulation of multicellular organisms using a machine-vision guided embryonic microinjection robot . GENETICS , 2024; 226 (4) DOI: 10.1093/genetics/iyae025

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Strange & offbeat.

Can nasal Neosporin fight COVID? Surprising new research suggests it works

A potential treatment for covid-19 may have been hiding in our medicine cabinets, a new study in pnas has found, by nicole karlis.

Four years ago, when COVID-19 first began to spread globally, it didn't just damage our physical health, but also the health of our information ecosystem. Ever since, the internet has been rife with health misinformation on ways to treat or protect oneself against the coronavirus. First, internet healers falsely suggested that gargling salt water and vinegar could prevent a coronavirus infection. Then, despite multiple studies debunking the effectiveness of ivermectin , an anti-parasitic drug used in horses (and less commonly in humans), Joe Rogan fans continued to cling onto it as a potential treatment .

Health misinformation is a symptom of a lack of certainty. When there is no guaranteed preventative measure or treatment, people are bound to find solutions on their own. Thanks to cognitive biases like confirmation bias , they might even appear to work. But what if a way to reduce exposure to COVID-19, and treat it, was hiding in our medicine cabinets all along — and it wasn’t pseudoscience? 

A new study published in the journal Proceedings of the National Academy of Sciences suggests that neomycin, an ingredient in the first aid ointment Neosporin , may prevent or treat a range of respiratory viral infections such as COVID-19 and influenza when applied to the nose. 

In the study, researchers found that mice who had neomycin in their nostrils exhibited strong antiviral activity against both SARS-CoV- 2 and a highly virulent strain of influenza A virus. It also mitigated contact transmission of SARS-CoV- 2 between hamsters. 

"When we compared the gene expression in the nose, Neosporin stimulated genes whereas those people who had Vaseline did not."

“We decided to see if neomycin applied into the nose can protect animals from infection with COVID as well as the flu,” Dr. Akiko Iwasaki , the lead author of the study and a professor of immunobiology at the Yale University School of Medicine, told Salon in a phone interview. “And what we found is that treatment with neomycin significantly prevented infection and also reduced disease burden in animals.”

Iwasaki described the work as “encouraging” because it shows that neomycin can trigger an antiviral response in animals by creating a localized immune response. “That’s resulting in this protection that we see,” Iwasaki said. 

Want more health and science stories in your inbox? Subscribe to Salon's weekly newsletter Lab Notes .

The results are encouraging for mice and hamsters. But what about humans? The researchers proceeded to recruit healthy volunteers and asked them to apply Neosporin with a cotton swab to their nose, twice a day. The placebo for some was vaseline. The researchers measured their antiviral response and found similar results.

“When we compared the gene expression in the nose, Neosporin stimulated genes whereas those people who had Vaseline did not,” Iwasaki said.  “So this suggests that we might be able to use Neosporin or neomycin in humans to induce this antiviral state that we also saw in animals.”

Does that mean we should all be applying Neosporin to our noses in high-risk situations? Not exactly, but it probably wouldn’t hurt either — as long as someone isn’t allergic to the cream, which is a combination of the antibiotics bacitracin, neomycin and polymyxin B. Notably, details around the dosage remain unclear. 

“We know from the dose response that we did in animals that we probably need to give humans more Neosporin, or neomycin,” she said. “Because Neosporin has very little neomycin compared to what we were able to achieve in the animal model.”

"This could be a potential broad spectrum antiviral treatment and prophylaxis."

Iwasaki added they know that Neosporin can produce a similar effect in humans as it did in animals, but whether or not it can reduce transmission has yet to be determined. 

“For that, we need different kinds of study and a much larger study to determine that,” she said. 

Amesh Adalja, a senior scholar at the Johns Hopkins Center and infectious disease doctor who wasn’t involved in the study, told Salon via email that the research could have broader implications that extend beyond COVID-19. 

“This could be a potential broad spectrum antiviral treatment and prophylaxis,”Adalja said. “The molecules in the topical antibiotic cream induce certain antiviral compounds to be made by cells where the ointment has been applied; these antiviral compounds produce non-specific immunity that impacts various viruses.”

Iwasaki cautioned against the idea that people swabbing their noses with Neosporin will be a cure-all in the future. Instead, she said she sees this as another possible layer of protection . 

We need your help to stay independent

“We know how important it is to layer protection against infections,” Iwasaki said. “Vaccines and masks and other measures are very important, but this type of strategy where we can trigger the host to produce antiviral factors may be another layer that we can add on to the existing ones.”

The more layers a person has, Iwasaki said, the less likely a person is to get infected. 

“And that's really important for preventing diseases like long COVID,” Iwasaki said, referring to a condition in which COVID symptoms last for months or even years . “So I think it's definitely worth kind of moving forward with an approach like this.”

An approach that was right under our noses all this time.

about COVID

• Do COVID-19 vaccines really have worse side effects than other vaccines? Here's what experts say
• Infectious desire: How the pandemic is still negatively impacting our sex lives
• Does your immune system need a workout? The bad science behind "immunity debt," explained

Nicole Karlis is a senior writer at Salon, specializing in health and science. Tweet her @nicolekarlis .

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UGA breaks ground on new medical education and research building

The groundbreaking was a "transformational moment at the University of Georgia"

The University of Georgia broke ground Friday on a new medical education and research building that will significantly expand teaching and research capabilities at the university’s future School of Medicine .

Located on UGA’s Health Sciences campus, preliminary plans for the building include medical simulation suites, standardized patient rooms, clinical skills labs, a gross anatomy lab, and a medical library. The building will also feature student support spaces like conference rooms, study spaces, lounges, and faculty and staff offices dedicated to student support.

In total, the proposed building will measure approximately 92,000 square feet. Roughly 67,000 square feet of the building will be dedicated to medical education while the remaining 25,000 square feet will house biomedical research laboratories.

Gov. Brian Kemp speaks at the groundbreaking ceremony for the Medical School Building on the Health Sciences Campus. (Andrew Davis Tucker/UGA)

The new building will complement existing facilities and provide the UGA School of Medicine with capacity to expand from 60 students per class to 120 in the future.

“Today is an exciting and transformational moment at the University of Georgia,” said UGA President Jere W. Morehead. “As a land-grant university and Georgia’s flagship research institution, the University of Georgia is uniquely positioned to address the health care needs of our state through world-class medical education, research and community outreach.”

Following the recommendation of Governor Brian Kemp, the Georgia General Assembly passed a fiscal year 2024 amended budget that includes $50 million in funding for a new University of Georgia School of Medicine facility.

President Jere W. Morehead speaks along with USG Chancellor Sonny Perdue and Gov. Brian Kemp at the groundbreaking ceremony for the Medical School Building on the Health Sciences Campus. (Andrew Davis Tucker/UGA)

The $50 million in state funding will be matched by private contributions to fund the $100 million medical education and research building.

The University System of Georgia Board of Regents authorized the University of Georgia to establish a new independent School of Medicine in Athens in February.

In March, Dr. Shelley Nuss was named founding dean of the UGA School of Medicine. She previously served as an associate professor of internal medicine and psychiatry in the Augusta University/University of Georgia Medical Partnership. In 2016, she was named campus dean of the Medical Partnership, which has been educating physicians in Athens since 2010.

“The fact is, Georgia needs more doctors, and we need them now,” said Nuss. “The new UGA School of Medicine will increase the number of medical students in the state, translating to more practicing physicians to help address Georgia’s greatest health care challenges.”

The creation of the UGA School of Medicine marks the natural evolution of the longest-serving medical partnership in the United States. Similar programs founded around the same time have already transitioned to independent medical schools.

USG Chancellor Sonny Perdue speaks from the podium along with Gov. Brian Kemp at the groundbreaking ceremony for the Medical School Building on the Health Sciences Campus. (Andrew Davis Tucker/UGA)

UGA will continue to work closely with the Medical College of Georgia to ensure a smooth transition for current medical students as UGA seeks accreditation from the Liaison Committee on Medical Education (LCME).

The development of a new public school of medicine at UGA promises to help address a significant shortage of medical professionals. Georgia’s growing population tops approximately 11 million residents, straining the state’s existing medical infrastructure.

Now the nation’s eighth largest state, Georgia is forecasted to experience further population growth in the coming years, and nearly one-third of the state’s physicians are nearing retirement.

“Georgia is growing,” said Sonny Perdue, chancellor of the University System of Georgia. “We may only be only eighth today, but in just a few short years Georgia could be the fifth largest state. And that means we are going to need more health care, and people are going to get it here and across the state.”

Founding Dean of the School of Medicine Shelley Nuss, middle, is surrounded by medical students at the groundbreaking ceremony for the Medical School Building. (Andrew Davis Tucker/UGA)

Georgia currently ranks No. 40 among U.S. states for the number of active patient care physicians per capita, according to the Association of American Medical Colleges (AAMC), while it ranks No. 41 for the number of primary care physicians and No. 44 for the number of general surgeons per capita. The shortage of medical providers is particularly acute in rural and underserved areas, where access is even more limited.

UGA faculty are already engaged in human health research, and the establishment of a school of medicine will bolster their efforts.

“Our flagship institution, the University of Georgia, is tasked with the vital mission of educating and preparing the next generation of leaders,” said Gov. Brian Kemp. “To that end, one of our top priorities is building a strong health care workforce pipeline. This UGA facility will be an essential part of those efforts.”

Alongside funding from state government, strong private support will fortify efforts to create a School of Medicine at UGA. Donors have demonstrated robust support for UGA initiatives in recent years. In fiscal year 2023, UGA raised over $240 million in gifts and pledges from alumni, friends and foundation and industry partners. The university’s three-year rolling fundraising average is now a record $235 million per year, with annual contributions exceeding $200 million for the past six consecutive years.

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• Dmitriy Zamarin

An autoantibody signature predictive for multiple sclerosis

An antibody screen of two distinct multiple sclerosis cohorts reveals an autoantibody signature that is detectable years before symptom onset and linked to a common microbial motif.

• Colin R. Zamecnik
• Gavin M. Sowa
• Michael R. Wilson

Demographic bias in misdiagnosis by computational pathology models

In a series of clinically relevant tasks in computational pathology, AI-driven models display marked performance disparities across demographic groups, which can only partially be mitigated by self-supervision on large training datasets and existing debiasing techniques.

• Anurag Vaidya
• Richard J. Chen
• Faisal Mahmood

Risk-based lung cancer screening performance in a universal healthcare setting

Implementation of organized low-dose computed tomography screening in over 4,000 individuals with high risk for lung cancer as part of the Ontario Lung Cancer Screening Pilot reported high cancer detection rates, early detection of cancer and low serious harms.

• Martin C. Tammemägi
• Gail E. Darling
• Linda Rabeneck

Development and validation of a new algorithm for improved cardiovascular risk prediction

The QR4 algorithm for prediction of 10-year cardiovascular disease risk, developed, tested and externally validated in datasets comprising 16.8 million people from the United Kingdom, improves upon the QRISK3 algorithm that is in current use by incorporating new risk factors.

• Julia Hippisley-Cox
• Carol A. C. Coupland
• Keith M. Channon

An Omicron-specific, self-amplifying mRNA booster vaccine for COVID-19: a phase 2/3 randomized trial

A self-amplifying mRNA vaccine shows promise in this new modality by eliciting neutralizing antibodies against the SARS-CoV-2 Omicron (BA.1) variant in a phase 2/3 trial.

• Rohan Gurjar
• Vijaykumar Barge

The fasciola cinereum of the hippocampal tail as an interventional target in epilepsy

The posterior hippocampal tail is an important seizure node in humans and may be a promising interventional target in epilepsy.

• Ryan M. Jamiolkowski
• Quynh-Anh Nguyen
• Ivan Soltesz

Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes

Using plasma samples collected over several time points during pregnancy from three different cohorts, associations between circulating placental IGFBP1 levels, metabolic traits and birth anthropometric measurements were measured, with low IGFBP1 levels identified as a potential risk factor for gestational diabetes mellitus.

• Marie-France Hivert
• Frédérique White
• Camille E. Powe

Prediction of tumor origin in cancers of unknown primary origin with cytology-based deep learning

Developed on cytology images of hydrothorax and ascites from 57,220 cases at four hospitals, a deep-learning model shows high accuracy in tumor origin prediction and presents prognostic value when patient treatment is consistent with the cancer origin predicted by the model.

• Xiangchun Li

Transparent medical image AI via an image–text foundation model grounded in medical literature

By learning to pair dermatological images and related concepts in a self-supervised manner, a visual-language foundation model is shown to have comparable performance to supervised models for concept annotation and is used to scrutinize model decisions for enhanced interpretability and accountability of medical imaging applications.

• Chanwoo Kim
• Soham U. Gadgil

Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease

An exploratory analysis of the 1-year clinical trial PASADENA in individuals with early-stage Parkinson’s disease suggests that prasinezumab might reduce motor signs progression to a greater extent in those with more rapidly progressing disease.

• Gennaro Pagano
• Kirsten I. Taylor

Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers

In an observational study evaluating functional precision medicine in children and adolescents with relapsed or refractory solid and hematologic malignancies, it was feasible to provide personalized treatment recommendations to treating physicians on the basis of genomic profiling and ex vivo drug sensitivity testing within 4 weeks.

• Arlet M. Acanda De La Rocha
• Noah E. Berlow
• Diana J. Azzam

Generative models improve fairness of medical classifiers under distribution shifts

By generating synthetic image samples specific to underrepresented groups, diffusion models help medical image classifiers to achieve greater fairness metrics across a variety of medical disciplines and demographic attributes.

• Olivia Wiles

Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother–child pairs

In a large multinational cohort study, maternal, gestational or pregestational diabetes was associated with only a small-to-moderate risk of ADHD in offspring, contrary to previous estimates that showed stronger effect sizes, attributing the differences in findings to confounding by shared genetic and familial factors.

• Adrienne Y. L. Chan
• Ian C. K. Wong

Continuous glucose monitoring and intrapersonal variability in fasting glucose

The analysis of continuous glucose monitoring measurements from a large cohort of nondiabetic individuals uncovered large inter- and intraindividual variabilities, with potential implications for current diagnostic cutoffs for diabetes diagnosis and several cardiometabolic clinical measures.

• Smadar Shilo
• Ayya Keshet

Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial

Treatment of patients with advanced hepatocellular carcinoma with a personalized DNA vaccine in combination with anti-PD-1 therapy was safe and led to encouraging clinical efficacy, with immunological analyses confirming the induction of tumor antigen-specific T cell responses.

• Mark Yarchoan
• Edward J. Gane
• Niranjan Y. Sardesai

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results

In an interim analysis of a phase 1/2 trial, a heterologous prime boost vaccine comprised of a chimpanzee adenovirus and self-amplifying mRNA that encodes neoantigens derived from common oncogenic driver mutations in combination with immune checkpoint blockade was safe and elicited neoantigen-specific T cell responses in patients with advanced solid tumors.

• Amy R. Rappaport
• Chrisann Kyi
• Karin Jooss

Risk factors associated with heatwave mortality in Chinese adults over 65 years

In a prospective cohort of Chinese participants aged 65 years and older, heatwaves doubled the risk of mortality, especially in adults with functional impairments and dependency on daily living activities.

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