Could
a novel herbal formula be as effective as steroids in alleviating
asthma symptoms? According to a 2006 landmark study from the Mt.
Sinai School of Medicine in New York and the Weifang Asthma Hospital
and the Weifang School of Medicine in China, it may well be. In
the original study, this herbal formula not only significantly improved
lung function and clinical symptoms, but increased cortisol production.
In contrast, the study found that steroids suppressed cortisol levels.
The novel herbal formula proved so effective in initial studies
that it is currently the subject of a new, National Institutes of
Health (NIH)-sponsored study at Mt. Sinai investigating whether
steroid-dependent asthma sufferers can be weaned off their medications
while taking these herbs.
According to Dr. Stephen Feig, DO, who utilizes these herbs in his
practice, "In a subset of patients, these herbs seems to provide
enhanced adrenal support that synergizes with more commonly used
adrenal glandular products and with the use of cortisol."
"Since February of 2007," writes clinical nutritionist
and chiropractor Linda Li, DC, MS, CCN, who has been in practice
for 30 years, "my family member, who suffered from severe,
refractory asthma, has been off all medications, on twice-daily
doses of these herbs based on the research, and has had no asthma
symptoms at all. My own experience is equally remarkable,"
she continues, noting that these herbs have also improved her stamina,
substantially decreased her need for sleep, helped her shed excess
weight, and reduced her frequent nocturia.
Such a wide spectrum of clinical efficacy suggests that the synergistic
power of this formula may help restore healthy adrenal function.
As the Mt. Sinai researchers wrote of these herbs, "This is
the first well-controlled study in which an anti-asthma Chinese
herbal medicine has been found to be as effective as a corticosteroid
drug. The mechanisms underlying the remarkable effects...are likely
a result of synergistic or additive effects of the complex nature
of its constituents."
In this article, we review the entire scope of published work on
this herbal formula and theorize as to how and why these herbs might
restore adrenal function in a wide range of disorders in which adrenal
function is compromised – particularly, asthma and allergies.
Asthma Is a Model for
Adrenal Dysfunction
The rate of asthma has tripled in the last quarter-century. Twenty
million Americans suffer from the condition, according to the Centers
for Disease Control (CDC). Asthma is the third-leading cause of
hospitalization among those under 18, reports a 2006 article in
the New England Journal of Medicine.
Asthma accounts for $16 billion in annual health care costs, and
there are 5,000 visits to the emergency room a day in the United
States for asthma. At the same time, chronic use of asthma drugs
may be harmful or even fatal. Steroids are well known to suppress
cortisol and immune function. Other asthma drugs, such as Servent
and Advair, have "black box" warning labels because of
the higher rate of deaths tied to exacerbations of asthma in patients
taking them. And according to a 2004 article in the Annals
of Internal Medicine, regular use of beta-agonist drugs for
asthma not only causes tolerance to the drugs themselves, but increases
airway inflammation compared to placebo use.
The entire picture of asthma – its soaring numbers, the dangers
of drug treatment, and the efficacy of selected herbs for this condition
– may serve as a model for a wide host of conditions marked
by low cortisol, adrenal fatigue, and chronic inflammation.
If we take a closer look at the Mt. Sinai research, it becomes apparent
that it is remarkable for how thorough and robust its design has
been all along. Chinese herbs have a long tradition of use in asthma,
but well-controlled clinical trials using herbs for the treatment
of asthma are rare. That is one reason this Mt. Sinai research is
so notable.
Of Mice and Men: The
Remarkable Research Behind ASHMI
The Mt. Sinai study is remarkable because the researchers followed
an unusually thorough and meticulous design over a period of many
years. Their first study, published in 2000, tested a blend of fourteen
herbal extracts commonly used in traditional Chinese herbal medicine
for allergic asthma. This formula, dubbed MSSM-002, was based on
a Traditional Chinese Medicine (TCM) formula used in the pediatric
department of the China-Japan Friendship Hospital in Beijing to
treat asthma and bronchitis in children. Unlike many asthma formulas,
this one contained no Ma-Huang, a source of ephedrine that has been
reported to cause central nervous system stimulatory activity, increased
blood pressure, and heart palpitations.
The researchers first tested this blend of herbs in a mouse model
of allergic asthma. Mice were sensitized to an egg-white protein
and then challenged with it. The mice reacted with allergic asthma
including pulmonary eosinophilia, airway hyperreactivity (AHR),
and increased antigen-specific IgE associated with inflammatory
cytokines, including IL-4 and IL-5 in bronchial lavage fluids.
In the Journal of Allergy and Clinical Immunology, researchers report
that treating mice with this formula "virtually eliminated
airway hyperreactivity and markedly reduced the total number of
cells and the percent eosinophils in bronchoalvealor fluid compared
with the sham-treated group." Inflammation and mucus were
reduced in the lungs as well. Treatment with MSSM-002 24 hours after
intratracheal antigen challenge of sensitized mice virtually eliminated
airway hyperreactivity, and this effect was equivalent to dexamethasone.
MSSM-002 down-regulated inflammatory cytokines, including IL-4,
IL-5, and IL-13, all involved in chronic asthma.
In comparison, "one of the most potent corticosteroids, dexamethasone,
also suppressed antigen-induced airway hyperreactivity and eosinophilic
inflammation in this model. However, unlike MSSM-002, dexamethasone
suppressed Th1 responses." The researchers concluded that
the herbal formula was as effective as the potent corticosteroid
dexamethasone – without the harmful side effects. The researchers
then "used the concept of traditional Chinese medicine to
reformulate several herbal blends into simplified formulas, and
tested these new formulas," says senior study researcher Xiu-Min
Li, MD, Associate Professor, Pediatrics and Assistant Professor,
Center For Immunobiology, Mt. Sinai School of Medicine. The formula
the researchers found most effective in mice contained three Chinese
herbal extracts – Ling-Zhi (Ganoderma lucidum), Ku-Shen (Sophora
flavascens), and Gan-Cao (Glycyrrhiza uralensis) (also known as
Reishi, Shrubby Sophora, and Chinese Licorice) and was dubbed anti-asthma
herbal medicine intervention (ASHMI). The ASHMI formula demonstrated
the same broad spectrum of therapeutic effects on the major pathogenic
mechanisms of asthma. "This formula was almost as effective
as the original fourteen herbs, and was the simplest," Li
explains. All three herbs have a long history of human use in China
and are considered to be safe when used according to TCM practice,
either alone or in formulas.
The next Mt. Sinai, NIH-sponsored study was on ASHMI in humans and
was published in the Journal of Allergy
and Clinical Immunology in September 2005. It reported the
remarkable finding that ASHMI was as effective as steroids, without
suppressing cortisol or immune function. This study included 13
researchers, 11 of whom were physicians from the Weifung Asthma
Hospital, the Weifang School of Medicine, and the Mt. Sinai School
of Medicine, and was remarkable for its methodical, careful design.
Forty-five non-steroid-dependent individuals received oral ASHMI
capsules and prednisone placebo tablets, and 46 non-steroid-dependent
individuals received oral prednisone tablets (20 milligrams) and
ASHMI placebo capsules for four weeks. Serum cortisol, cytokine,
and IgE levels were evaluated before and after treatment, as well
as symptom scores, side effects, and spirometry measurements. Spirometry
literally means "the measuring of breath" and is the most
common pulmonary function test.
The study began with a week-long "run-in period" before
initiating treatment. Average daily symptom scores were evaluated
during this period to establish a baseline. Beta agonist inhalation
was allowed as needed during the study, but all other medications,
such as leukotriene modifiers, antihistamines, and either inhaled
or intravenous steroids, were prohibited.
Symptom scores rated cough, chest tightness, wheezing, dyspnea,
night awakening or early morning awakening caused by dyspnea, allergic
rhinitis, and beta agonist use. Lung function was evaluated with
a spirometer; serum IgE was measured; eosinophil counts were collected
from finger stick blood; serum cortisol levels were measured; and
serum cytokines, including IL-5, IL-13, and IFN-y were measured.
After four weeks, both groups showed an equal, significant improvement
in symptom scores, pulmonary function, and eosinophil levels.
In both groups, pre-treatment cortisol levels were slightly below
normal, as is common in asthma. However, after treatment, the corticosteroid
group showed suppression of the hypothalamic-pituitary-adrenal axis,
marked by even more depressed cortisol levels. In contrast, patients
in the ASHMI formula group showed increased levels of serum cortisol
into the normal range. After four weeks, the prednisone group had
significant weight gain, while the ASHMI group did not. The difference
between the two groups was statistically significant.
"The relationship between cytokine imbalance and the expression
of both atopy and asthma is of considerable interest and importance,"
the researchers note. "A Th1-Th-2 imbalance has been hypothesized
in asthma, with a shift in immune responses away from Th1 (IFN-y)
toward Th2 (IL-4, IL-5, and IL-13). In a cohort study, patients
with severe asthma exhibited significantly reduced IFN-y production
in response to allergen, compared with control subjects and subjects
with resolved asthma. In addition, all patients with asthma...showed
increased generation of IL-5...numerous studies have shown that
IL-4, IL-5 and IL-13 secretion...is the major driving force behind
persistent asthma."
ASHMI significantly reduced IL-3 and IL-5 levels. It also increased
human interferon Y (IFN-y), a potent antiviral and immunomodulator,
while cortisone suppressed IFN-y. These findings suggest strong
immunotherapeutic effects of the Chinese herbal. Now, says Li, "we
have an ongoing FDA-approved clinical trial using ASHMI as an investigational
new drug. In the last study, our patients were not steroid-dependent.
In this study, our patients are steroid-dependent, and we are trying
to wean them off their steroids. They really don't want to
be on steroids anymore, and our results will be more significant
if, with the use of ASHMI, we can reduce or replace steroids. We
are almost finished with our Phase I trial, which included 18 patients,
and we will begin our Phase II trial with 60 patients."
How Do These Herbs Work?
Individually, these herbs all have a long history of use in asthma
and other allergic, autoimmune, and immune disorders, allergic rhinitis,
hepatitis B, jaundice, adrenal insufficiency, peptic ulcers, and
many other conditions. The researchers speculate that these herbs
work both individually and synergistically. For instance, the increase
in serum cortisol into the normal range could be in part due to
the glycyrrhizin in Chinese licorice, "which affects the conversion
of cortisol to cortisone by inhibition of 11-B-hydroxysteroid dehydrogenase
enzyme activity." In addition, previous research has shown
that Chinese licorice decreases IgE levels. Chinese licorice is
a staple botanical in TCM for asthma and allergic rhinitis.
Ku-Shen, in turn, has been widely used for eczema, pruritis, and
asthma. Ku-Shen is particularly interesting. It is proving to have
therapeutic value for a surprisingly wide range of conditions. The
impact of Ku-Shen, which has excitatory modulator activity, was
studied by Ba Hoang and colleagues. An open and selective three-year
follow-up of 14 chronic refractory asthmatics aged between 22 and
70 was used. Participants received an extract of Sophora flavascens.
Medication use, a diary card of symptoms, and respiratory function
were recorded. The study was retrospective, and all patients gave
written informed consent. The quality of life, clinical symptoms,
and respiratory function improved during all periods of measurement.
The use of inhaled corticosteroid and beta-agonists were reduced
or eliminated. There were no significant adverse reactions reported.
It appears that the extract of S. Flavascens as an excitatory modulator
may be safe and effective for chronic refractory asthma.
Within two weeks of starting therapy with Ku-Shen, the patients
had reduced daytime and nighttime symptoms of asthma, and had begun
to reduce their beta-agonist doses. By three years, all patients
were off their corticosteroid medication, had almost entirely eliminated
beta-agonist medications, and their symptoms of asthma were significantly
reduced.
How does Ku-Shen work? Though the plant contains a rich cornucopia
of chemicals, the focus has been on two principle alkaloids, matrine
and oxymatrine, which have been the subject of research for years.
The toxicity of both alkaloids is very low, and Ku-Shen may contain
about two percent of these two alkaloids. According to Dr. Ba Hoang's
theory, these alkaloids "act as modulators of membrane excitability...they
can decrease body temperature, have a significant analgesic effect,
have a tranquilizing effect, and have an inhibitory action on glutamate-induced
excitatory nerve impulses. They can also have an anti-arrhythmic
effect." Glutamate receptors have been found in the lungs
and airways, and the activation of glutamate receptors has led to
increased airway submucosal glandular secretion. Activation of the
glutamate receptor might be an important, unrecognized mechanism
of airway inflammation and hyper-reactivity and might explain one
of the ways that Ku-Shen helps in asthma.
In fact, Dr. Ba and colleague Dr. Stephen Levine propose a novel
mechanism for asthma in a 2006 article in Medical
Hypotheses entitled, "Bronchial Epilepsy or Broncho-Pulmonary
Hyperexcitability as a Model of Asthma Pathogenesis." In this
separate paper, Ba and Levine have hypothesized that membrane hyperexcitability
may reflect a more generalized disease mechanism.
In sum, not only are the herbs in ASHMI remarkably effective in
asthma, but the increase in cortisol levels and the shift away from
inflammatory cytokines toward a balanced immune response suggests
that adrenal and immune function are being restored. This would
argue for a far wider use of herbal formulas like ASHMI, in conditions
associated with low cortisol, chronic inflammation, and adrenal
fatigue. Illnesses treated with corticosteroids would theoretically
benefit from herbal formulas like that of ASHMI.
References
Hoang BX, Shaw DG, Levine S, Hoang C, Pham P. New approach in asthma
treatment using excitatory modulator. Phytotherapy
Research. 2007 Jun:21(6): 554-7.
Hoang BX, Levine SA, Shaw DG, Pha P, Hoang C. Bronchial epilepsy
or broncho-pulmonary hyperexcitability as a model of asthma pathogenesis.
Med Hypothesis. 2006 Jun;67(5):1042-51.
Wallenstein S, Sapson H, Kattan M, Li XM. Efficacy and tolerability
of anti-asthma herbal medicine intervention in adults with moderate-severe
allergic asthma. J Allergy Clin Immunol.
2005 Sep;116(3):517-24.
Wen MC, Wei CH, Hu ZQ, Srivastava K, Ko J, Xi ST, Mu DZ, Du JB,
Li GH, Li XM, Huang CK, Zhang TF, Teper, A, Srivastava K, Schofield
B, Sampson H. The Chinese herbal medicine formula MSSM-002 suppresses
allergic airway hyperreactivity and modulates Th1/Th2 responses
in a murine model of allergic asthma. J
Allergy Clin Imunol. 2000 Oct;106(4):627-9.
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