Vol.3, No.5, 300-303 (2011)
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
The efficacy of ma-huang-tang (maoto) against influenza
Mizue Saita, Toshio Naito, Soushin Boku, Yukiko Watanabe, Mai Suzuki, Fukuko Oka,
Miki Takahashi, Takako Sakurai, Eiichirou Sugihara, Tomomi Haniu, Yuki Uehara,
Kazunori Mitsuhashi, Hiroshi Fukuda, Hiroshi Isonuma, Keiko Lee, Hiroyuki Kobayashi*
Department of General Medicine, Juntendo University School of Medicine, Tokyo, Japan;
*Corresponding Aut hor: koba@med.juntendo.ac.jp
Received 1 February 2011; revised 20 April 2011; accepted 27 April 2011.
In this study, we compared Ma Huang Tang
(maoto), a traditional Jap anese medicine (Kampo),
with antiviral drugs to evaluate their respective
and combined effect on the duration of fever
and other subjective symptoms of influenza.
Forty-five patients enrolled in this randomized
control trial had positive type A influenza on
rapid influenza antigen test, provided written
consent, and sought treatment at Juntendo
University Hospital between November 2008
and March 2009. Using a computer-gen-erated
list, patients were randomly assigned to one of
the four intervention groups: 1): maoto (TJ-27),
9 subject s; 2): Tamiflu (o seltamivir), 13 subject s;
3): Relenza (zanamivir), 6 subjects; and 4):
maoto/oseltamivir combination, 9 subjects. Six
outcome measures were evaluated, including
fever, myalgia, headache, arthralgia, fatigue,
and cough. Statistical differences were deter-
mined by the Bonferroni-adjusted t-test for mul-
tiple comparisons. Our results showed that
there were no significant differences among the
four groups in the time-course profile of fever
and the number of days until fever resolution
since treatment was initiated. In addition, no
significant intergroup differences were detected
in the number of days until resolution of myal-
gia, headache, fatigue, and cough. However, the
maoto group reported a more rapid improve-
ment in joint pain than the oseltamivir group (P =
0.01). In conclusion, maoto showed comparable
efficacy as antiviral medications in reducing
fever and influenza symptoms. As serious con-
cerns over the indiscriminate use, adverse re-
actions, and resistance to current antiviral
drugs continue to grow, maoto may serve as an
elegant option for the treatment of influenza.
Keywords: Ma Huang Tang (Maoto); Influenza;
Joint Pain; Oseltamivir and Zanamivir
The influenza virus was first isolated by Smith, An-
drews, and Laidlow in 1933. Six decades have passed
and influenza continues to circulate worldwide despite
substantial research and advances in early and effective
vaccination use [1]. In the wake of WHO Declaration of
“Pandemic Phase 6 for Novel Influenza A (H1N1)”, an
expedited search for potent antiviral agents was sum-
moned [2]. Antiviral drugs remain the mainstay of in-
fluenza treatment but their use has given rise to a num-
ber of problems. The widespread and often indiscrimi-
nate use of antiviral drugs has generated reports on ac-
celerated drug resistance in viruses [3-5] and adverse
drug reactions notwithstanding unclear causal relation-
ship [6,7].
Human influenza infection is predominantly an upper
respiratory tract infection, yet most patients present and
complain of various systemic symptoms. Despite em-
pirically demonstrated efficacy of Kampo medicines in
relieving systemic manifestations, such data often fall
short as clinical recommendation s. Of the two traditional
Japanese (Kampo) medicines-maoto and chikujyount-
anto—which are covered under the National Health In-
surance scheme for the treatment of influenza, we sought
to investigate the efficacy of maoto as the front-line
Kampo drug prescribed during the acute stage of influ-
During the 2008-2009 influenza season, we prospec-
tively compared the efficacy of maoto with antiviral
drugs in reducing fever and flu symptoms (myalgia,
headache, arthralgia, fatigue, and cough) in adult pa-
tients with seasonal influenza type A.
The Juntendo University School of Medicine Hospital
Institutional Review Board reviewed and approved all
study procedu r es (app roval number: 208-037).
M. Saita et al. / Health 3 (2011) 300-303
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Adult patients ages 20 and over with a positive naso-
pharyngeal swab for influenza type A on rapid diagnostic
test (rapid flu test, Sekisui Medical Co., Ltd) and sought
treatment at the Department of General Medicine at
Juntendo University Hospital between November 2008
and March 2009 enrolled in the study. A total of 45 pa-
tients provided written consent (mean age 32.4 ± 11.5
years: 21 men, 24 women) upon full comprehension of
the study procedures. A computer-generated list was
used to assign patients to four different interventions (I:
maoto (TJ-27), II: Tamiflu (oseltamivir), III: Relenza
(zanamivir), and IV: maoto/oseltamivir combination
therapy), and the efficacy of each treatment was evalu-
ated as a randomized control study. Main outcome
measures included fever onset, arthralgia, myalgia,
headache, cough, and fatigue. Patients were instructed to
keep a record of their symptoms on an evaluation post-
card and to rate the intensity of their arthralgia, myalgia,
headache, cough, and fatigue on a 5-point scale (score
0-4). They were also advised to track their fever, medi-
cation schedule, and body temperature for five days after
their diagnosis. The time it took for the highest score to
drop to zero for a given symptom was defined as the
“number of days until symptom relief”; the symptom
severity was calculated as the difference between the
highest and lowest scores and termed “reduction in
symptom score”. The product of the “number of days
until symptom relief” and “red uction in symptom score”
was statistically analyzed using the Bonferroni-adjusted
t-test for multiple comparisons.
Eight out of 45 patients failed to return their evalua-
tion postcards (I: 2 subjects, II: 1 subject, III: 3 subjects,
IV: 2 subjects), resulting in a final analysis based on 37
patients (I: 9 subjects, II: 13 subjects, III: 6 subjects, and
IV: 9 subjects).
At the time of treatment allocation, no significant dif-
ferences were observed in age, onset and duration of
fever, and vaccination rate among the patients (Table 1).
Maoto-treated subjects (I and IV) had near-equivalent
reduction in fever (body temperature: fever duration)
relative to those of oseltamivir-(III) and zanamivir-(IV)
treated subjects, thus no significant differences in anti-
pyretic effects were found among the three groups (Fig-
ure 1) (p = 0.90). Further, all groups showed comparable
effects in alleviating headache, cough, fatigue, and myal-
gia (Figure 2), with an exception of a more rapid im-
provement in joint pain in the maoto grou p than th e osel-
tamivir group (Figure 3) (P = 0.02). However, without a
placebo group to compare against, we were unable to
determine whether maoto could alleviate joint pain bet-
ter than placebo. Nevertheless, Ito et al. previously dis-
covered that the duration of joint pain in the placebo
group without treatment was 2.8 days (± 1.7 SD) whereas
it was 3.5 days (± 2.0) in the amantadine group in a RCT
that evaluated the efficacy of amantadine against influ-
enza type A . Thus, a joint pain of 2 day (± 1.1) duration
in the maoto group in our study appears to be shorter
than the duratio n observ ed in the placebo group in Ito et
al.’s study [8].
With the H1N1 influenza outbreak, the shortage of
antiviral drugs has become a burgeoning public health
Figure 1. Time-course profiles of fever of the four treatment
Table 1. Demographics and medical history.
I Mao-to II OseltamivirIII Zanamivir IV Oseltamivir and Mao-to
Number n = 9 n = 13 n = 6 n = 9
Age (Mean age ± SD*) 31.2 ± 10.433.3 ± 14.8 34.3 ± 6.07 31.5 ± 8.5
Sex (n) Male: 2
Female: 7 Male: 7
Female: 6 Male: 3
Female: 3 Male: 4
Female: 5
Mean (SD) Duration of Fe v er before Medication 14.25 ± 7.6325.8 ± 15.59 21.0 ± 11.91 24.0 ± 14.36
Mean (SD) Baseline Temperature (˚C ± SD*) 38.0 ± 0.6638.7 ± 0.60 38.0 ± 0.61 38.4 ± 0.66
Number of Patients Immunized with Current I n fluen z a V a c c in e5 6 5 2
M. Saita et al. / Health 3 (2011) 300-303
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Figure 2. Severity of headache, muscle pain, cough and fatigue.
Figure 3. Severity of joint pain.
problem. Moreover, unequal dispensation and inade-
quate access to antiviral drugs have been speculated as
causing an aggravation of the disease in compromised
Much controversy exists over oseltamivir, the first-line
agent for influenza, regarding its dosage, development of
drug-resistant strains, and adverse drug reactions. Ac-
cording to published data, Japan comprises 77% of all
oseltamivir usage in the world, while the United States
occupies the 22% of world consumption. Between 2008
and 2009, the majority of H1N1 viruses isolated world-
wide were reportedly oseltamivir-resistant strains; in
Japan, the resistance rate reached 99.6% (1234/1239) by
March 2009 [9].
In contrast, maoto, which is composed of mao (Ephedrae
herba), annin (Armeniacae semen), keishi (Cinnamomi
cortex), and kanzo (Glycyrrhizae radix), has been long
touted as the leading prescription for early stages of
common cold in the ancient Chinese medical literature
Shang Han Lun. Influenza primarily affects the upper
respiratory tract, yet patients often present and suffer
from systemic symptoms. Kampo medicines have puta-
tive ability to address generalized symptoms thro ugh the
synergy of multiple botanical raw materials. For instance,
a preliminary investigation of antiviral properties of
Kampo medicines showed that keishi exerted a
dose-dependent antiviral effect [10]. Hattori et al. fur th er
suggested that the antiviral effect of keishi against mul-
tiple strains were associated with its suppressive effect
on various aspects of endocytosis [11].
In the present study, maoto showed comparable effi-
cacy as antiviral drugs in influencing the duration of
fever and subjective symptoms, including headache,
cough, fatigue, and myalgia. Also, maoto demonstrated
M. Saita et al. / Health 3 (2011) 300-303
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
greater efficacy than oseltamivir or zanamivir in im-
proving joint pain . This finding is corroborated by Ku bo
and Nishimura who found that treatment with maoto or
maoto-oseltamivir combination was more effective than
oseltamivir alone in shortening the duration of fever [12].
If we take into account the fact that maoto has been his-
torically used to treat cold symptoms based on (symptom)
pattern diagnosis in Kampo medicine, it is not surprising
to discover its efficacy to be on par with antivirals which
are specifically designed to suppress viral replication.
Hence, our results are clinically significant, given the
scarcity of data on maoto’s efficacy in influenze from
prospective randomized trials.
Oseltamivir showed strong but statistically insignifi-
cant antipyretic effect. Figure 1 depicts the antipyretic
effect of both oseltamivir administered groups (II and
Zanamivir-treated group showed a rapid improvement
in cough than the other three group s. Though statistically
unremarkable, our results un dergird the trad itiona l use o f
Zanamivir as a potent respiratory agent.
While efforts to discover novel antiviral agents and
oseltamivir-related problems continue to attract attention,
maoto’s effect in influenza as endorsed by the NHI and
observed in our prospective study are useful information
for both healthcare practitioners and patients.
Except for one patient developing nausea from the
maoto’s distinct odor, no other serious adverse events
were reported during the study. Based on our observa-
tions, nine patients on maoto/oseltamivir combination
therapy, who were anticipated to achieve a greater over-
all symptom relief than patients in other treatment
groups, did not demonstrate apparent benefits of the
combination therapy.
The absence of a control group with inert placebo and
a control group without treatment due to insurance pur-
poses were two important caveats in this study. Addi-
tionally, we did not investigate the effect of maoto in
other influenza types because all patients recruited for
the study were uniformly infected with type A virus,
although Toriumi et al. had previously found that maoto
was as effective as oseltamivir and zanamivir in reduc-
ing fever in pediatric patients with type B influenza [13].
As the speed and routes of H1N1 propagation gain mo-
mentum, clinically-oriented studies based on isolated
strains may halt further global catastrophe.
In summary, we found that maoto improved systemic
influenza symptoms during the active disease phase as
effectively, if not, better than antiviral drugs. Moreover,
because none of the patients receiving maoto or maoto/
antiviral combination therapy suffered adverse drug re-
actions, maoto appeared to have a slightly wider safety
margin than antiviral drugs. Maoto may curb the devel-
opment of drug resistance to antivirals caused by their
misuse and overuse, and serve as an elegant option for
the treatment of influenza.
[1] WHO (2008) Brief summary of analyses of the 2007
survey on the capacity of National Influenza Centres.
World Health Organization Geneva, 83, 133-1448.
[2] WHO (2009) Interim planning considerations for mass
gatherings in the context of pandemic (H1N1) 2009 in-
[3] Dharan, N.J., Gubareva, L.V., Meyer, J.J., Okomo-
Adhiambo, M., McClinton, R.C., Marshall, S.A., St.
George, K., Epperson, S., Brammer, L., Klimov, A.I.,
Bresee, J.S., Fry, A.M. (2009) Infections with osel-
tamivir-resistant influenza A(H1N1) virus in the United
States. Journal of the American Medical Association, 301,
1034-1041. doi:10.1001/jama.2009.294
[4] Hatoyama, S. and Koeike, K. (2009) Development and
management of oseltamivir-resistant influenza. The Japa-
nese Society of Internal Medicine, 98, 1733-1741.
[5] Centers for Disease Control and Prevention (CDC) (2006)
High levels of adamantane resistance among influenza A
(H3N2) viruses and interim guidelines for use of antiviral
agents-United States, 2005-2006 influenza season. Mor-
bidity and Mortality Weekly Report, 55, 44-46.
[6] IDSC (2008) Infectious Disease Surveillance Center,
2007/2008 influenza season, Japan. Infectious Agents
Surveillance Report, 29, 297-298.
[7] World Health Organization 2009) Influenza A(H1N1)
virus resistance to oseltamivir—2008/2009 influenza
season, northern hemisphere.
[8] Ito, S., Iijima, N., Kanemaki, K., Hayashi, S., Hujii, S.,
Watanabe, T., Hosokawa, T. and Kakehi, K. (2000)
Therapeutic efficacy of amantadine hydrochloride in pa-
tients with epidemic influenza A virus infection. Nihon
Kokyuki Gakkai Zasshi, 38, 897-902.
[9] Chiharu, K., Masatsugu, O., Miwako, S., Yuzo, N., Ma-
koto, U., Takako, O., Mami, I., Takahiro, T. and Masato,
T. (2009) Isolation of oseltamivir-resistant influenza
A/H1N1 virus of different origins in Yokohama city, Ja-
pan, during the 2007-2008 influenza season. Japanese
Journal of Infectious Diseases, 62, 83-86.
[10] Hayashi, K., Imanishi, N., Kashiway ama, Y., Kawano, A.,
Terasawa, K., Shimada, Y. and Ochiai, H. (2007) Inhibi-
tory effect of cinnamaldehyde, derived from Cinnamomi
cortex, on the growth of influenza A/PR/8 virus in vitro
and in vivo. Antiviral Research, 74, 1-8.
[11] Hattori, T. (2007) Hochuekito for biodefense and viral
infections. Mebio, 24, 16-21.
[12] Kubo, T. and Nishimura, H. (2007) Antipyretic effect of
Mao-to, a Japanese herbal medicine, for treatment of
type A influenza infection in children. Phytomedicine, 14,
96-101 (article in Japanese with En g l i s h ab s t r a c t ).
[13] Toriumi, Y., Takahashi, I., Kamei, T. and Murata, K.
(2010) Antipyretic effect of Maoto in treatment of type B
influenza infection in children. Journal of Epidemiology,
20, 360, (Article and abstract in Japanese).