Factors Influencing Clinical Trials of Herbal Medicinal Products – Using Ginger as Example

Abstract

Ginger (Zingiber officinale) has a global use as a spice, an ingredient of beverages, food supplements (syn. dietary supplements), as well as herbal medicinal products. Since the last update of ginger in ESCOP Monographs in 2009 a significant number of papers concerning its bioactive constituents and clinical uses have been published. From this large number and selecting those references (almost 500) considered most relevant to clinical aspects and therapeutic indications, the following issues are considered to be potentially important to research on other medicinal plants: [i] quality assessment; [ii] pre-clinical (in vivo) studies; [iii] quality of clinical trials; [iv] ethnicity of clinical trial participants and [v] effects of sex-gender on activity and therapeutic indications.

Keywords

Ginger - Zingiber officinale - Zingiberaceae - factors influencing clinical trials

Introduction

Herbal medicinal products [HMPs] are particularly suitable for treating non-life-threatening ailments, and the use of plants or herbs to manage health conditions [phytotherapy] has become increasingly popular and commercially important in recent years. However, a number of aspects have arisen regarding the quality and scientific assessment of these herbal products [1], [2], [3]. International (such as the European Medicines Agency; EMA) and national regulatory bodies have the responsibility of monitoring the quality of medicinal products including herbal ones. Like for all other medicines, their controlled quality is mandatory, but – apart from those products on tradition only – clinical data to assess their safety and efficacy are required. Many aspects of publications concerning human clinical trials with herbal materials are too variable, with reviews and analyses often concluding “that problems exist regarding the quality of the material sampled, the small sizes of the trials and poor evaluation systems or parameters employed to reach conclusions”. Also, scientific evidence is often limited and needs to be improved to allow integration into guidelines and standard regimens of evidence-based clinical practice [4], [5], [6].

Search Strategy

The second edition of ESCOP Monographs was published in 2003 and included Zingiberis Rhizoma with 58 references. Another version (updated by I. Hook) followed in 2009 with 147 references. To bring the information up to date, the CAS SciFinder from 2007 to 2022 was searched with the words “Zingiber officinale, ginger, rhizome”. This resulted in a potential 34 004 references. To rationalise this large number, the additional terms then applied were “activity, bioactivity, clinical trials”, resulting in 1,485 references. Finally the process was repeated for 2023 when a further total 1012 references were reported, which were then rationalised again with the terms “bioactivity, clinical trials”, resulting in a further 217 relevant references. Abstracts of all these were examined for methodology and relevance resulting in a total of 1701 publications, which on further scrutiny, resulted in many in vitro trials being excluded. Full publications were always examined for greater details, such as ginger product and dose information, animal and human genders, toxicity, etc.

Quality Assessment

Constituents

A challenge with herbal medicines is the large number of constituents with potential bioactivity versus conventional drugs with usually only one or two biologically active constituents [7], [8]. However, as with all medicines, the ultimate demonstration of therapeutic usefulness is clinical trials for safety and efficacy, but these can only be scientifically evaluated when the herbal material being used is authenticated, standardized and quality controlled. The active constituents of ginger are considered to be a series of pungent polyphenolic homologues of gingerol (mainly 6-gingerol) [9] and shogaols, present in the oleoresin which makes up 4 to 7.5% of the dried rhizome material. Of this oleoresin, 25% are the pungent principles; i.e. circa 1 to 2%. Also present is an essential oil (0.25 to 5% v/w) made up predominantly of sesquiterpenes [10] such as a-zingiberene (17 to 37%).

The regulation of herbal medicines varies greatly between countries and global regions [11], but national Pharmacopoeial monographs defining the expected quality are published. However, what is expected by way of quality is variable. For example in the Chinese Pharmacopoeia [12] the quality of dried ginger is determined by the essential oil content (not less than 0.8%) and 6-gingerol (not less than 0.6%) analysed by HPLC. In the European Pharmacopoeia [13], the quality is assessed by the amount of essential oil (not less than 1.5%) with constituent identification by (HP)TLC. For comparison the USP-NF states that ginger should contain not less than 1.8% of essential oil, not less than 0.8% of gingerols and gingerdiones and not more than 0.18% of shogaols as analysed by TLC and HPLC [14]. Marketing authorization and licencing of these herbal materials is also ambiguous with three categories potentially classified as HMPs being available on the European market: (i) HMPs (ii) food supplements or (iii) cosmetics [15]. According to the EMA/HMPC document [16] there are currently 13 officially licensed products containing ginger in the EU [Germany, Lithuania, Netherlands, Poland each with × 1, Austria with × 3 and UK with × 5]. However, a market survey carried out in 2022 found that in addition, many foods and food supplements have appeared on the market over the last ten years, with demand expected to grow in the coming years [17]. In 2021 the UK FSA Exposure team examined information on ginger supplements and food intake in women of childbearing age to assess the potential of its constituents and possible contaminants (including heavy metals) on reproductive toxicity, on a long-term basis. They listed × 18 supplements, × 7 foods and × 21 juices/drinks/teas [18].

In the United States ginger products are marketed as dietary supplements, not as herbal medicinal products, and neither the FDA nor any other federal or state agency routinely tests these supplements for quality, prior to sale. A recent market survey of sales in the United States showed ginger to be one of the most widely consumed herbal supplements [19] and a search by Husain [20] in the NIHʼs Dietary Supplement Label Database resulted in more than 3500 ginger-based products sold via major retailers. Products are highly variable in quality. Schwerter [21] for example found that 6-gingerol concentration of the ginger powder of dietary supplements ranged from 0.0 to 9.43 mg/g, 6-shogaol from 0.16 to 2.18 mg/g, 8-gingerol from 0.00 to 1.1 mg/g and 10-gingerol from 0.00 to 1.40 mg/g. Similarly a quality assessment in 2022 by an independent company [22] found that of 18 products, 7 contained low levels of active constituents and nearly all had shogaol levels higher than USP specifications. In many clinical trials the content of actives is not determined or published.

Pesticides

In 2022 the annual world production of ginger was approximately 4.1 million metric tons, with China, India and Nigeria among major producers. It has long crop-growing periods in the fields (210 to 240 days after planting) thereby requiring intensive use of various pesticides [23]. After harvesting, ginger processing can include washing, peeling, boiling, drying and powdering, before solvent extraction or distillation occurs. Each process varies in how the levels of pesticides resulting in the ginger end-product are affected. Since ginger is also commonly used for cooking or as a dietary supplement, a risk for exposure to pesticides exists from frequent or excessive consumption, resulting in pesticide residue analysis of ginger being required by many countries [23]. Evaluation of more than 3 million sets of data on residues in herbal drugs available to European manufacturers, found that in most cases (98%) the limits of quantitation were lower or equal to 0.05 mg/kg (0.05 ppm), with 63% lower or equal to 0.01 mg/kg, indicating that the Ph.Eur. limits on pesticide residues were not exceeded [24].

Heavy metals

Apart from pesticide residues Pharmacopoeial monographs specify, as part of quality, limits on microbial contaminants and heavy metals (arsenic, cadmium, chromium, cobalt, lead, mercury, nickel, vanadium). These purity determinations are rarely carried out or results published. Such heavy metal contamination above accepted threshold concentrations in herbal medicines is presently a global threat to human health. A recent analysis of 1773 samples from around the world of 86 different types of commonly used Chinese herbal medicines found 30.5% with at least one, over the accepted Chinese Pharmacopoeia limit [25]. Also, Danggui (Radix Angelica sinensis) commonly consumed by pregnant and nursing mothers in Malaysia, was found on sample analysis to contain high concentrations of heavy metals, posing a potential health risk of transfer from mother to foetus and infant [26]. Heavy metal content of soil and root accumulation is a known cause of abiotic stress affecting plant health, annual growth, enzyme activity affecting bioactive metabolite contents (e.g. ginsenosides in Panax ginseng C. A. Meyer) [27]. Some medicinal plants are also active hyper-accumulators of heavy metals from contaminated soil, for example St. Johnʼs Wort (Hypericum perforatum L.) and Chamomile (Matricaria recutita L.) can amass a relatively high concentration of cadmium ranging from 1 to 4% of biomass [28], [29].

Ginger also can accumulate toxic levels of mercury from polluted soil [30] and the recent quality assessment in the US [22] found 0.53 mcg of lead per g of a product, exceeding the daily allowance and indicative of “reproductive harm”. Analysis of ginger from Ethiopia for heavy metals found mean concentrations (mg/kg) ranging from 4.63 to 5.43 for cadmium, 2.17 to 4.44 for chromium, 62.52 to 65.14 for copper, 77.71 to 81.12 for iron, 6.49 to 7.58 for nickel and 16.74 to 19.31 for zinc, but lead was not detected [30]. There is therefore a ʼpotentialʼ for ginger products when taken during pregnancy and lactation to have reprotoxic effects at high supplemental doses. For heavy metals the Ph. Eur. general monograph Herbal drugs [13] has the following limits: cadmium 1.0 ppm, lead 5.0 ppm, mercury 0.1 ppm. According to EMA/HMPC/765 220/2022 [16] in EU/EEA member states there are currently 13 medicinal ginger products of Ph. Eur. quality marketed as well as many foods and food supplements of varying quality [18]. Although pesticide residues [24] or heavy metal contamination in products in general appear not to be a major problem, analysis of ginger rhizome samples (x6) for contents of heavy metals found cadmium and lead levels to be within limits, but 2 out of the 6 samples had mercury above the permitted limit [31]. Overall the Ph. Eur. limits set for cadmium, lead and mercury are considered appropriate and samples from organic production have revealed a lower occurrence of these elements as compared to samples from conventional production. However, compared to the period 2008 – 2015, the results from the current updated period (2016 – 2021) show significantly more positive findings for heavy metal elements in herbal drugs and essential oils [32].

Pre-clinical (in vivo) animal studies

The use of animals in testing of herbal medicines, while offering undeniable advantages, remains a subject of intense debate and contention, mainly arising from the ethical challenges it presents, the substantial financial burden it imposes, as well as its inability to reliably predict human responses [33]. To overcome this, newer approaches (e.g. systems pharmacology) are being applied to explore pharmacological effects of multi-component herbal medicine [34] and help to identify and prevent the risk of herb–drug interactions at an early stage of the drug development process [35].

Although sampling animals of both sexes and of various hormonal states has produced new discoveries that influence drug development and patient care, and countries have typically enacted legislation that requires sex/gender diversity in sponsored human studies, these guidelines are rarely enforced to studies on animals. Much basic research still uses animal models that focus on males and excludes females [36], creating a sex bias in biomedical studies that needs to be minimised [37].

The use of appropriate animal models to assess a possible effect in humans is invaluable and rodents are the most frequently used, with mice and rats making up approximately 95% of all laboratory animals. However, for example in diabetes mellitus research, for T1D Yagihashi [38] lists six strains of rats + mice and for T2D, four types of rat and eight types of mice. Overall this type of research is poorly standardised, as not only is model type important, but also age, sex, genetic background and husbandry practices, all of which can impact the results [39]. For example, in the Morris water maze test using ICR mice, females showed superior learning to, and greater memory abilities than, males [40], an effect however that was not found using C57BL/6 mice [41]. Female mice are often excluded from animal studies but their inclusion is important to improve detection of real drug effects [42]. This gender bias creates three problems: [i] less knowledge about disease processes in females due to underutilization of female animals, [ii] an inability to use sex as a variable, e.g. in regulation of immune function and [iii] missed female-specific phenomena such as pregnancy and menopause. Data extracted from drug dossiers submitted to the EMA for marketing authorisation between 2011 and 2015, showed female animals were included in only 9% of the pharmacodynamics studies, although both female and male animals were included in all toxicology studies [43]. Also, for drugs in general there is a “poor translation rate (over 90%) from animal results to human studies” [44] and often with a citation bias on the positive with under-citation of the negative [45].

Conventional medicines are known to affect male and female human patients differently and this has now occasionally been reported in animals when treated with herbal extracts. For example, with a St. Johnʼs Wort (H. perforatum L.) extract, hypericin plasma levels were significantly more elevated in female three-month-old mice than in males [46], while in rats cognitive impairment was found, possibly through a reduction in the levels of neurotrophic factors, an effect that was expressed more in females than in males [47]. In Centella (Centella asiatica (L.) Urban) an extract was found to have different effects in the memory retention of male and female C57BI/6 mice [48]. Similarly when 5 xFAD mice (a model of Alzheimerʼs disease) were given this C. asiatica extract, results showed that after 4.5 weeks, in female mice there was no loss in the conditioned fear response, but this was diminished in male mice [49]. To better understand the effects of gender and how varying concentrations of C. asiatica aqueous extract affects the brain differently, a metabolomic analysis of cortical tissue collected from male and female 5 xFAD mice and wild-type (WT) litter mates was carried out. With a dose of 500 mg/kg/d, for example, in 5 xFAD females nine pathways were altered significantly compared to seven in 5 xFAD males and six pathways in WT females compared to four in WT males [50]. With Rosemary (Salvia rosmarinus Spenn.) a dose of 500 mg/kg resulted in a significant decline in spermatogenesis of male rats attributed to a significant decrease in testosterone, while in female rats it led to reduced fertility due to an increased number of foetal resorptions [51]. In ginger different doses (200 mg/kg for males and 250 mg/kg for females) were found to modulate gamma radiation-induced conditioned taste aversion in rats in a gender-specific manner due to hormonal fluctuations [52].

Examination of the references for the ESCOP Zingiberis Rhizoma Monograph update, the following was found: in vivo animal studies cited a total of 87 trials of which 74 used rats or mice. Rats were used in 41 trials with the following use of genders: male × 29, female × 1, both sexes × 7 or no gender given × 4. Mice were used in 33 trials with the genders as follows: male × 21, female × 6, both sexes × 1 or no gender × 4; i.e. where gender was given 77% were male. Rarely were results for the genders analysed separately and/or results given. Also, the vast majority of results showed a positive effect after ginger treatment, which could suggest a possible selection bias for studies that could confirm the therapeutic indications of ginger. Similarly in the narrative review by Crichton [53] on mechanisms of ginger actions of 36 in vivo animal studies, mainly mice and rats were used and no gender was given in 36%, but where gender was given 87% were male.

Clinical Trials

In a recent systematic review of all the published 109 clinical trials with ginger [54], critical evaluation showed that only 43 met the criterion of having a “high quality of evidence”; i.e. 60% are poorer in quality. Similarly in the umbrella review by Crichton [55] of 22 trials, only 4 (18%) were considered to be of “high quality”. In this study, 133 clinical trials were included (see [Table 1]). Some variables in clinical trials are highlighted below.

Table 1 Cited clinical trials (n = 133) in different indications.

Indication	No. of cited studies	No. of studies with positive outcome
a with a response to ginger of 80 to 100%; b with a response to ginger of 60 to 80%; c with a response to ginger of less than 60%
Gastrointestinal effects
Motility, dyspepsia, salivary flow	7	7 a
Early pregnancy nausea & vomiting (NVP)	15	12 a
Postoperative nausea & vomiting (PONV)	18	13 b
Nausea & vomiting of motion	14	8 c
Chemotherapy nausea & vomiting	19	10 c
Other antiemetic effects	5	5
Anti-inflammatory and analgesic effects
Arthritis (Osteo- & Rheumatoid)	8	7 a
Dysmenorrhoea	8	5 b
Migraine	3	2 b
Metabolic syndrome
Weight management	3	3 a
Blood lipids	8	5 b
Glycaemic (insulin) control	9	7 b
Other clinical effects	16

Participant ethnicity, dietary habits, pharmacokinetics

The analysis of ginger clinical trials by Anh [54] showed that they took place in the following countries: Iran (× 24), the US (× 13), Australia (× 5), Europe (× 4), Thailand (× 3) and one each in Brazil, China, India and Israel. Data suggests that ethnicity, dietary habits and geographical provenance are closely interlinked and their interrelationship is a key player in determining gut microbiome diversity [56]. Food group intakes – particularly fruit, vegetables and fish – and diet quality scores differ between ethnicities [57], [58] and influences gut microbial composition (microbiome) [59], [60], [61], [62], [63]. For example the infant gut microbiome arises after three months of age and persists through childhood, a variation that is associated with race and ethnicity [64]. South Asian infants were found to have a higher abundance of lactic acid bacteria, while Caucasian infants had higher Clostridiales genera attributed to differences in maternal and infant diets in the first year of life [65]. A large-scale analysis of gut microbiota diversity across US ethnicities (African American, Asian American and Pacific Islander, Caucasian, Hispanic) showed recurrent associations between specific taxa and ethnicity [59]. A two-week intake of ginger powder by healthy American participants (71% female) also resulted in altered aspects of gastrointestinal bacteria composition [66], while a six-week ingestion of ginger by subjects with prior colorectal adenoma, had a limited, but real effect on the faecal microbiome [67]. In healthy Chinese (63 male:60 female) participants a short-term intake of ginger juice was found to have substantial effects on the composition and function of gut microbiota. Significant differences were identified in bacterial genera (× 19) between the control group (women) and ginger group (women) and 15 significant differences at the genus level between the control group (men) and ginger group (men), indicating the importance of analysing both male and females separately [68].

The effects of race or ethnicity on the pharmacokinetics of conventional Western medicines are well recognised [69], but less so for herbal medicines. However, examination of the pharmacokinetics of a multicomponent Chinese herbal preparation (Kang 601) found significant pharmacokinetic differences between healthy male African and Chinese volunteers [70]. With ginger, pharmacokinetic studies have shown that concentrations of actives peaked at circa 1 hr after oral administration when given to healthy volunteers (Americans; gender not specified) [71]. Similarly in mostly Caucasian participants (American; 9 M:22F) t_max for 10-gingerol was at 75 mins and for 6-shogaol at 66 mins with half-lives of the main constituents and their metabolites of 1 – 3 h [72], compared to t_max for 10-gingerol at 38 mins and for 6-shogaol at 30 mins in healthy Indonesian participants (13 M:8F) with half-lives of the metabolites of these constituents at 2.5 – 5.6 h [73].

It is also important to remember that differences in pharmacokinetic effects exist between whole-plant extracts versus pure constituents. In rodent malaria models it was found that interactions occurred between constituents of Sweet Wormwood (Artemisia annua L.) tea or dried whole plant, so that its artemisinin content was more rapidly absorbed than the pure drug and thereby reducing resistance [74], [75]. With ginger similarly a whole-plant extract had different absorption profiles in male mice and enhanced bioavailability compared to single compounds [76]. Also, a study in rats demonstrated that plasma levels of madecassoside, and to a lesser extent asiaticoside, were higher after administration of a standardised extract of C. asiatica than for the pure compounds [77].

Effects of sex-gender on activity and therapeutic indications

Countries typically have enacted legislation that requires inclusion of women in government-sponsored human studies. For example, the U. S. National Institutes of Health require “that women and members of minorities and their subpopulations be included in all human subjects research. Nevertheless sufficient representation of women to allow for sex analysis is required only for Phase III clinical trials” [78]. Data from dossiers submitted to the EMA between 2011 and 2015 [43] showed that inclusion of women in Phase III clinical trials was variable and they were underrepresented for certain diseases. Sex differences in metabolism (Phase I and II) are believed to be the major cause of differential pharmacokinetics. Many CYP450 enzymes (Phase I metabolism) show a sex-dependent difference in activity. Most of Phase II enzymes have a higher activity in men than in women [79]. Sex differences in efficacy are observed with some drugs [43]. Also, the role of gender as a biological factor in the generation of adverse drug reactions (ADRs) is poorly understood with women experiencing almost twice as many ADRs as men. Since most approved clinical trials are conducted on men, it suggests that women could be over-medicated leading to this greater incidence of ADRs [36]. Gender-specific medicine “needs to focus the attention and efforts of the scientific community on understanding the differences of pathophysiology, clinical signs, prevention and treatment of diseases equally represented in men and women” [80], [81], [82].

It is also recognised that journals inconsistently publish sex disaggregated data on drug efficacy [83], although it is known that males and females differ in pharmacological responses to many drug treatments [84], [85], [86]. Examples include motion (travel) sickness, which is more common in children than in adults, more common in women (particularly during menstruation or pregnancy) than in men and not in simulator sickness (e.g. viewing a rotating optokinetic drum) [87]. Ethnic groups differ in how they experience car sickness, with the highest incidence reported in China and the lowest in Germany [88]. Asian women compared to European American and African American women were shown to have a hypersensitivity to motion sickness, while a second study yielded similar results in American-born children of Asian parents [89], [90]. Different ethnic groups also differ in their sensitivity to pain [91], [92] as in post-operative pain and nausea (PONV) [93], [94]. Women of African ethnicity have been shown to have a decreased incidence of PONV compared to Caucasian [95]. Also, pain tolerance was found to be different in Asian as compared to white women [96]. In general women are more susceptible to pain than men [97] and women perceive more pain than men as in pain scores [98], [99]. Migraines too are three to four times more common in women than men [100] and the number of women experiencing osteoarthritis is higher than in men [101]. Women also react differently to drug treatments such as antiemetics [102], [103], anaesthetics [104] and experience different side effects [105]. With depression there are gender-specific mechanisms in activating symptoms and depressive states [106], [107] and womenʼs psychotic symptoms respond to antipsychotic drugs at doses lower than menʼs [108]. Other gender-specific effects include immune responses [109], inflammation [110] and infectious diseases [111].

With medicinal plants it is of interest to note the effect of gender and ethnicity for preferences of essential oils [112]. For example, in healthy school-aged children, male Latinos were more likely to describe Peppermint (Mentha x piperta L.) as “energetic” than male Caucasians, while female Latinos more likely than Caucasian females found Sweet Orange (Citrus x aurantium f. aurantium) “calming”. Effects of ethnicity and gender in odour perception and olfactory evaluation are known to be complex but well-referenced in Chen [113]. Campesi [114] highlighted how gender-sex differentially can influence activities of plant phenols in herbal medicines during critical periods of womenʼs lives. Ingestion of C. asiatica attenuated the age-related decline in cognitive function in healthy middle-aged and elderly adults but the results also suggested that C. asiatica can modulate cognitive function differently at different time periods [115]. Recent pharmacokinetic studies with a standardised hot water extract of C. asiatica, when given to healthy older adults (white, Caucasian), demonstrated a significant difference in C_max between male and female participants for the 2 g dose [5]. When a 60% ethanolic dry extract of Dandelion (Taraxacum officinale (L.) Weber) corresponding to 6.3 g leaf/day was tested in ten individuals (5F;5 M) for seven days and pooled for male and female participants, a more pronounced increase in the relative amount of Tamm-Horsfall protein/creatinine was observed on day three in women than men [116]. This could be possibly explained as a self‐defence mechanism to overcome the higher infections pressure by the female anatomical properties, since women have a tendency to have higher Tamm-Horsfall protein (THP; Uromodulin) concentration and excretion rates than men [117]. The effect of a Hypericum perforatum extract [300 mg containing 900 mg hypericin] taken three times a day for 14 days by healthy male and female participants, demonstrated an induction of the enzyme CYP1A2 only in females [118]. When Liquorice (Glycyrrhiza glabra L.) 100 g (containing 150 mg glycyrrhetinic acid) was consumed daily for four weeks, the relative change in serum aldosterone levels, showed men being more responsive than women, but not in patients with essential hypertension compared to healthy subjects [119]. A gender-specific benefit was also found with a standardized extract of ginger over placebo in Functional Living Index Emesis [FLIE] in female cancer patients receiving high-dose cisplatin [120].

Evaluation of the 150 human studies using ginger (pharmacological studies + clinical trials) showed that they were carried out in 25 countries. The main contributors were: Iran 39.6%, Thailand 8.7%, the US 8.1%, Europe collectively 17.4%, East Asia collectively 5.4% and the Indian subcontinent 5.4%. Gender analysis showed that (where gender was given) 55.5% of all studies included both men and women, 8% included men only, and 36.5% used only women. Trials for female-only conditions (NVP and primary dysmenorrhoea) represented 15.3%. Regarding the quality of ginger used in these studies, 53% were found to have used commercially available products.

Concluding Remarks

Ginger has a long tradition of benefit for various human ailments and although evidence has been scarce, recent meta-analyses and systematic reviews, together with the large number of clinical trials, now suggest effectiveness in [i] gastrointestinal disorders [121] and [ii] pain and metabolic syndrome [53], [54], [55], [122]. Similarly for nausea and vomiting in [iii] early pregnancy [123], [124], [125], [126], [iv] as an adjunct antiemetic in cancer chemotherapy [120], [127], [128], [129], [130] and [v] post-operatively [131], [132], [133]. However, as an antiemetic in the prevention of motion-induced sickness, observed results have been mixed depending on the experimental conditions used, i.e. travel or simulator [134], [135]. Promising results have however been reported for [vi] painful inflammatory conditions such as osteoarthritis [54], [55], [136], [137], [vii] neurodegenerative diseases [138], as well as for [viii] glycaemic control in type 2 diabetes mellitus and metabolic syndrome [139], [140], [141], [142] (see [Fig. 1]).

Fig. 1 Overview over results of clinical studies in different indications. – Several studies with positive results; – Studies with promising results; · – · Studies with mixed results; *** response to ginger of 80 to 100%; ** response to ginger of 60 to 80%; * response to ginger of less than 60%

Many publications argue that such positive outcomes can be explained by the fact that ginger constituents interact with receptors of neurotransmitters mediating nausea and vomiting [143], as well as COX-2 associated with inflammation [144] and have anti-nociceptive activity involved in pain [122], [145], thereby proving activity. Similarly in silico mechanistic, in vitro and in vivo animal studies are indicative of supporting the findings from human clinical trials [53], [137]. However, such positive health benefits need to be interpreted with caution. Few clinical trials meet the criterion of ʼhigh qualityʼ, with too many small patient sizes and unstandardized evaluation systems including ginger quality and dosage regimes in the long-term [54], [55], [146]. Also, since most of the included trials were conducted in Asia, pharmacogenetics and outcome expectancy regarding ginger intervention could differ across cultures and ethnicities [137] and although there is an EMA guidance document concerning Ethnic Factors in the Acceptability of Foreign Clinical Data [147] this is rarely applied to herbal medicinal products. Finally, although ginger is a ʼuniversally usedʼ medicinal plant, surveys from around the world – Taiwan [148], Australia [149], Brazil [150], the US [151] and Europe [152] – show that women continue to be the primary users for conditions including stress, depression, menopause, pregnancy associated nausea, primary dysmenorrhoea and arthritis. Few references specifically relate to effects or recommended dosages for men, and such facts need to be reflected in the genders that are used for animal in vivo and human clinical trials.

Contributorsʼ Statement

Conception and Design of the work: I. Hook, L. Krenn, B. Steinhoff, E. Wolfram; Data collection, analysis and interpretation of the data and drafting the manuscript: I. Hook; Critical discussion and revision of the manuscript: L. Krenn, B. Steinhoff, E. Wolfram

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

The authors thank other members of the Scientific Committee of the European Scientific Cooperative on Phytotherapy for their input (ESCOP, https://escop.com/about-escop/scientific-committee/).

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