Chronic fatigue is a common complaint that is prevalent among, approximately over 10% of the general population. Unlikely fatigues caused by any disorders or conditions, medically unexplained chronic fatigue such as idiopathic chronic fatigue (ICF) and chronic fatigue syndrome (CFS), are debilitating illnesses that impair the quality of life physically, socially, and occupationally. ICF is a sustained fatigue condition that does not meet the criteria of CFS, and shows prevalence 10 times higher than that of CFS in the general population.
To date, no effective therapeutics exist yet. For example, based on results from a large-scale clinical study (called the PACE trial) recommended therapies were abandoned or revised in both the U.S. and UK due to serious criticism by both scientists and patients. Scientists argued flaws in its design, while patients complained that exercise dramatically worsens their condition. Another trial that used an antibody, rituximab, did not show better therapeutic effects than the placebo used.
These unexplained chronic fatigue diseases are multidimensional or multifactor phenomena, manifesting as a form of syndrome. With a fundamental logic of "multiple compounds and multiple targets", there is increasing evidence for herbal remedies as a suitable strategy for chronic fatigue disorders. Many recent studies demonstrated that medicinal herbs and phytochemicals can serve as a viable source to offer benefits for the management of medically unexplained chronic fatigue. For example, some medicinal herbs such as extracts from Quercus Robur or Astragali Radix plus Salviae Radix have demonstrated anti-fatigue effects in clinical pilot studies for CFS or ICF. Thus herb-derived drug research could be promising strategy to scientists and practitioners; however, big challenges remain such as development of adequate animal models, identifying potential resources including their corresponding active compounds and underlying mechanisms, and clinical based evaluations of their safety and efficacy, respectively.
This Research Topic will include evidence-based studies of medicinal herbs or phytochemicals that rigorously assess the beneficial effects, or lack thereof, of such treatment approaches on chronic fatigue including ICF and CFS. Original Research submitted to the Research Topic must include well-designed experiments and techniques capable of confirming or refuting hypotheses of the underlying mechanisms of this approach to the treatment of chronic fatigue in the form of clinical studies or animal-based research. In general, animal study would need to adapt the well-established behavior tests and supportive data using parameters of hormone, cytokines, redox, immune or brain neurotransmitters. Beside Original Research articles, other types of manuscripts including Mini-Review, Review, and Perspective are also welcomed. The aim of this Research Topic is to enhance the discovery of the potential therapeutics from medicinal herb resources, which will contribute to treating ICF and CFS. The editors of this Research Topic welcome contributions on the ethnopharmacology of traditional herbal medicines from around the globe. Any non-pharmacological interventions such as acupuncture however, are outside the scope of this Research Topic.
The four pillars of best practice in ethnopharmacologyWith these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of
Frontiers in Pharmacology.
1) Pharmacology
a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.
b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.
Specifically antioxidant activity must be based on a pharmacologically relevant
in vivo or cell based model. Simple
in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.
c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.
d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.
e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach.
f) Docking studies must be justified with affinity experiments, or other well established experimental methods to support a proposed mechanism of action. Algorithmic docking studies will not be accepted; these indicate if a compound will "fit" into a binding site but do not indicate the binding affinity or the ability to induce a conformational change.
2) Composition:
a) Botanical:
The identification of the study material must be described well. All species are fully validated using
Kew MPNS portal or
The Plant List initiative or
Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.
b) Chemical
- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph
- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in
in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration
- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.
c) Multiherbal preparations:
Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.
3) Basic requirements and research ethics
Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:
a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.
b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).
c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).
d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.
e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.
4) Other specific requirements
a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the
ConSEFS standards including any updates.
b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.
c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.