Introduction
Despite intense focus, so far no effective treatment has been developed for severe
cases of COVID-19. SARS-CoV-2 infection results in a multisystem hyperinflammatory
syndrome with acute respiratory distress syndrome (ARDS), acute kidney failure, and
cardiovascular and neurological complications (Wang et al., 2020). Severe cases of
this condition are characterized by a “cytokine storm” and rampant inflammation (Renu
et al., 2020; Ye et al., 2020). The hyperinflammation is associated with the generation
and release of reactive oxygen and nitrogen species (ROS/RNS), which can further amplify
inflammation (Lucas and Maes, 2013). Histopathological observation of COVID-19 has
revealed diffuse alveolar damage with vascular endothelialitis, thrombosis, and intussusceptive
angiogenesis (Ackermann et al., 2020). The angiocentric inflammation is not limited
to the COVID-19-induced lung injury but also involves prolonged inflammation in other
organs, such as the liver, brain, heart, or the gut (Ackermann et al., 2020; Wang
et al., 2020). Any treatment that could limit the “cytokine storm,” reduce ROS/RNS
production, and counteract the formation of thrombosis would be highly attractive,
and, in the best-case scenario, such a treatment would additionally interfere with
viral replication. Recently, a preliminary study reported that the administration
of dexamethasone, a corticosteroid with anti-inflammatory effects, could elicit a
30% reduction in mortality for patients receiving invasive mechanical ventilation
(Horby et al., 2020).
In a previous study, we screened a panel of 99 ethanolic herbal extracts for their
anti-inflammatory properties. Hop (Humulus lupulus, cones) and Ceylon cinnamon (Cinnamomum
verum alias C. zeylanicum, bark) extracts were found to elicit particularly drastic
reductions in activation of the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer
of activated B cells), a key regulator of pro-inflammatory cytokines (Schink et al.,
2018b).
The literature search was mainly performed in MedLine. In a first round, we looked
for studies describing anti-inflammatory effects for Ceylon cinnamon, hops, and their
major compounds. In a second approach, we then searched for clinical studies testing
the efficacy of the plants in treating human disease.
HOPS
Hops, the seed cones of the plant Humulus lupulus from the family Cannabaceae, contain
several pharmaceutically active compounds, such as humulone, lupulone, and xanthohumol
(Gerhäuser, 2005; Knez Hrncic et al., 2019; Lin et al., 2019). Crude hop extracts
as well as individual compounds have been described to exert anti-viral effects against
several DNA and RNA viruses (Buckwold et al., 2004; Fuchimoto et al., 2013). For example,
humulone, the most important bitter acid of hops, can suppress replication of the
respiratory syncytial virus (RSV alias Human orthopneumovirus) in cell culture by
disturbing the formation of viral filaments (Fuchimoto et al., 2013). Xanthohumol
from hops showed synergistic effects with IFN-α in the treatment of bovine viral diarrhea
virus (BVDV), and a combination of the two substances was more effective than IFN-α
or xanthohumol alone (Zhang et al., 2010).
Scientific reports on the biological effects of hops and hop compounds are not limited
to anti-viral properties; anti-bacterial activity, anti-fungal properties, and anti-malarial
action have also been reported (Gerhäuser, 2005; Cermak et al., 2017; Weber et al.,
2019). Lupulone and xanthohumol exhibit synergistic effects with selected clinically
used antibiotics (Natarajan et al., 2008).
Hops also counteract inflammation; humulone can exert an anti-inflammatory effect
on the TNF-induced expression of cyclooxygenase with effective doses that are in the
same order of magnitude as dexamethasone (Yamamoto et al., 2000). Moreover, humulone
can inhibit Toll-like receptor 4 (TLR4) and NF-κB signaling (Yamamoto et al., 2000;
Fu et al., 2016; Schink et al., 2018b). In an animal model, topically applied humulone
was shown to inhibit NF-κB, AP-1, and mitogen-activated protein kinases (MAPKs) (Lee
et al., 2007). Xanthohumol from hops was found to reduce the expression of IL-1β,
IL-6, IL-8, and TNF in virus-infected and LPS-stimulated porcine primary alveolar
macrophages (Liu et al., 2019), and hop-derived humulone and lupulone were shown to
mitigate the expression of IL-6 (Weber et al., 2019).
Hop extracts are further effective in counteracting oxidative and nitrosative stress;
hop compounds were shown to mitigate neural nitric oxide synthase (nNOS) activity
and 3-morpholinosydnonimine (SIN-1)-induced oxidation of LDL (Stevens et al., 2002).
The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a key
regulator of the expression of antioxidant genes (Yamamoto et al., 2018). Hop compounds
and especially xanthohumol were shown to activate NRF2 in different studies (Dietz
et al., 2005; Lee et al., 2011; Yao et al., 2015). A small, placebo-controlled, clinical
study showed that a low-intake dose of 12 mg/day xanthohumol decreased oxidative stress-induced
DNA damage (Ferk et al., 2016).
Xanthohumol was also shown to be effective in preventing thrombosis in animal models
(Xin et al., 2017). In contrast to what has been observed for blood thinners, no increased
bleeding was seen when the substance was administrated orally in two doses of 10 mg/kg
xanthohumol per day for 60 days (Xin et al., 2017). The antioxidant effects of xanthohumol
were also confirmed in this same study (Xin et al., 2017). Further, hops exert anti-fibrogenic
effects in vitro, and specifically xanthohumol was shown to possess this property
in vivo (Dorn et al., 2012; Saugspier et al., 2012).
Ceylon Cinnamon
The genus Cinnamomum belongs to the family Lauraceae and comprises more than 100 species
in the NCBI Taxonomy Database. Here, we review specifically Ceylon cinnamon (Cinnamomum
verum alias C. zeylanicum, NCBI:txid128608), which we have used in our studies (Schink
et al., 2018a,b; Ose et al., 2020). Generally, Chinese cassia or Chinese cinnamon
(Cinnamomum cassia alias Cinnamomum aromaticum) is commercially sold as a spice for
foods and does not represent a risk to human health per se (Oketch-Rabah et al., 2018).
However, it can comprise high amounts of coumarin, which is highly hepatotoxic in
higher doses. The German Federal Institute for Risk Assessment (BfR) therefore recommends
that Cassia cinnamon with high coumarin content be consumed only at moderate levels.
The differences between Ceylon cinnamon and Cassia have been reviewed recently (Oketch-Rabah
et al., 2018).
Ethanolic extracts of Ceylon cinnamon possess anti-inflammatory activity and antagonize
TLR2 and TLR4 activation in a dose-dependent manner with minimal effects on viability
in cell culture (Kanuri et al., 2009; Schink et al., 2018b). We identified several
active compounds in these extracts, amongst others, trans-cinnamaldehyde, cinnamic
acid, cinnamyl alcohol, cinnamyl methyl ether, p-cymene, methyl salicylate, 1-tetradecanol
(myristyl alcohol), and benzoic acid. We found synergy among the anti-inflammatory
properties of the different compounds: the efficacy of the complex mixture was greater
than those of the pure active compounds of cinnamon (Schink et al., 2018a).
Cinnamaldehyde is an effective NRF2 inducer (Long et al., 2015) and acts in this way
to detoxify ROS/RNS (Wondrak et al., 2010). Further, cinnamaldehyde can inhibit angiogenesis
and metastasis via mitigation of the PI3K/Akt pathway (Patra et al., 2019). A specific
inhibition of VEGFR2 kinase and of angiogenesis was shown for a water-based extract
from Ceylon cinnamon (Lu et al., 2010).
In an animal model, an extract of Ceylon cinnamon was shown to protect the aorta from
dexamethasone-induced atherosclerosis and minimized the atherogenic risk (Nayak et
al., 2017).
Retrieved Results from Clinical Studies
We searched for clinical studies on Cinnamon using the search term “Ceylon Cinnamon
OR Cinnamaldehyde,” while for clinical studies on hops we used the search term “Humulone
OR Lupulone OR Xanthohumol OR hops” (Tables 2, 3). For both search terms, we restricted
the results to “Clinical Trial.” For Cinnamon we obtained 123 hits, from which we
excluded 57 hits, as cinnamon was not used to treat human disease in these studies.
The ethanolic extract, as used in cell culture experiments, was not directly given
to patients in any of the clinical studies. Rather, for the majority of clinical studies
with Ceylon cinnamon, powder was administered in an encapsulated form; the clear advantage
of administering Ceylon cinnamon in this way is that the formulation does not comprise
ethanol. Since we cannot give here an appropriate dosage of cinnamon for the treatment
of COVID-19, we refer to clinical studies that have used cinnamon to treat other conditions.
Thirty of the clinical Cinnamon studies deal with diabetes, glucose levels, and insulin
tolerance, five with polycystic ovary syndrome, and three with overweight and obesity.
We could not find any clinical studies on “cytokine storms,” but we hypothesize that
the strong anti-inflammatory properties of Ceylon cinnamon may mitigate this complication.
Ranasinghe et al. evaluated the safety of Ceylon cinnamon in healthy adults, concluding
that there were no significant side effects and toxicity of Ceylon cinnamon for the
dosages applied (Ranasinghe et al., 2017b).
When searching for hops and compounds found in hops, we obtained 92 hits for clinical
studies, from which we excluded 50 as non-matching. This is because many hits refer
to the verb “to hop,” i.e., “to jump.” Eight studies are linked to sleep disorders,
six to adiposity and metabolic syndrome, six to menopause, and two clinical studies
are on anti-bacterial effects. Often hops are given orally as an extract (water, oil),
which is frequently administered in combination with other drugs such as valerian.
One study concerns specifically the use of iso-alpha-acids from hops, which include
humulone, to dampen inflammation in knee osteoarthritis (Hall et al., 2008).
Taken together, among the so-far performed clinical studies on Ceylon cinnamon and
hops, we could not find any that specifically described efficacy in preventing the
“cytokine storm” or sepsis. However, results from diverse cell culture experiments
make it likely that hops and Ceylon cinnamon may exert these effects.
Discussion
Both hop and cinnamon extracts have been shown to exert several anti-inflammatory
functions (Yamamoto et al., 2000; Schink et al., 2018a,b). For instance, both can
dampen the release of pro-inflammatory cytokines (Lee et al., 2007; Schink et al.,
2018b; Liu et al., 2019; Weber et al., 2019). Moreover, hop and cinnamon extracts
can inhibit angiogenesis, thrombosis, and vascular endothelialitis (Dorn et al., 2012;
Saugspier et al., 2012; Xin et al., 2017; Patra et al., 2019). Further, these herbal
extracts can activate the key regulator of the antioxidant response, NRF2, which mitigates
the ROS/RNS production generally associated with inflammation (Dietz et al., 2005,
2013; Wondrak et al., 2010; Lee et al., 2011; Pinto et al., 2014; Long et al., 2015;
Yao et al., 2015). Taken together, we suggest that hop and Ceylon cinnamon extracts
may ameliorate complications that are associated with severe cases of COVID-19 and
that testing both extracts, either alone or in combination, and particularly as a
supplemental treatment to other medications, might be a promising therapeutic approach.
If the preliminary results for dexamethasone can be confirmed, this glucocorticoid
may be widely used to treat cases of COVID-19 (Horby et al., 2020). Supplementation
with Ceylon cinnamon extract could then ameliorate the potential side effects of dexamethasone
such as atherosclerosis (Nayak et al., 2017). Hop extracts exert anti-viral effects
against some virus strains, but whether these extracts are also effective against
SARS-CoV-2 has not yet been experimentally verified (Buckwold et al., 2004; Zhang
et al., 2010; Fuchimoto et al., 2013).
Pneumonia caused by bacteria is a frequent complication after artificial ventilation
(Póvoa et al., 2020; Wu et al., 2020; Zhang et al., 2020). The anti-bacterial effects
of hops (Gerhäuser, 2005; Natarajan et al., 2008; Cermak et al., 2017; Weber et al.,
2019) and Ceylon cinnamon (Ranasinghe et al., 2013; Vasconcelos et al., 2018; Doyle
and Stephens, 2019) could act preventatively in such cases. As they are derived from
common foodstuffs, both hop and Ceylon cinnamon extracts can be regarded as safe.
Of course, an allergy against a hop or cinnamon ingredient or alcohol intolerance
would contraindicate their intake.
It has become clear that many COVID-19 patients suffer from inflammatory complications
(Heneka et al., 2020; Portincasa et al., 2020). We suggest that treatment with the
here-discussed extracts could also mitigate such complications. Should cinnamon and
hops prove to exert positive effects in the treatment of COVID-19, they would be readily
available at low cost and can be produced at multi-ton scales. In western medicine,
it is common to use pure substances rather than less well-defined herbal extracts.
Of course, the individual compounds as listed in Table 1 can be used for treatment,
but a certain loss of synergy may result (Schink et al., 2018a).
Table 1
Active compounds from hops and Ceylon cinnamon.
Plant
Active compound
References
Hops
humulone
Palamand and Aldenhoff, 1973; Gerhäuser, 2005; Knez Hrncic et al., 2019; Lin et al.,
2019
lupulone
Palamand and Aldenhoff, 1973; Gerhäuser, 2005; Knez Hrncic et al., 2019; Lin et al.,
2019
xanthohumol
Palamand and Aldenhoff, 1973; Gerhäuser, 2005; Fu et al., 2016; Knez Hrncic et al.,
2019; Lin et al., 2019
Ceylon cinnamon
trans-cinnamaldehyde
Schink et al., 2018a; Vasconcelos et al., 2018
cinnamic acid
Schink et al., 2018a; Vasconcelos et al., 2018
cinnamyl alcohol
Schink et al., 2018a
Table 2
Selected clinical studies on Ceylon cinnamon.
Disease/condition or observed effect
Dosage form
References
Ceylon Cinnamon
type 2 diabetes
encapsulated cinnamon power
Khan et al., 2003; Mang et al., 2006; Crawford, 2009; Akilen et al., 2010; Wainstein
et al., 2011; Talaei et al., 2017; Mirmiran et al., 2019; Zare et al., 2019
cinnamon extract
Lu et al., 2012; Ranasinghe et al., 2017a
cinnamon in black tea
Azimi et al., 2016
polycystic ovary syndrome
encapsulated cinnamon power
Kort and Lobo, 2014; Borzoei et al., 2018; Hajimonfarednejad et al., 2018
dysmenorrhea (painful periods)
Jahangirifar et al., 2018
metabolic syndrome
Gupta Jain et al., 2017
migraine attacks and inflammatory markers
Zareie et al., 2020
pharmacodynamic properties and safety
Ranasinghe et al., 2017b
postmenopausal type 2 Diabetes
Vanschoonbeek et al., 2006
overweight or obese pre-diabetic subjects
Liu et al., 2015
non-alcoholic fatty liver disease
Askari et al., 2014
Ceylon cinnamon does not affect postprandial plasma glucose or insulin
Wickenberg et al., 2012
overweight or obese subjects
cinnamon extract
Roussel et al., 2009
effect on electrocardiographic parameters
Pender et al., 2018
perineal pain and healing of episiotomy
Mohammadi et al., 2014
Helicobacter pylori
Nir et al., 2000
type 1 diabetes
cinnamon pill
Altschuler et al., 2007
overactive bladder
cinnamon patch
Chen et al., 2021
postprandial (after meals) capillary blood glucose level
cinnamon tea
Bernardo et al., 2015
Table 3
Selected clinical studies on hops.
Disease/condition or observed effect
Dosage form
References
Hops
quality of sleep
standardized extracts of Valeriana officinalis, Passiflora incarnate, and Humulus
lupulus
Maroo et al., 2013
linolenic and linoleic acids in association with Humulus lupulus extract.
Cornu et al., 2010
valerian/hop extract combination
Müller-Limmroth and Ehrenstein, 1977; Koetter et al., 2007; Dimpfel and Suter, 2008
Vigilance
tablets containing valerian and hops
Gerhard et al., 1996
menopausal symptoms
hop extract
Erkkola et al., 2010; van Breemen et al., 2020
hop tablets
Aghamiri et al., 2016
appetite suppression
hop flower extract suspended in canola oil
Walker et al., 2019
body fat
matured hop extract
Morimoto-Kobayashi et al., 2016; Suzuki et al., 2018
dental plaque regrowth
hop bract polyphenols
Shinada et al., 2007
clinical safety and efficacy
combination of iso-alpha acids from hops, rosemary, and oleanolic acid
Minich et al., 2007
self-reported depression, anxiety, and stress levels
dry hop extract
Kyrou et al., 2017
overactive bladder
combination of seed oil from Uromedic pumpkin, Rhus aromatica (bark extract, and hop
cone extract)
Gauruder-Burmester et al., 2019
intestinal conversion of isoxanthohumol in 8-prenylnaringenin
dose of isoxanthohumol
Possemiers et al., 2006
endothelial functions
isomerized hop extract
Tomita et al., 2017
In conclusion, we recommend future experiments on hops and Ceylon cinnamon to evaluate
their potential in limiting overshooting immune reactions in COVID-19. We work mainly
with ethanolic extracts in cell culture. However, encapsulated cinnamon powder or
water extracts of hops may be better suited for administration to patients. We suggest
that appropriate doses for treatment of COVID-19 patients may be determined with reference
to the clinical studies that have used hops and Ceylon cinnamon to treat other conditions.
Author Contributions
KL and MA initiated the idea of the review and were involved in the manuscript writing.
J-FN was involved in manuscript refinement. NO was involved in the literature search.
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.