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 Phytomedicine 85 (2021) 153476

Contents lists available at ScienceDirect

Phytomedicine
journal homepage: www.elsevier.com/locate/phymed

Review

Toxicity as prime selection criterion among SARS-active herbal medications

Franz Oesch a, *, Barbara Oesch-Bartlomowicz b, Thomas Efferth c
a
Institute of Toxicology, Johannes Gutenberg University, 55131 Mainz, Germany
b
Oesch-Tox, Rheinblick 21, 55263 Ingelheim, Germany
c
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, 55128, Mainz, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: We present here a new selection criterion for prioritizing research on efficacious drugs for the fight against
COVID-19 COVID-19: the relative toxicity versus safety of herbal medications, which were effective against SARS in the
Cytochrome P450, Phytochemicals 2002/2003 epidemic. We rank these medicines according to their toxicity versus safety as basis for preferential
Rational phytotherapy
rapid research on their potential in the treatment of COVID-19. The data demonstrate that from toxicological
Public health
information nothing speaks against immediate investigation on, followed by rapid implementation of Lonicera
Toxicity
japonica, Morus alba, Forsythia suspensa, and Codonopsis spec. for treatment of COVID-19 patients. Glycyrrhiza
spec. and Panax ginseng are ranked in second priority and ephedrine-free Herba Ephedrae extract in third priority
(followed by several drugs in lower preferences). Rapid research on their efficacy in the therapy - as well as safety
under the specific circumstances of COVID-19 - followed by equally rapid implementation will provide sub­
stantial advantages to Public Health including immediate availability, enlargement of medicinal possibilities, in
cases where other means are not successful (non-responders), not tolerated (sensitive individuals) or just not
available (as is presently the case) and thus minimize sufferings and save lives. Moreover, their moderate costs
and convenient oral application are especially advantageous for underprivileged populations in developing
countries.

Introduction and background
All over the world researchers are engaged to rapidly find medica­
tions useful for the therapy of patients infected with the new coronavirus
SARS-CoV-2 and/or for the prevention of COVID-19 (Hoffmann et al.,
2020; Magrone et al., 2020). The development of effective and safe
vaccines is time-intensive due to several complication factors. A first
problem arises by the mutability of the virus. SARS-CoV-2 possesses
multiple mutations, which optimize binding properties to ACE2 as its
receptor and the polybasic cleavage site in the viral spike protein
(Anderson et al., 2020). Coronaviruses rapidly mutate by recombination
(Kottier et al., 1995). Mutations of SARS-CoV-2 already led to several
strains of SARS-CoV-2 (Wang et al., 2020). Vaccines should be able to
deal with all of them as well as with future mutations. Therefore, rela­
tively stable SARS-CoV-2 proteins should be identified as antigens to
raise antibodies against SARS-CoV-2. In addition, vaccine-induced
aggravation of infections by “antibody-dependent enhancement” (Luo
et al., 2018) should be avoided, as well as severe organ damage as
observed with vaccines directed against SARS-CoV-1 in ferrets and mice
(Tseng et al., 2012). Dealing with all these issues including the required
trials predictably will demand quite some time.
The time span to actual readiness of application is of obvious
importance. Hence, medications already in clinical use and known for
producing only few unwanted effects stand in front line. Thus, repur­
posing of drugs developed for other disease indications appears to be
promising. At present, several such drugs are under clinical develop­
ment, e.g. the Ebola drug remdesivir, the HIV drugs lopinavir and rito­
navir and the antimalarial chloroquine (Costanzo et al., 2020; Kumar
et al., 2020; Sanders et al., 2020). Unfortunately, their usefulness is
hampered by as yet unknown effectivity (“The FDA has authorised
remdesivir for use in COVID-19 patients: but there’s no good evidence it re­
duces mortality”, Center for Evidence-Based Medicine, communication of
May 12, 2020 https://www.cebm.net/covid-19/the-fda-has-authorise
d-remdesivir-for-use-in-covid-19-patients-but-theres-no-good-evide

Abbreviations: ACE2, angiotensin converting enzyme 2; COVID-19, Coronavirus disease 2019; CYP, cytochrome P450 monooxygenase; HIV-1, human immuno­
deficiency virus 1; IKK, inhibitor of κB kinase; JNK, c-Jun N-terminale kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor- κ B cells; NO, nitric
oxide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOD, superoxide dismutase; Th2, T helper cells, type 2.
* Corresponding author. Institute of Toxicology, Johannes Gutenberg University, Obere Zahlbacherstr. 67, 55131 Mainz, Germany
E-mail address: oesch@uni-mainz.de (F. Oesch).

https://doi.org/10.1016/j.phymed.2021.153476
Received 30 June 2020; Received in revised form 10 November 2020; Accepted 15 November 2020
Available online 28 January 2021
0944-7113/© 2021 Published by Elsevier GmbH.
F. Oesch et al.
nce-it-reduces-mortality/). Further drawbacks are technical in­
conveniences (such as the necessity of intravenous treatment of
remdesivir) or quite massive adverse side effects, especially true for
chloroquine.
One treasury of rapidly available medications with acceptable side
effects has been largely overlooked thus far: Some herbal remedies used
since centuries in traditional medicine may be realistically promising to
treat SARS-CoV-2-infected patients based on experiences made with
SARS-CoV-infected patients during the 2002/2003 epidemic. These
may, therefore, merit immediate, rigorous investigations. It is reason­
able to hypothesize that chemical constituents in medicinal plants such
as Lonicera japonica, Morus alba, Forsythia suspensa, Codonopsis spec.,
Glycyrrhiza spec., Panax ginseng which were useful for SARS therapy may
also be useful to fight COVID-19.
Undesirable effects of any drug obviously are essential limiting fac­
tors. Thus, the degree of toxicity may present a valuable basis for
prioritizing urgently needed research on the rapid development of
effective and sufficiently safe treatments for COVID-19 patients. This
review presents published data regarding the toxicity of herbal medi­
cations from Far East traditional medicine, which have been reported to
be useful for the therapy of SARS-CoV-1-infected patients during the first
SARS epidemic (Liu et al., 2006; 2012a, 2012b; Wang et al., 2014; Luo
et al., 2020). Irrespective of whether all these reports withstand rigorous
scientific criteria, these herbal drugs are recommended by some physi­
cians in despair and taken by some patients in despair, believing in their
safety “as natural products” without knowledge of their respective safety
or toxicity.
In China more than 85% of SARS-CoV-2-infected patients received
therapies from traditional Chinese medicine (Yang et al., 2020). It is of
outstanding importance, therefore, to disseminate the knowledge on the
safety versus toxicity of these drugs. Many of them may in fact have
therapeutic or preventive potential for COVID-19. The relative safety or
toxicity of them may represent a rational basis for prioritizing urgently
needed, convincing research on potentially useful herbal drugs with a
much longer experience than with relatively newly developed drugs. It is
not impossible that some of the latter may lead to adverse effects, which
do not become visible in controlled clinical trials, but only after a latency
of several decades (as we painfully had to learn with many carcinogens).
At present, we do not yet have remedies for immediate use for preven­
tion or treatment of COVID-19. For the sake of the present patients and
for attempting prevention of a possible second wave of infections, it is
mandatory to keep an open mind to include into proper research all
possible sources of medication which realistically promise to be effective
for the prevention and/or cure of COVID-19, including herbal drugs
used in traditional medicine. Several of them have been more recently
investigated using rigorous scientific methods and criteria (Cheng et al.,
2016; Rai et al., 2017; Li et al., 2018). including analysis and structure
elucidation of their constituents (Yu et al., 2008; Sun et al., 2019; Qu
et al., 2020) as well as demanding quality control of preparations for use
(Li et al., 2009; Han et al., 2016; Gao et al., 2017). Lonicera japonica has
proven to be a top candidate for COVID-19 therapy by virtual docking
experiments on over 40,000 drugs showing their excellent binding ca­
pacity to critical target molecules of SARS-CoV-2 (spike protein, nucle­
ocapsid protein, and 2’-O-ribose methyltransferase) (Kadioglu et al.,
2020). Glycyrrhizin has recently been shown to have the potential to
bind to ACE2 (Ren et al., 2020), and Glycyrrhizic-acid-based carbon dots
have been reported to show high antiviral activity by multisite inhibi­
tion mechanisms (Tong et al., 2020).
The intention of this review article is to specifically provide an
overview on published results on preclinical toxicity studies. Chinese
medicine with its millennia-long experience follows holistic principles, i.
e. the complexity of the human body is seen in its entirety. Hence,
fighting diseases starts already with prevention and disease treatment
attempts to restore the disease-causing imbalances in the whole body.
This is achieved by influencing the meridians of the body, i.e. invisible
channels connecting the organs and allowing body fluids to flow such as
2
Phytomedicine 85 (2021) 153476
the life energy qi (Efferth, 2008). For intervention of meridians, external
approaches are applied (e.g. acupuncture and moxibustion, massage,
cupping, tai chi chuan etc.) and internal practices are used (e.g. complex
herbal mixtures, meditation and others). By contrast, western academic
medicine follows reductionistic approaches to reduce the complex dis­
eases to its single disease causes and fight diseases by attacking single
disease mechanisms.
Drug development and marketing underlies strict rules and regula­
tions to ensure safety and efficacy of new drugs. Like Western academic
medicine, Chinese medicine also aims to apply efficient and safe medi­
cations. This is reached by bringing the right plant constituents together
in herbal mixtures. In this context, the “emperor-minister-servant”
principle is of interest. The “emperor” plant exerts the main pharma­
cological effect, the “minister plants” support the activity of the “em­
peror” plant, and the “servant” can reduce possible side effects and
toxicities. During the past decades, Chinese medicine gained enormous
interest in the Western world as a complement to academic Western
medicine. If Chinese medicine should find its way to the European
pharma-market, applicable laws for drug approval have to be followed
which are valid for any drug – being of synthetic or natural origin
(Efferth and Greten, 2012). Hence, the scientific investigation of phar­
macological activity and toxic adverse effects of Chinese plants is of
utmost importance to open the European market for Chinese herbal
medicine. During the past two decades, we focused on both pharma­
cology and toxicology of Chinese herbs and their chemical constituents
(Efferth et al., 2007; Konkimalla and Efferth, 2008; Youns et al., 2010;
Efferth and Kaina, 2011; Quedraogo et al, 2012; Allard et al., 2013;
Efferth and Greten, 2012; Bhakta-Guha and Efferth, 2017).
In the present review, our intention is to give an overview on the
toxicology of Chinese plants that may help to treat COVID-19. While
specific reviews on the toxic effects are rare or even absent as of yet, a
tremendous number of investigations on antivirally active Chinese
plants to inhibit SARS-CoV-2 and to cure COVID-19 have been published
in the year 2020 (Huang et al., 2020; Luo et al., 2020; Li et al., 2020;
Yang et al., 2020). Therefore, in the present review we focused only on
toxicology and refer the reader to the excellent reviews on the phar­
macology of anti-COVID-19 Chinese plants and clinical trials performed
with Chinese herbal medicine to treat this pandemic that appeared in
parallel in this special issue of Phytomedicine (Hu et al., 2020; Wang
et al., 2020; Xia et al., 2020; Zhang et al., 2020; Zhao et al., 2020a; Zhao
et al., 2020b; Zheng et al., 2020).
Based on their already existing safety profile, the data presented here
may provide a rational basis for ranking individual herbal medications
for investigations on efficacy against COVID-19 (or, where the safety
profile shows no concern, possibly even carefully controlled, immediate
compassionate use). Potential advantages for patients’ welfare and
Public Health benefit include: (1) Enlargement and diversification of
pharmacological options where other drugs are not effective (non-re­
sponders), not tolerated (susceptible individuals) or not available (as is
presently the case). (2) Convenient oral application by the patient
himself without continuous necessity for professional assistance, and
moderate costs, both of these especially advantageous for financially
disadvantaged populations in developing countries. (3) Therapy opti­
mization may become possible by using the presented information for
complementary, synergistic or adjuvant combination treatment. (4)
Finally and of basic importance, in cases where the pharmacological
effect does not exceed placebo, the toxicological data presented in this
review and the consequent selection of a non-toxic herbal drug will at
least allow a psychological support without causing additional toxic
effects.
Lonicera japonica (Flos Lonicerae Japonicae)
Lonicera japonica used since thousands of years belongs to the oldest
drugs, and is one the most frequently prescribed drugs in Far East
traditional medicine (Shang et al., 2011). Nowadays it is widely used
F. Oesch et al.
also in cosmetics, soft drinks and health-oriented food (Shang et al.,
2011; Li et al., 2019), thus possessing a large fundus of experience.
Shang et al. (2011) reviewed in detail the antiviral, antibacterial and
antioxidative activities of Lonicera japonica as well as the isolation and
characterization of more than 140 of its chemical constituents. Since
then many further compounds were isolated from Lonicera japonica and
characterized with respect to their pharmacological activities such as
antiviral activities (Yu et al., 2008; Ding et al., 2017; Li et al., 2018; Ge
et al., 2019), suppression of inflammation-stimulating signaling path­
ways (Kang et al., 2010; Kao et al., 2015; Kwon et al., 2015; Lee et al.,
2015; Han et al., 2016; Zhang et al., 2020) or terminal enzymes (Xu
et al., 2007). As already stated in the Introduction, Lonicera japonica is
one of the herbal medicines which were successfully used for the therapy
of the SARS-CoV infected patients in the 2002/2003 SARS epidemic (Liu
et al., 2006; 2012a, 2012b; Wang et al., 2014; Luo et al., 2020).
Regarding the scope of the present review Lonicera japonica (and
Lonicera caerulea) did not lead to any toxicologically relevant changes in
rats or mice tested up to high doses (Thanabhorn et al., 2006; Lu et al.,
2014; Kim et al., 2015; Jeong et al., 2019). No cytotoxicity of poly­
phenols extracted from Lonicera japonica was observed at doses required
for suppressing mediators of neurodegeneration released from
lipopolysaccharide-treated microglia (interleukin-1β, tumor necrosis
factor α, prostaglandin E2) (Han et al., 2016). Lonicera japonica has
proven excellent binding properties for SARS-CoV-2 critical target
molecules (spike protein, nucleocapsid protein, and 2’-O-ribose meth­
yltransferase) in virtual docking experiments using supervised machine
learning (Kadioglu et al., 2020). Luteolin (the main flavonoid in Loni­
cera) binds with high affinity to the main protease of SARS-CoV-2.
Interaction of luteolin with the main viral protease indicates its poten­
tial as antiviral molecule and is worthy of further investigations (Yu
et al., 2020).
From the toxicological point of view these findings taken together
allow to rank Lonicera japonica for specific investigations on its potential
to cure and/or prevent COVID-19 at high priority.
Morus alba (Folium Mori)
Morus alba has been used since a long time as fodder for animals and
as food for humans providing much experience with its use. Antimi­
crobial, antioxidant, anti-diabetic, anti-hyperlipidemic, anti-
atherosclerotic, anti-obesity, cardioprotective, and cognitive enhance­
ment activities of Folium Mori have been reported (Chan et al., 2016).
Furthermore, efficacy against airway inflammation (by interruption of
NF-κB and JNK/c-Jun signaling) by the Morus constituent Moracin M
(Lee et al., 2016) and inhibition of metalloproteinases were seen
(Yiemwattana et al., 2019; Wongwat et al., 2020). Specifically activity
against human corona virus of Folium Mori has been observed (Thabti
et al., 2020). As already stated in the Introduction section, Morus alba is
one of the herbal medicines which were successfully used for the therapy
of the SARS-CoV infected patients in the 2002/2003 SARS epidemic (Liu
et al., 2006; 2012a, 2012b; Wang et al., 2014; Luo et al., 2020).
With respect to safety, the overwhelming majority of publications
showed neither toxicity nor genotoxicity for Morus alba leaf, fruit or root
extracts investigated in vitro as well as in rats and mice in vivo (Chi­
chioco-Hernandez et al., 2011; De Oliveira et al., 2015; 2016; Chang
et al., 2016; Marx et al., 2016;Wu et al., 2018; Yimam et al., 2018). One
investigation showed several forms of damage, if mice were treated with
an ethanol extract of Morus alba by the less physiological intraperitoneal
route, but not after oral treatment (De Oliveira et al., 2015). A clinical
study, comparing 25 patients topically treated with 75% mulberry
extract oil with 25 placebo-treated individuals (Alvin et al., 2011) and
another study on 45 participants with osteopenia perorally exposed to
Morus alba and Polygonum odoratum leaves containing congee (rice
mash) (Wattanathorn et al., 2018) observed clinical improvement, but
no adverse effects.
From the toxicological point of view these findings allow to rank
3
Phytomedicine 85 (2021) 153476
Morus alba for specific investigations on its potential to prevent and/or
cure COVID-19 at high priority.
Forsythia suspensa (Fructus Forsythiae)
The aqueous extract of the fruit of Forsythia is widely used in tradi­
tional medicines against many frequently occurring disorders including
inflammation, pain, fever, nausea, vomiting and abscess, leading to a
rich treasure of information on its use (Wang et al., 2018). Forsythoside
A (Law et al., 2017; Zheng et al., 2019) and labdane diterpenoids (Xiang
et al., 2020; Zhao et al., 2020) isolated from the fruits of Forsythia sus­
pensa showed antiviral activities and, as already stated in the Intro­
duction, Forsythia is one of the herbal medicines, which were
successfully used for the therapy of the SARS-CoV infected patients in
the 2002/2003 SARS epidemic (Liu et al., 2006; 2012a, 2012b; Wang
et al., 2014; Luo et al., 2020).
Studies in rats and mice on Forsythia and its major bioactive con­
stituent forsythin did not show toxicities (Shin et al., 2020; Han et al.,
2017). Several in vivo and in vitro tests showed no genotoxicity (Shin
et al., 2020).
Phillyrin and forsythoside, important constituents of Forsythia sus­
pensa, showed in rats (in vitro and in vivo) significant effects on CYP
(cytochrome P450 monooxygenase) 1A2, CYP2C11, CYP2D1 and
CYP3A1/2 (Cheng et al., 2017). Their human homologues are important
for the metabolism of many clinically used drugs (Oesch-Bartlomowicz
and Oesch, 2007). Prior to the introduction of Forsythia or its constitu­
ents into clinical use, it should be clarified whether CYP interactions are
relevant in vivo in human beings at the required doses. Except for this
caveat, from the toxicological point of view the findings taken together
allow to rank Forsythia suspensa for specific investigations on usefulness
against COVID-19 at high priority.
Codonopsis spec. (Radix Codonopsicis)
Codonopsis has widely been used in traditional medicine for hema­
topoiesis improvement, regulation of gastrointestinal, endocrine and
immune function (He et al., 2015; Gao et al., 2018). Codonopsis lan­
ceolata extract dampens allergic lung inflammation by inhibiting Th2
cell activation and augmenting mitochondrial superoxide dismutase
(SOD2) expression (Seo et al., 2019). Lancemaside A from Codonopsis
lanceolata prevents hypertension by inhibiting NADPH oxidase 2-medi­
ated MAPK signaling and improving NO bioavailability (Shin et al.,
2019) and attenuates the inflammatory responses mediated by mono­
cytes and macrophages by blocking the activation of inhibitor of κB
kinase (IKK) and p65/NF-κB (Kim et al., 2014). Phosphorylated Codo­
nopsis pilulosa polysaccharide has been reported to inhibit duck hepatitis
A virus replication (Ming et al., 2017). As already stated in the Intro­
duction, Codonopsis is one of the herbal medicines which were suc­
cessfully used for the therapy of the SARS-CoV infected patients in the
2002/2003 SARS epidemic (Liu et al., 2006; 2012a, 2012b; Wang et al.,
2014; Luo et al., 2020). Moreover, Codonopsis has also been and still is
used as food such as soup, wine and tea (He et al., 2015). Thus, there
exists much experience with its use.
Codonopsis appears to have little toxicity (Gao et al., 2018). Studies in
rats, rabbits and in patients on Codonopsis itself and on Codonop­
sis-containing medicinal mixtures did not reveal any marked toxicities
(Ai et al., 2014; Lee et al., 2015). Isolated constituents such as the
saponin codonoposide showed practically no in vitro cytotoxicity (MTT
assay) (Lee et al., 2002). Thus, investigations on the potential usefulness
of Codonopsis for therapy or prevention of COVID-19 is recommended
with high priority. Lau et al. (2013) reported that Codonopsis tangshen
herb extract inhibited CYP3A4 in vitro. This CYP is responsible for the
metabolism of a vast array of clinically used drugs (Oesch-Bartlomowicz
et al., 2001; Oesch-Bartlomowicz and Oesch, 2007). This potentially
important interaction should, therefore, be tested in vivo prior to a po­
tential clinical use of Codonopsis in the fight against COVID-19. Except
F. Oesch et al.
for this caveat, from the toxicological point of view the findings taken
together allow to rank Codonopsis for specific investigations on its po­
tential to cure and/or prevent COVID-19 at high priority.
Glycyrrhiza spec. / Radix et Rhizoma Glycyrrhizae
Glycyrrhiza (gancao in Chinese) (Radix et Rhizoma Glycyrrhizae) is
among the most frequently used TMC drugs and licorice (root of Gly­
cyrrhiza glabra, G. uralensis or G. inflata) is one of the worldwide most
frequently used medicinal plants, well studied (Olukoga and Donaldson,
2000; Fiore et al., 2005; Wang et al., 2013; National Library of Medi­
cine, 2018; Pastorino et al., 2018; Luis et al., 2018; Li et al., 2019; Kwon
et al., 2020; Wang et al., 2020), including research on antiviral activity
(Utsunomiya et al., 1997; Pilcher, 2003; Fiore et al., 2008; Sun et al.,
2019; Luo et al., 2020). Favorable effects include several actions which
may offer relieve of COVID-19 symptoms such as downregulation of
proinflammatory cytokines, reducing the accumulation of intracellular
reactive oxygen species and reducing the hyperproduction of airway
exudates (Luo et al., 2020) as well as, most notably, binding to ACE2
(Kuhn et al., 2004). The guancao (Glycarrhizae Radix et Rhizoma) con­
stituent Glyasperin F strongly binds to the ACE2 site 1 (grid3) and its
constituent isorhamnetin binds strongly to the ACE2 site 2 (grid4) (Ren
et al., 2020). Moreover, antiviral activity, elucidated mechanisms of
which include sialylation of the hepatitis B virus surface antigen and
inhibition of the fusion of HIV-1 membrane with cell membranes due to
reduction of membrane fluidity have been reported (Fiore et al., 2008).
The major licorice constituent glycyrrhizin interferes with H5N1 virus
replication and H5N1-induced pro-inflammatory gene expression (Fiore
et al., 2008; Nishimoto et al., 2010; Michaelis et al., 2011). Most worthy
of note, glycyrrhizin had antiviral activity against the SARS coronavirus
of the 2002/2003 epidemic, which was more effective in patients
compared with several antiviral drugs (Cinatl et al., 2003). Moreover,
licorice is widely used as sweetener and spice (Nazari et al., 2017) as well
as thirst quencher (Omar et al., 2012). Therefore, rich experience is
documented on its use.
Chronic intake of high doses of “seemingly harmless” licorice in
human subjects led to massive disturbance of the renin-angiotensin-
aldosterone axis as apparent mineralocorticoid excess syndrome with
increased Na+ and water retention and K+ loss, alkalosis, hypertension
and edema (Nazari et al., 2017). Also, licorice’s modest estrogenic ac­
tivity (Kundu et al., 2018) and antithrombotic action (Francischetti
et al., 1997; Mendes-silva et al., 2003) may lead to undesirable effects.
However, in the latter case licorice as thrombin inhibitor (Francischetti
et al., 1997; Mendes-silva et al., 2003) may have a beneficial influence
on increased coagulation in COVID-19 patients (Tang et al., 2020).
A considerable number of toxicity studies in animals gave non-
uniform results tending to tolerable toxicities at moderate doses (Mir­
salis et al., 1993; Nakagawa et al., 2008; Shin et al., 2008). The results of
genotoxicity tests were in its majority negative (Isbrucker and Burdock,
2006; Nakagawa et al., 2008; Chandrasekaran et al., 2011). These re­
sults of toxicological investigations together with the wide and
long-lasting experience with human use of licorice, apparently safe at
moderate, non-chronic doses favor the recommendation of in­
vestigations on its usefulness for therapy or prevention of COVID-19
with relatively high priority. However, prior to its clinical use the
occurrence of serious drug-drug interactions at the required doses
should be excluded, a potential which appears realistic based on pre­
vious studies (Oesch-Bartlomowicz et al., 2001; Park et al., 2011; Li
et al., 2019; Wang et al., 2020). Thus, except of this caveat, from the
toxicological point of view the findings taken together recommend to
rank Glycyrrhiza spec./Radix et Rhizoma Glycyrrhizae for specific in­
vestigations on its potential to cure and/or prevent COVID-19 at rela­
tively high priority, followed by clinical application which should be
carefully supervised on grounds on the somewhat unclear picture from
the toxicological investigations.
4
Phytomedicine 85 (2021) 153476
Panax ginseng (Radix Panaci)
Radix Panaci is a medicinal herb known in Eastern traditional
medicine since ancient times and up to now for its reported anti-
oxidative, anti-aging, anti-cancer and adaptogenic activities (Gillis,
1997; Coon and Ernst, 2002; Murthy et al., 2018). The popularity of
Panax ginseng in Western countries has been increasing for several rea­
sons, including wide-spread attempts to restore or enhance vitality and
wellness. All of this led to much experience with its use. Activities
against a broad range of viruses were reported (Wang et al., 2018).
Panax ginseng is one of the herbal medicines which were successfully
used for the therapy of the SARS-CoV infected patients in the 2002/2003
SARS epidemic (Liu et al., 2006; 2012a, 2012b; Wang et al., 2014; Luo
et al., 2020).
Several studies on potential toxic effects of Panax ginseng in rats and
mice did not show any serious general toxicity (Park et al., 2008; 2013;
2018; National Toxicology Program, 2011, Shin et al., 2014a) and
studies on potential genotoxicities were negative (National Toxicology
Program, 2011; Shin et al., 2014b). Clinical studies did not reveal
serious treatment-related adverse effects (Lee et al., 2012; Shergis et al.,
2013; Kim et al., 2015; 2017). Use during pregnancy did not lead to
adverse effects (Seely et al., 2008). No human data appear to exist
concerning use during lactation, while minimal risks were seen in ani­
mal studies (Seely et al., 2018). Special care needs to be taken against
excessive doses (leading to problems including hypertension and spon­
taneous bleeding) as well as interactions with other drugs such as an­
ticoagulants (Paik and Lee, 2015).
Use of Panax ginseng in mixtures with further components did not
show any toxic effects in many cases. In few cases, where toxicities were
observed, it was unclear which component(s) were responsible (Park
et al., 2008; Seo et al., 2019).
If individual components or metabolites of Panax ginseng were tested,
some studies showed no toxicities (Shin et al., 2014; Li et al., 2020)
while others did (Li et al., 2020), especially embryotoxicities (Chan
et al., 2004; Liu et al., 2005; Huang et al., 2019). It is recommended to
abstain from the respective preparations and even from Panax ginseng
itself during the first trimester of pregnancy, until the safety is suffi­
ciently established.
Investigations on the potential usefulness of Panax ginseng in mod­
erate, non-chronic doses for therapy/prevention of COVID-19 is, there­
fore, recommended (except during the first trimester of pregnancy).
Apart from this caveat, from the toxicological point of view the findings
taken together allow to rank Panax ginseng for specific investigations on
its potential to cure and/or prevent COVID-19 at relatively high priority,
followed by clinical application which should be carefully supervised on
grounds on the somewhat unclear picture from the toxicological
investigations.
Ephedra sinica (Herba Ephedrae)
Herba Ephedrae (Lee, 2011) is used as commercial dietary supple­
ment (Haller et al., 2004; Mehendale et al., 2004), especially for weight
loss (Boozer et al., 2002). As already stated in the Introduction, Ephedra
sinica is one of the herbal medicines from Traditional Chinese Medicine
which were successfully used for the therapy of the SARS-CoV infected
patients in the 2002/2003 SARS epidemic (Liu et al., 2006; 2012a,
2012b; Wang et al., 2014; Luo et al., 2020). The severity of toxic re­
actions to ephedra in comparisons to other botanical products has been
described (Woolf et al., 2005). In animal experiments Herba Ephedrae
damaged rat kidneys and salivary glands already at only moderately
high doses (Han et al., 2018). Humans consuming dietary supplements
containing Ephedra alkaloids experienced adverse cardiovascular and
central nervous system events (Haller and Benowitz, 2000). Use of
Herba Ephedrae was associated with liver damage at low incidence
(Woo et al., 2015). More frequently the use of Herba Ephedrae led to
myocardial infarction, stroke and sudden death. These cardiovascular
F. Oesch et al.
adverse effects did not depend on preexisting vascular or heart disease
and did not only occur at massive doses, rather they were reported to
have occurred within the manufacturer’s dosing guidelines (Samenuk
et al., 2002). This practically excludes Herba Ephedrae from being rec­
ommended for its usefulness against COVID-19. However, the anti-viral
activity of Herba Ephedrae (Mantani et al., 1999; Wei et al., 2019) may
be separable from the adverse effects. Hyuga et al. developed and
investigated an ephedrine-free Herba Ephedrae extract, which still
exerted anti-influenza virus activity in a comparable manner as the full
Herba Ephedrae extract, but without ephedrine-typical adverse effects
(the ephedrine alkaloids in all likelihood being responsible for
myocardial infarction, stroke and sudden death in Herba
Ephedrae-treated patients) (Hyuga et al., 2016). From the toxicological
point of view this processed, ephedrine-free Herba Ephedrae extract is
interesting and is recommended for specific investigations on its use­
fulness to cure and/or prevent COVID-19 at medium to high priority,
followed by clinical application which should be carefully supervised on
grounds on the somewhat unclear picture from the toxicological
investigations.
Overall conclusions
Several Far East traditional medicines, known for their wide range of
pharmacological applications and at present also increasingly used in
Western countries with the intention to promote health and improve
wellness, had been reported as effective for SARS treatment during the
2002/2003 epidemic. Some of them have been characterized concerning
their side effects and/or potential toxicities as discussed above. The
available toxicological information allows to rank them as recom­
mendable for immediate investigations on potential usefulness for
treatment or prevention of COVID-19, followed by immediate imple­
mentation, at various priorities:
• High priority: Lonicera japonica, Morus alba, Forsythia suspensa,
Codonopsis spec.
• Relatively high priority: Glycyrrhiza spec., Panax ginseng
• Medium to high priority: Ephedrine-free Herba Ephedrae extract
Further possibilities not discussed in this publication are, on toxi­
cological grounds, recommended at the following lower priorities, based
on the review of the available literature by the authors of this
publication:
• Intermediate priority: Astragalus membranaceus root, Eriobotrya
japonica leaves, Galla chinensis, Scutellaria baicalensis root, Panax
notoginseng root,
• Relatively low priority: Chrysanthemum morifolium, Pinellia
rhizome, Lithospermum erythrorhizon root
• Low priority: Prunus armeniaca seeds, Bupleurum chinense root
• Low priority at best: Angelica sinensis root, Toona sinensis, Gardenia
jasminoides fruits, Pueraria lobata root
We all hope for a medicinal cup to treat COVID-19 in the very near
future. Possibilities include the development of vaccines as well as novel
or repurposed synthetic drugs. Although hyped in public discussions, it
is realistic to predict a substantial time until they will be a ready-to-use
cup of remedy. However, between the cup and mouth is still time to die.
We therefore strongly recommend rapid investigation of readily avail­
able herbal drugs, which were effective in the therapy of SARS, on their
efficacy for the treatment of COVID-19 followed by immediate appli­
cation in the treatment of COVID-19. As tool for prioritization of the
needed research we recommend to use the priorities according to their
relative toxicities versus safety as described in this review.
The current emergency threatens the global public health with the
tough reality, where no realistic chance should be overlooked or ignored
on grounds of emotional prejudices.
5
Phytomedicine 85 (2021) 153476
Author contribution statement
FO, BOB and TE have equally contributed to the concept of this re­
view. Contributions to writing were in the sequence FO, BO, TE. Critical
review of the medical, toxicological and phytochemical aspects was by
BO, FO and TE, respectively. All data were generated in-house, and no
paper mill was used. All authors agree to be accountable for all aspects of
work ensuring integrity and accuracy.
Declaration of Competing Interest
FO and BOB are members of Oesch-Tox Toxicological Consulting and
Expert Opinions GmbH & Co. KG, Ingelheim-Wackernheim, Germany.
All three authors declare that the study was conducted in the absence of
any commercial or financial relationship that could be construed as a
potential conflict of interest.
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