ArticlePDF Available

Bee Venom Therapy and Low Dose Naltrexone for Treatment of Multiple Sclerosis



Treatments for multiple sclerosis are still being investigated despite the long history of the disease. Some disease-modifying drugs were introduced into clinical practice during the last decade. However, their high cost, low safety profile, and most important, limited benefit drive many patients to discontinue these treatments and seek alternatives. This paper describes two alternative treatments that appear particularly effective — bee venom therapy, and low dose naltrexone.
Nepal Journal of Neuroscience, Volume 3, Number 2, 2006 71
Vladimir V. Markelov, MD
Kazan Rehabilitation Medical Health Center “Sanatorium
Kazan, Russia
Maxim V. Trushin, PhD
Kazan Institute of Biochemistry and Biophysics
Laboratory of Molecular Pathogenesis
Kazan, Russia, and
Department of Genetics
Kazan State University
Kazan, Russia
Address for the corresspondence:
Kazan Institute of Biochemistry and Biophysics
Laboratory of Molecular Pathogenesis
P.O. Box 30
Lobachevskiy St. 2/31
420111, Kazan, Russia
Received, June 12, 2006
Accepted, June 22, 2006
Treatments for multiple sclerosis are still being
investigated despite the long history of the disease. Some
disease-modifying drugs were introduced into clinical
practice during the last decade. However, their high cost,
low safety profile, and most important, limited benefit drive
many patients to discontinue these treatments and seek
alternatives. This paper describes two alternative treatments
that appear particularly effective — bee venom therapy,
and low dose naltrexone.
Key words: bee venom therapy, low dose naltrexone,
multiple sclerosis
by reactivation of the JC virus.42 The benefits of
immunomodulating drugs like statins and immunoglobulins
have been questioned.50.55
As a rule, these treatments affect only immunological
and magnetic resonance imaging (MRI) parameters of MS,
and provide little actual relief of symptoms. When patients
feel nothing but side effects, they become depressed and
discontinue treatment. When MS patients perceive positive
benefits from treatment, this provides the most favorable
psychological setting for further improvement. We would
like to describe here two alternative treatments — bee venom
and low dose naltrexone — that appear enormously
beneficial in relieving multiple sclerosis symptoms.
Bee Venom Therapy For MS
Apitherapy, the medicinal use of honey bee products,
has been practiced since ancient times. It was described by
Hippocrates (circa 400 B.C.) and Galen (circa 130-200 A.D.),
who used honey, bee venom, pollen, propolis, and other
substances in their medical practice. Today, honey bee
products are widely used to treat arthritis and other
inflammatory, autoimmune, and degenerative diseases.
Bee venom therapy (BVT) is widely used against MS in
the hospitals of Japan, South Korea, Taiwan and other Far
East countries, although not recognized by Western
medicine.34 In the West, bee venom therapy for multiple
sclerosis has largely been folk-medicine. In recent years,
Review Article Nepal Journal of Neuroscience 3:71-77, 2006
Bee Venom Therapy and Low
Dose Naltrexone for Treatment
of Multiple Sclerosis
Multiple sclerosis (MS) is a chronic neurological
disease characterized by inflammation,
demyelination, and axonal degeneration in the
central nervous system (CNS). Typical symptoms are
spastic paralysis, blurred vision, paresthesias, and
incoordination. Emotional disturbances complicate the
clinical picture of MS patients, and intensify problems in
their daily pursuits.
In the mid 1990s, recombinant interferons for multiple
sclerosis were introduced into clinical practice. However,
these drugs did not live up to their expectations. It soon
became apparent that their primary effects were a modest
reduction of the rate of exacerbation in relapsing-remitting
MS during the first two years of administration, without
preventing the progression.45 A synthetic amino acid
polymer, glatiramer acetate, had no benefit on MS
progression and relapse rate, though it was safer than
recombinant interferons.41 Cytostatic agents like
mitoxantrone or methotrexate have been associated with
increased risk of leukemias and cardiotoxicity.22,38 Various
human monoclonal antibodies against inflammatory
cytokines and adhesion molecules or their components
(e.g. Adalimumab and Natalizumab, a human monoclonal
tumor necrosis factor-alpha antibody, and an antibody
against alpha-4-integrin of the adhesion molecule VLA-4,
respectively) may provoke opportunist infections like
tuberculosis49 or multifocal leukoencephalopathy caused
Nepal Journal of Neuroscience, Volume 3, Number 2, 2006
however, positive changes have taken place. Since 1992,
bee venom therapy has been used to treat multiple sclerosis
in Chelyabinsk city, Russia. Over 2000 MS patients have
been treated in a special treatment and rehabilitation center
under the guidance of Prof. I.V. Krivopalov-Moskvin. The
primary positive effects of BVT for MS, according to Prof.
Krivopalov-Moskvin, are presented in Table 1 (http:// Prof. Krivopalov-Moskvin concluded
that only 5-7% of MS patients showed no improvement
after application of BVT.
Some antioxidant and immunomodulating properties of
bee venom have been known since the 1980s. Hadjipetrou-
Kourounakis and Yiangou reported that constituents of
bee venom inhibit the activation of T and B cells, and
possibly the activation of an endogenous virus which might
induce an adjuvant-related disease23; Somerfield and
colleagues showed an antioxidant action of bee venom,
which inhibited production of superoxide anions by
neutrophils.53 Quite recently, Castro and coworkers
published a phase I study of the safety of BVT for MS
patients.10 Nine patients 21 to 55 years old with progressive
MS received intradermal injections of bee venom over one
year. Three patients experienced subjective improvement,
two others experienced objective improvement. In four
patients, however, symptoms worsened: the reasons of the
observed negative reactions remain an enigma. However,
no reliable conclusions could be made about the efficacy
of the treatment because of the small number of patients
(six women and three men) investigated. Moreover, the
authors did not specify the sites of the bee venom injections
or other essential information (use of other honey bee
products, vitamins, and avoiding some nutrients).
The recent article by Wesselius, et al., described no
benefit from bee venom therapy for treatment of MS.56
Physicians used MRI to monitor brain lesions and measured
some symptoms including fatigue. MS patients received
up to twenty stings each session, three times a week, applied
to the thighs (the exact stinging points were not indicated).
Dr. M. Simics, a member of the American Apitherapy Society
(AAS), recently commented on the study by Wesselius et
al. M. Simics noted that 24 weeks is not enough time to
observe any improvements detectable by MRI.52 He also
remarked that not all the MS patients received the same
bee venom from the viewpoint of quality and quantity,
because these parameters vary significantly with the season
of the year. Simics also noted that Wesselius et al. did not
use the proper amount of necessary vitamins (namely, the
amount of vitamin C was significantly lower than suggested
by Mraz40, while B vitamins were not used at all).
Furthermore, contraindicated foods (alcohol, tobacco,
sugar, coffee, red meat and milk) and other useful
supplements (pollen, bee-bread, royal jelly, and propolis)
were not mentioned. Thus, Simics concluded that the lack
of positive results of BVT for MS in Wesselius et al. was
due to inappropriate experimental design. The investigators
should be thanked, however, for their willingness to examine
the effects of BVT.
Bee venom contains a variety of peptides (melittin,
apamin, mast-cell degranulation peptide (MCDP), secapin,
tertiapin, adolapin, protease inhibitor, procamine A, B,
minimine, cardiopep, compound X), enzymes
(phospholipase A2, hyaluronidase, acid
Table 1. Possible beneficial effects of BVT for MS according to Prof. I.V. Krivopalov-Moskvin and co-workers.
Effects pf BVT Possible Mechanisms Mediating These Effects
Immunomodulation Stimulation of phagocytosis and complimentary activity,inhibition of
rosette formation and migration of white blood cells
Inhibition of myelin damage Antiinflammatory effects of melittin, MCDP and phospholipase A2.
Antianoxic effects of bee venom components Is mediated by their
combination with pollen and royal jelly
Remyelination Bee venom contains 18 of 20 essential amino acids necessary for the
synthesis of myelin
Restoration of physical activity Improvement of neurotransmission through nerve fibers
Treatment of MS-related blood Anticoagulant and fibrinolytic effects of bee venom
coagulation syndrome
Improvement of mental condition Analgesic effect of adolapin, stimulation of endogenous opioid production,
sedative effects of tertiapin and secapin
Nepal Journal of Neuroscience, Volume 3, Number 2, 2006 73
Markelov & Trushin
phosphomonoesterase, glucosidase, lysophospholipase),
active amines (histamine, dopamine, norepinephrine,
serotonin) and other components with possible adjuvant
action in MS patients.40 For example, melittin, the principle
substance of bee venom, is one of the most potent anti-
inflammatory agents known (100 times more potent than
hydrocortisol). Adolapin, another strong anti-inflammatory
substance, inhibits cyclooxygenase; it thus has analgesic
activity as well. Apamin may significantly inhibit the activity
of C3 complement, and blocks calcium-dependent
potassium channels, thus enhancing nerve transmission.
Compound X, hyaluronidase, phospholipase A2, histamine,
and MSDP, are also involved in the inflammatory response
of venom, with softening of tissue and facilitation of flow
of other beneficial substances to damaged areas of nervous
tissue.40 Recently published studies suggest that the anti-
inflammatory and analgesic properties of bee venom therapy
are related to modulation of adrenoreceptor activity and
serotonergic neurotransmission.31,34,35,57 Local inflammatory
reactions due to bee stings may increase the sympathetic
tone favorable for neuroimmunomodulation of MS.20
Moreover, bee venom contains much tryptophan47, which
has positive effects on MS.26
Special attention should be given to histamine. Bee
venom contains about 1% histamine.28 Histamine treatment
for MS originated with Bayard Horton at the Mayo Clinic
in the 1940s. Its greatest success was at the MS Clinic of
St. Joseph Hospital in Tacoma, Washington from 1946 to
1959. Over 3000 patients with MS and related conditions
were treated with the CNS vasodilator histamine
diphosphate. Most of them improved, and the disease often
stabilized.24 Histamine injections were also effective in acute
attacks and relapses.11,12 Although some side effects
occurred (e.g. headache), histamine was well tolerated in
general. Unfortunately, vasodilation therapy for MS fell
out of fashion after the 1950s.
Recently, however, Gillson, et al., tested a transdermal
histamine cream, Prokarin, usually applied to the anterior
thigh with a skin patch.17,18 MS patients showed decreased
sensitivity to heat and chronic pain, reduction of fatigue,
improved sleep, elevation of mood, increased ability to
concentrate, and other positive effects. Possible
mechanisms of histamine’s action were presented in a
companion paper.18 A recent report by Packard and Khan43
described histamine effects on Th1/Th2 balance. The
authors claim that histamine plays a significant role in
upregulating anti-inflammatory cytokines including IL-4,
IL-5, IL-10 and IL-13.43 Jutel et al. suggest that the primary
allergic components of bee venom — histamine and
phospholipase A2 — induced IL-10 production by Th-2
cells and suppressed T-cell proliferation.29
As stated above, other bee products should be used
along with bee venom. Pollen and bee-bread may improve
liver function and strengthen the heart, as well as provide
amino-acids to the nervous system. They should be taken
as pollen extract, as bee-bread, or pollen in combination
with honey (1 part pollen : 1 part honey, or 1 part pollen : 2
parts honey). The first week after meals, the second week
before meals, and the third week and later between meals.
Pollen administration causes production of the cytokine
IL-10 by CD4+CD25+ regulatory T cells thus favoring the
Th1 to Th2 shift.15
Honey gives energy to the whole body, cleanses the
digestive system, softly stimulates the immune system,
cures skin wounds, and relaxes tight muscles. If there is no
diabetes, patients can take up to 60 grams a day, before
meals, in water or ideally in herb tea. The best honeys are
honeydew honey, poli-floral honey, and linden honey. Al-
Waili and Boni reported that honey reduces the activities
of cyclooxygenase-1 and cyclooxygenase-2, thus showing
anti-inflammatory effects.2 Honey also demonstrates
antioxidant and immunomodulatory activity.3,4
Royal jelly has been proven to improve the quality of
cellular regeneration, fight autoimmune diseases, and
increase longevity. The best royal jelly is fresh, taken
directly from a queen’s cell, but the pharmaceutical forms
are also effective. 100-600 mg a day is recommended,
according to your condition, in two or three doses, 30
minutes before meals. Immunomodulatory effects of royal
jelly were reported recently.32
Propolis, known worldwide as an excellent immune-
modulating agent, also stimulates the thymus, and has anti-
viral, anti-inflammatory, regenerative, and anti-toxic
properties; it strengthens the body’s cellular membranes.
Propolis can be taken in raw form (5-7 grams a day) or in a
20-30 % tincture (10-20 drops, three times a day) between
meals, in a spoon of herb tea. MS patient may eventually
add 2-3 grams of raw, un-processed and unfiltered honey.
Caffeic acid phenethyl ester, an active component of
propolis, has antioxidant properties — it diminishes
production of reactive oxygen species (ROS) by
suppressing nuclear factor kappa B activation and by
directly inhibiting inducible nitric oxide synthase.27 Other
beneficial effects of propolis on human health were recently
summarized by Lofty.37
Thus, apitherapy for multiple sclerosis should include
the whole spectrum of techniques, from bee stinging to
bee products (honey, propolis, royal jelly, pollen, etc.) and
special diet. In some cases, apitherapy has been combined
with medicinal plants: stinging nettle (Urtica dioica),
calendula (Calendula off.) and milfoil (Achillea millefolium)
as well as Echinacaea tincture and powder of bladderwrack
(Fucus vesiculosus).5 Considering the lack of systemic
allergic reactions, bee venom therapy for MS demonstrates,
in general, very good results, primarily improvement of
motor activity, bladder control, and decreased fatigue.
Undoubtedly, bee venom therapy should be considered a
first line treatment when multiple sclerosis is diagnosed.
Low Dose Naltrexone For MS
Naltrexone (17-(cyclopropylmethyl)-4,5-alpha-epoxy-
3,14-dihydroxymorphinan-6-one) is an opioid-receptor
antagonist used primarily to treat alcohol and opioid
dependencies (daily dose 50-150 mg). It was first
synthesized in 1963 and patented in 1967 as “Endo 1639A”
(US patent no. 3332950) by Endo Laboratories, a small
pharmaceutical company in Long Island, (NY, USA)
( Naltrexone and 6-beta-
naltrexol (its active metabolite) are competitive antagonists
at mu- and kappa-opioid receptors, and to a lesser extent at
Nepal Journal of Neuroscience, Volume 3, Number 2, 2006
delta-opioid receptors. This reversible blockade or
attenuation of opioid receptors is the basis of its
effectiveness against opioid dependence.
The history of low dose naltrexone (LDN) for treatment
of autoimmune disorders began in 1980 when New York
physician Dr. Bernard Bihari used it to maintain patients
with AIDS. A daily dose of 1.75 mg LDN prevented further
progression of AIDS (these results were presented at the
IV International AIDS Conference in Stockholm, June 1988).
Experiments then showed that MS sufferers might also
experience relief from LDN. The first MS patient of Dr. Bihari
has had no progression of her disease since she began
taking LDN over 15 years ago. Since that time, there has
been increased interest in LDN. The first international
conferences on LDN was held in 2005 at the New York
Academy of Sciences (USA), and the second in 2006 on
the campus of the National Institutes of Health, in Bethesda,
Maryland (USA). All materials from these conferences
including audio and video files are available at
At present, over 3,000 MS patients have been prescribed
LDN by their family doctors or neurologists. Most of the
Information on dosage and effects was obtained from the
LDN websites and newspaper articles and books such as:;;;;;;;
The Herald (, April 12, 2004, “MS
victim finds hope in heroin users’ drug; Campaign launched
for urgent trials of naltrexone”;
The Sunday Business Post (, May 10,
2004, “MS Experimental Drug Could Save State Millions of
The Brattleboro Reformer of Brattleboro, VT
(, May 15, 2004, “Drug Offers Hope for
MS Patients”;
The Columbia Spectator (,
May 1, 2004, “Coping with an unprofitable cure”;
The Eastern Daily Press of Norfolk (,
May 21, 2004, “MS Sufferers Campaign for Drug Aid”;
The Sunday Herald (,
October 16, 2005, “This drug could help MS victims... but
they can’t get it”;
The Auburn Journal (daily newspaper of Auburn, CA),
May, 2006, “Lake of the Pines woman finds pain relief from
MS with experimental drug”; and
Mary Anne Boyle Bradley “Up the Greek with a paddle.
Beat MS and many autoimmune disorders with low dose
naltrexone (LDN)”, Publish America, NY, 2005.
The recommended initial dose of LDN is 3 mg daily
between 9 p.m. and midnight, and after a month a dose of
4.5 mg daily for life. Introductory side effects may include
disturbed sleep with vivid, bizarre and disturbing dreams,
fatigue, muscle spasm, and pain. However, these should
disappear after a week of LDN administration. If the 3 mg
initial dose causes too prominent or persistent side effects,
the dose can be decreased to 2 or 1 mg until the body
adjusts. In general, LDN users experience fewer spasms
and fatigue, improved bladder control, improved heat
tolerance, and improvements in mobility, sleep, pain, tremor
and other symptoms. During LDN treatment, no
immunodepressants (e.g the interferons Rebif, Avonex and
Betaseron) or glucocorticoids should be administered.
It is widely believed that the main benefits of LDN in
multiple sclerosis are due to increased levels of beta-
endorphins that help maintain immune balance. Beta-
endorphins are endogenous opioid peptides with important
regulating functions in the CNS.9 Receptors for these
neurotransmitters have been detected on immune system
cells.39 Beta-endorphins are also able to decrease cAMP in
immunocytes when it is high, and increase cAMP when it
is low. Thus, these neurotransmitters may modulate levels
of cAMP.30 At present, it is known that beta-endorphins
may be synthesized both in the CNS and in immune cells.8,44
MS patients show lower values of beta-endorphins than
normal individuals, deficiency of the neurotransmitter
correlates with type of disease.20,21 Similar findings were
observed in patients with rheumatic arthritis and Crohn’s
disease. Some authors suggested that beta-endorphins may
stimulate anti-inflammatory cytokines.25,48 Interestingly,
direct injection of beta-endorphins into the brain of mice
infected with neurotropic murine coronavirus (a virus
causing encephalitis and paralytic-demyelinating disease
in susceptible strains of mice and rats, thus a model for
human demyelinating diseases such as multiple sclerosis)
resulted in significant reduction of virus replication in the
brain.19 It should be noted here that LDN also shows
positive effects in cancers.7,36,58,59 Therefore, it is possible
that LDN acts as a neuroimmunomodulator rather than an
immunoactivator or immunosuppressant.
It is now widely accepted that MS is caused by
overactivity of immune system. However, Dr. Bihari asserted
that the immune system of MS patients should be stimulated,
not inhibited. Recent experimental data indicates that the
immune system of MS patients shows premature
senescence.54 If this true, stimulation of the immune system
might be useful. Dr. Bihari suggested that LDN provokes
an increase of T-helper and T-supressor cells, which
restores the normal balance of T cells. Other recent evidence
indicates that boosting the immune system improves the
condition of patients with another Th1 autoimmune disease
— Crohn ’s disease.33 By the way, Mraz also suggested
that bee venom may boost the level of beta-endorphins.40
However, not all agree that MS is an autoimmune
system. Chaudhuri and Behan contend that MS is a
metabolic and neurodegenerative disease, and that
oxidative stress is the final pathway for
neurodegeneration.13,14 Other authors also suggested to
administer neuroprotective agents like Co-enzyme Q10
(Shults et al, 2002) and carnitine participating in
mitochondrial metabolism (Beal, 2003).6,51 Agrawal (2005)
proposed that the benefit of LDN might be anti-
BVT & Naltrexone
Nepal Journal of Neuroscience, Volume 3, Number 2, 2006 75
inflammatory, by inhibiting the activity of inducible nitric
oxide synthase.1 Decreased formation of peroxynitrites
means less inhibition of glutamate transporters, thus
preventing the death of oligodendrocytes from glutamate
Patients with MS need long-term management.
Reduction of the relapse frequency without preventing the
progression may compromise the treatment. MS patients
are very sensitive. They should feel that a method really
works, and symptomatic improvements should be evident.
Otherwise depression may develop after an unsuccessful
treatment. Low dose naltrexone and bee venom allow MS
patients to perceive real changes. Of course, BVT and
therapy with LDN changes one from another (Table 2).
However, despite the differences between these treatments,
many MS patients attest to their effectiveness at preventing
further progression. Thus, the discussed treatments
combine rapid effects and possibility to manage the MS
pattern for a long time.
The authors would like to thank Mr. Peter Good
(Multiple Sclerosis Studies, P.O. Box 7834, Bend, OR 97708,
USA) for his very useful comments in the preparation of
this manuscript. We are also grateful to Mr. Frank Bernstein,
apitherapist, a member of the American Apitherapy Society,
from Pardess Hana, Israel, and Dr. Bob Lawrence from
Dietary Research Limited, 10 Heol Gerrig, Treboeth,
Swansea, SA5 9BP, UK for critical reading our article.
1. Agrawal YP: Low dose naltrexone therapy in
multiple sclerosis. Med Hypotheses 64:721-724,
2. Al-Waili NS, Boni NS: Natural honey lowers
plasma prostaglandin concentrations in normal
individuals. J Med Food 6:129-133, 2003
3. Al-Waili NS: Effects of daily consumption of
honey solution on hematological indices and
blood levels of minerals and enzymes in normal
individuals. J Med Food 6: 135-140, 2003
4. Al-Waili NS, Al-Waili TN, Al-Waili AN, et al:
Influence of natural honey on biochemical and
hematological variables in AIDS: A case study.
TSW Holistic Health & Med 1:21–25, 2006
5. Aosan C: Apitherapy, apipuncture and their related
methods in the daily practice. Presentation of 3
clinical cases. The Fourth German apitherapy
Congress, Passau, Germany, March 25-28, 2006
6. Beal MF: Bioenergetic approaches for
neuroprotection in Parkinson’s disease. Ann
Neurol 53 (Suppl 3):39–48, 2003
Markelov & Trushin
Parameter Bee Venom Therapy Therapy With Low Dose Naltrexone
Dose depends on age, sex, stageof
disease, type of physical
abnormalities, reaction on bee
stinging, coexistent diseases.
Usually a few courses a year;
duration of each course is about
a few months (continuous use of
bee venom is contraindicated).
However, courses should be
taken for many years.
Special diet is required
Before beginning treatment,
however, patients should be
tested for allergic reaction to
bee venom. Patients with heart
disease should take BVT with
Constant dose regardless of stage of disease and physical
Continuous treatment (throughout life)
Special diet is unnecesary (however, increased
consumption of antioxidants and some minerals is
Initial side effects are most common (disturbed sleep with
vivid, bizarre and disturbing dreams, fatigue, muscle
spasm, and pain). People with liver or kidney problems
should take LDN with care
Duration of
Side effects and
THERAPY Increase in sense of well-being, improvements in mobility, bladder control, and sleep, pain, tremor;
reduction of fatigue, pain, tremor and spasticity, prevention of disease progression. Remyelination
and significant diminution of relapse rate are possible
Table 2. Comparison between bee venom therapy and low dose naltrexone for MS.
Nepal Journal of Neuroscience, Volume 3, Number 2, 2006
7. Berkson BM, Rubin DM, Berkson AJ: The long-
term survival of a patient with pancreatic cancer
with metastases to the liver after treatment with
the intravenous alpha-lipoic acid/low-dose
naltrexone protocol. Integr Cancer Ther 5: 83-89,
8. Blalock JE: A molecular basis for bidirectional
communication between the immune and
neuroendocrine systems. Physiol Rev 69:1–32,
9. Bloom FE, Rossier J, Battenberg ELF, et al: Beta-
endorphin: cellular localization,
electrophysiological and behavioral effects. Adv
Biochem Psychopharmacol 18:89–109, 1978
10. Castro HJ, Mendez-Inocensio JI, Omidvar B, et al.
A phase I study of the safety of honeybee venom
extracts as a possible treatment for patients with
progressive forms of multiple sclerosis. Allergy
Asthma Proc 26:470-476, 2005
11. Brickner RM: Pharmacological reduction of
abnormality in multiple sclerosis within minutes: a
statistical study. J Nerv Ment Dis 127:308-322,
12. Brickner RM: Phenomenon of relief by flush in
multiple sclerosis. Its use as a foundation for
therapy. Arch Neurol Psychiat 73:232-240, 1955
13. Chaudhuri A, Behan PO: Multiple sclerosis is not
an autoimmune disease. Arch Neurol 61:1610-
1612, 2004
14. Chaudhuri A, Behan PO: Treatment of multiple
sclerosis: beyond the NICE guidelines. Q J Med
98:373–378, 2005
15. Francis JN, Till SJ, Durham SR: Induction of IL-10
CD4+CD25+ T cells by grass pollen
immunotherapy. J Allergy Clin Immunol 111:
1255-1261, 2003
16. Chen YN, Li K-C, Li Z, et al: Effects of bee venom
peptidergic components on rat pain-related
behaviors and inflammation. Neuroscience 138:
631-640, 2006
17. Gillson G, Wright JV, DeLack E, et al: Transdermal
histamine in multiple sclerosis. Part two: a
proposed theoretical basis for its use. Altern Med
Rev 5:224-248, 2000
18. Gillson G, Wright JV, DeLack E, et al: Transdermal
histamine in multiple sclerosis: part one – clinical
experience. Altern Med Rev 4: 424-428, 1999
19. Gilmore W, Moradzadeh DS. Beta-endorphin
protects mice from neurological disease induced
by the murine coronavirus MHV-JHM. J
Neuroimmunol 48:81-90, 1993
20. Gironi M, Martinelli V, Brambilla E: Beta-endorphin
concentrations in peripheral blood mononuclear
cells of patients with multiple sclerosis. Arch
Neurol 57:1178–1181, 2000
21. Gironi M, Furlan R, Rovaris M, et al: Beta-
endorphin concentrations in PBMC of patients
with different clinical phenotypes of multiple
sclerosis. J Neurol Neurosurg Psychiatry 74: 495-
497, 2003
22. Gray O, McDonnel GV, Forbes RB. Methotrexate
for multiple sclerosis. Cochrane Database Syst
Rev 2:CD003208, 2004
23. Hadjipetrou-Kourounakis L, Yiangou M: Bee
venom, adjuvant induced disease and interleukin
production. J Rheumatol 15:1126-1128, 1988
24. Hess GH: A successful treatment for multiple
sclerosis patients. Northwest Med 58:377-382,
25. Hosoi J, Ozawa H, Granstein RD: Beta-endorphin
binding and regulation of cytokine expression in
Langerhans cells. Ann NY Acad Sci 885:405-413,
26. Hyyppa MT, Jolma T, Riekkinen P, et al: Effects of
L-tryptophan on central indoleamine metabolism
and short-lasting neurologic disturbances in
multiple sclerosis. J Neural Transm 37:297–304,
27. Ilhan A,Akyol O,Gurel A, et al: Protective effects
of caffeic acid phenethyl ester against experimental
allergic encephalomyelitis-induced oxidative stress
in rats. Free Radic Biol Med 37:386-394, 2004
28. Ioyrish N: Bees and people. MIR Publishers,
Moscow, 1974
29. Jutel M, Akdis M, Blaser K, et al: Are regulatory T
cells the target of venom immunotherapy? Curr
Opin Allergy Clin Immunol 5:365–369, 2005
30. Kavelaars A, Ballieux RE, Heijnen CJ: Differential
effects of beta-endorphin on cAMP levels in
human peripheral blood mononuclear cells. Brain
Behav Immun 4: 171–179, 1990
31. Kim HW, Kwon YB, Han HJ, et al: Antinociceptive
mechanisms associated with diluted bee venom
acupuncture (apipuncture) in the rat formalin test:
involvement of descending adrenergic and
serotonergic pathways. Pharmacol Res 51:183-
188, 2005
32. Kohno K, Okamoto I, Sano O, et al: Royal jelly
inhibits the production of proinflammatory
cytokines by activated macrophages. Biosci
Biotechnol Biochem 68:138-145, 2004
33. Korzenik JR, Dieckgraefe BK, Valentine JF, et al:
Sargramostim for active Crohn ’s disease. N Engl
J Med 352:2193-2201, 2005
34. Lee JD, Park HJ, Chae Y, et al: An overview of bee
venom acupuncture in the treatment of arthritis.
Evid Based Complement Alternat Med 2:79–84,
35. Lee JY, Kang SS, Kim JH, et al: Inhibitory effect of
whole bee venom in adjuvant-induced arthritis. In
Vivo 19:801-805, 2005
36. Lissoni P, Malugani F, Malysheva O:
Neuroimmunotherapy of untreatable metastatic
solid tumors with subcutaneous low-dose
interleukin-2, melatonin and naltrexone: modulation
of interleukin-2-induced antitumor immunity by
blocking the opioid system. Neuro Endocrinol
Lett 23:341-344, 2002
Nepal Journal of Neuroscience, Volume 3, Number 2, 2006 77
37. Lofty M. Biological activity of bee propolis in
health and disease. Asian Pac J Cancer Prev 7:
22-31, 2006
38. Martinelli Boneshi F, Rovaris M, Capra R, et al:
Mitoxantrone for multiple sclerosis. Cochrane
Database Syst Rev 5:CD002127, 2005
39. McCarthy L, Wetzel M, Sliker JK, et al: Opioids,
opioid receptors, and the immune response. Drug
Alcohol Dependence 62:111–123, 2001
40. Mraz C: Health And The Honeybee; Queen City
Publishing, Burlington, VT, 2001
41. Munari L, Lovati R, Boiko A: Therapy with
glatiramer acetate for multiple sclerosis. Cochrane
Database Syst Rev 1:CD004678, 2004
42. Niino M, Bodner C, Simard ML, et al: Natalizumab
effects on immune cell responses in multiple
sclerosis. Ann Neurol 59:748 –754, 2006
43. Packard KA, Khan MM: Effects of histamine on
Th1/Th2 cytokine balance. Int Immunopharmacol
3:909–920, 2003
44. Przewlocki R, Hassan AH, Lason W, et al: Gene
expression and localization of opioid peptides in
immune cells of inflamed tissue: functional role in
antinociception. Neuroscience 48: 491–500, 1992
45. Rice GP, Incorvaia B, Munari L, et al: Interferon in
relapsing-remitting multiple sclerosis. Cochrane
Database Syst Rev 4:CD002002, 2001
46. Roda LG, Bongiorno L, Trani E, et al: Positive and
negative immunomodulation by opioid peptides.
Int J Immunopharmacol 18:1–16, 1996
47. Romani AP, Marquezin CA, Soares ASE, et al:
Study of the interaction between Apis mellifera
venom and micro-heterogeneous systems. J
Fluoresc 16: 423-430, 2006
48. Sacerdote P, Manfredi B, Gaspani L: The opioid
antagonist naloxone induces a shift from type 2 to
type 1 cytokine pattern in BALB/cJ mice. Blood
95:2031–2036, 2000
49. Schneinfeld N: Adalimumab: a review of side
effects. Expert Opin Drug Saf 4:637-641, 2005
50. Schmeer C, Kretz A, Isenmann S. Statin-mediated
protective effects in the central nervous system:
General mechanisms and putative role of stress
proteins. Restor Neurol Neurosci 24:79–95, 2006
51. Shults CW, Oakes D, Kieburtz K, et al: Effects of
coenzyme Q10 in early Parkinson’s disease:
evidence for slowing of the function decline. Arch
Neurol 59:1541–1550, 2002
52. Simics M: Comments on a randomized crossover
study of bee sting therapy for multiple sclerosis.
J Am Apither Soc 13:10-14, 2006
53. Somerfield SD, Stach JL, Mraz C, et al: Bee venom
melittin blocks neutrophil O2-production.
Inflammation 10:175-182, 1986
54. Thewissen M, Linsen L, Somers V, et al: Premature
immunosenescence in rheumatoid arthritis and
multiple sclerosis patients. Ann N Y Acad Sci
1051:255-262, 2005
55. Trebst C, Stangel M: Promotion of remyelination
by immunoglobulins: implications for the treatment
of multiple sclerosis. Curr Pharm Des 12:241-
249, 2006
56. Wesselius T, Heersema DJ, Mostert JP: A
randomized crossover study of bee sting therapy
for multiple sclerosis. Neurology 65:1764-1768,
57. Yoon SY, Kim HW, Roh DH, et al: The anti-
inflammatory effect of peripheral bee venom
stimulation is mediated by central muscarinic type
2 receptors and activation of sympathetic
preganglionic neurons. Brain Res 1049: 210-216,
58. Zagon IS, McLaughlin PJ: Opioids and the
apoptotic pathway in human cancer cells.
Neuropeptides 37:79-88, 2003
59. Zagon IS, McLaughlin PJ: Opioids and
differentiation in human cancer cells.
Neuropeptides 39:495-505, 2005
... In the modern literature, honey has been documented to have antimicrobial activities [17], wound healing effects and use in tissue regeneration [18], gastrointestinal tract diseases [19,20], anti-diabetic effect [21], cardio protective effect [22][23][24], antioxidant effects [25,26], and anti-inflammatory effects [27][28][29]. ...
... Studies have demonstrated that lipopolysaccharide, a bacterial endotoxin, can upset the balance in antiinflammatory and proinflammatory mediators in favor of proinflammatory mediators, leading to an increase oxidative/nitrosative stress markers, pro-inflammatory cytokines and the disruption of the brain cholinergic system in brain tissue due to chronic microgliosis [4,28]. ...
... Glutathione (GSH), an endogenous antioxidant involved in protecting cells from the adverse effects of free radicals [28], was assessed. Results obtained from the study showed that treatment with honey effectively restored the glutathione level, which was significantly suppressed by lipopolysaccharide (LPS). ...
Full-text available
Objectives: Honey contains phenolic acids and flavonoids, which are significant in developing drugs against neuroinflammation. The study was designed to evaluate the ameliorative potential of honey in lipopolysaccharides-induced neuroinflammation.Methods: Thirty male Wistar rats were divided into six groups, namely: the control group (10 mL/kg vehicle), the LPS only group (250 µg/kg), the honey (0.26, 0.31 and 0.36 g/kg) and the ibuprofen (100 mg/kg). LPS (250 µg/kg i.p) was administered for 7days followed by the treatment with honey and Ibuprofen for another 7days. Animals were assessed for memory impairment and anxiety levels using a Novel object recognition test (NORT), elevated plus maze (EPM), and open field test (OFT). Brain levels of pro-inflammatory cytokine level, acetylcholinesterase activity, and oxidative stress were determined. The neuronal alteration was assessed histologically using cresyl fast violet staining of the hippocampus, prefrontal cortex, and striatum.Results: Honey (0.31 and 0.36 g/kg) significantly ameliorated LPS-induced memory impairment on NORT and increased time spent in the open arm and increased the locomotor activity in the OFT. Honey significantly (p < 0.05) reduced LPS-induced elevation of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). It significantly reduced malondialdehyde and nitrite levels in mice brains and reversed depletion of reduced glutathione levels. Honey attenuated LPS-induced elevation of acetylcholinesterase activity in rat brains. Cresyl violet staining showed the restoration of neuronal organization and Nissl body distribution in the hippocampus, prefrontal cortex and striatum compared to the LPS only group.Discussion: Honey effectively ameliorated LPS-induced poor cognitive performance, anxiety, motor coordination responses to neuroinflammation, and oxidative stress.
... [33] 6. Honey may possess anti-inflammatory activity and stimulate immune responses within a wound [34], [35] . Honey reduces the activities of cyclooxygenase-1 and cyclooxygenase-2, thus showing antiinflammatory effects [36] . Contents In The Bark Extract. ...
Full-text available
The oral cavity is prone for a countless of changes with the exposure to several kinds of factors like alcohol, tobacco and betel nut consumption, environmental and lifestyle related factors in our day to day life. Oral mucosal lesions, Gingivitis and Periodontitis occur as a result of infections, local trauma or irritation, systemic diseases and excessive consumption of tobacco, betel nut and alcohol. Other etiologies like contact allergic stomatitis are with aromas and preservatives present in dental preparations and food items according to the various study results. Inflammation is a local reactive change that involves the release of antibacterial agents from nearby cells that defend the host against infection. It also facilitates early tissue healing and repair. The Inflammatory process significantly affects the periodontium. Agada tantra is one branch of Ayurveda which deals with the management of various ill effects of visha (poison) ranging from Sthavar visha (plant poison) to jangama visha (animal poison). Visha (poisoning) in any form to the oral cavity can be understood under the topic Danta gata visha. In present day these chemicals can be considered as Gara Visha (poison) and visha chikitsa can be applied to these entities. Hence, this article is an attempt to appraise the drugs and procedures explained for Danta Gata Visha (toxins induced oro-dental diseases).
... In recent years, interest has increased in bee products for medical purposes. [11], GIT diseases [12,13], diabetes [14], antiinflammatory and immunomodulatory [15,16], antioxidant activities [17] and cardiovascular diseases [18]. The A. cerana reported containing fructose (37.27 -40.51 %) along with glucose (35.12 -38.04 %) while reducing sugar 73 % [19]. ...
... In recent years, interest has increased in bee products for medical purposes. [11], GIT diseases [12,13], diabetes [14], antiinflammatory and immunomodulatory [15,16], antioxidant activities [17] and cardiovascular diseases [18]. The A. cerana reported containing fructose (37.27 -40.51 %) along with glucose (35.12 -38.04 %) while reducing sugar 73 % [19]. ...
Full-text available
The water-soluble extract is a gummy semi-solid content of Apis cerana indica beehive (WSE-BH). The present study reports the neuropharmacological effects of beehive derived from Apis cerana indica. The neuropharmacological results evaluated by modified open field, hole cross, elevated plus maze and hole board (OF-HC-EPM-HBT) test by Swiss Albino mice of both sexes after single oral administration where parameters for sedative and anxiolytic activity was square movements, hole crossing, time spent in open arm and head dipping which is the unpunished or unlearned response. A time-dependent manner activity observed by WSE-BH (200 and 400 mg/kg) and diazepam (1 mg/kg) against negative control normal saline. At low dose (200 mg/kg), the OF and HC possess significant reducing effects in time dependence manner while EPM and HBT exhibited significant anxiolytic activity avoiding sedation, whereas at 400 mg/kg exhibited an irregular effect. The current results were suggesting that WSE-BH might a good source of anxiolytic and sedative effects at low dose concentration.
... Honey diminishes cyclooxygenase-1 and cyclooxygenase-2 activities and thus demonstrating anti-inflammatory properties. Honey also has the ability to validate immunity boosting activities (106,17). Lacerations cured with honey display less edema, less necrosis, better wound ...
Full-text available
Honey is a natural domestic sweet food material and chemically diverse superfluous product of nectar acquired from flowers. Owing to the presence of higher amounts of antioxidant compounds covering phenolic, enzymes, organic acids and bioactive peptides, holds a strong ability to prevent various maladies. In addition, honey has also been exploited in certain cardiovascular, gastrointestinal, neoplastic and inflammatory states along with its role in treatment of copious infections and surgical wounds. Flavonoids and polyphenols are important bioactive components present in honey and have antioxidant properties. Some bioactive compounds, for example luteolin, galangin, isorhamnetin, quercetin and kaempferol are present in honey. Phenolic acids and flavonoids have important pharmacological activities such as anti-allergic, anti-biotic, anti-carcinogenic and hypoglycemic. Moreover, curative potential of bioactive components and their utilization in value added food products are also the limelight of article.
... Honey reduces the activities of cyclooxygenase-1 and cyclooxygenase-2, thus showing anti-inflammatory effects [41] and demonstrates immunomodulatory activities [42]. Furthermore, ingestion of diluted natural honey showed reduction effect on concentrations of prostaglandins such as prostaglandin E2, prostaglandin F2α, and thromboxane B2 in plasma of normal individuals [43]. ...
Honey is one of the most nutritional natural products that not only provides us healthy nutrition but also has a potential to be an alternative treatment option for different pathologies from microbial infection to metabolic disease. Honey is a byproduct of flower syrup produced by honeybees and possesses an intricate chemical composition that varies with botanical sources and geographical locations. This chapter is aimed to provide readers an understanding of complex composition, biological activities, adverse effect, and therapeutic benefits of honey. Honey possesses many biological activities, such as antioxidant, anti-microbial, anti-inflammatory, anti-proliferative, anti-cancer, and anti-metastatic effects, suggesting potential therapeutic roles in many human pathologies. Flavonoids and polyphenols in honey are the two active ingredients, which are of therapeutic importance in many diseases. In conclusion, honey may be developed as a natural therapeutic agent for many pathologies, and extensive studies are therefore recommended.
Honey has been used for its nutritional and medicinal values since the Stone Age. Being one of the oldest foods known to humans, honey as a natural product has become an important part of food, economy and health care for most of the population. Honey stands as the most vastly discussed natural product across religions and civilizations. Traditional knowledge of these natural products has served as the base for many breakthrough discoveries, especially in the medicinal field. Today honey holds a strong position among its natural counterparts in terms of global market. This chapter provides an in-depth review of historical evidences of honey in different civilizations, religions and cultures, its use as an ethnomedicine, its application in different traditional system of medicine like Unani and Ayurveda, its physico-chemical properties, its modern application as antioxidant, antimicrobial, wound healing and antiviral agent, its application in ophthalmology, cough, diabetes and inflammation, intellectual properties and patent insights on honey, and industry and marketing insights of honey.
Background Dysmenorrhea is one of the most frequent pelvic pains among young women impairing their quality of life. Objective This research aims to investigate the effect of ginger-chamomile herbs plus honey in reducing dysmenorrhea pain, associated symptoms, and the extent of bleeding. Methods In this randomized clinical trial (IRCT No.: 2016100825031N5), 200 female students with primary dysmenorrhea from Arak universities were randomly divided into two groups. All the students were evaluated for one cycle without intervention, then group (A) received mefenamic acid (250 mg) and group (B) received ginger (1000 mg), chamomile (5000 mg) plus one teaspoonful of honey for two days before up to the first three days of menstruation, three times a day in two consecutive cycles. Pain severity, associated symptoms of dysmenorrhea and bleeding were respectively assessed using visual analogue scale, Andersch-Milsom Verbal Scale and Higham chart. Data were analyzed by descriptive and inferential statistical tests through SPSS21. Results The pain intensity in group B diminished significantly after the intervention in comparison to group A (p <0.05). The mean severity of dysmenorrhea accompanying symptoms decreased significantly in group B compared to group A (P=0.009). However, mean quantity of bleeding significantly decreased in group A (P = 0.004), with no increase in the extent of bleeding in group B. Conclusion The present study indicated that the combination of ginger-chamomile sachet with honey has the same effect of nonsteroidal anti-inflammatory drugs for pain mitigation also associated symptoms reduced better than mefenamic acid.
Full-text available
Histamine has a long history of therapeutic use in many diseases, including multiple sclerosis (MS). Recently, transdermal histamine has been successfully employed for the amelioration of symptoms of both relapsing-remitting and progressive multiple sclerosis. This paper summarizes preliminary experiences with transdermal histamine for MS at the Tahoma Clinic: 67 percent of 55 patients using histamine transdermal cream had improvements in one or more areas, including extremity strength, balance, bladder control, fatigue, activities of daily living, and cognitive functioning, sustained for periods of up to three months. One-third of patients had improvements in three or more areas of functioning. Five possible mechanisms of action are postulated: augmentation of subnormal cerebral tissue levels of histamine; improved electrical function of demyelinated fibers; increased cerebral blood flow; suppression of autoimmune responses; and stimulation of remyelination. These will be discussed in detail in Part 2 of this article.
The aim of this study was to assess the inhibitory effect of whole bee venom (BV) on adjuvant-induced arthritis in the rat. Rats were divided into pre-apitherapy, post-apitherapy and control experimental groups. The pre-apitherapy group was subcutaneously stung with a honeybee (Apis mellifera L.) and the control group was subcutaneously injected with 0.1 ml of physiological saline solution one day prior to complete Freund's adjuvant (CFA) injection. The post-apitherapy group was subcutaneously stung with a honeybee on day 14 after CFA injection. When arthritis had developed in the rat, the post-apitherapy group was subcutaneously administered whole BV every other day for a further 14 days. Clinical signs, hematological values and radioglogical features were observed during the entire experimental period. In the pre-apitherapy group, the development of inflammatory edema and polyarthritis was inhibited. Significant differences in lameness score, hind paw edema volume and radiological features were observed between control and pre-apitherapy rats. White blood cell counts indicated that the degree of leucocytosis was significantly different between the pre-apitherapy and control groups (p < 0.01). Inflammatory edema, polyarthritis and bone change into the tight hind paw were effectively inhibited in preapitherapy rats during the two-week period post-CFA injection. In conclusion, whole BV was found to inhibit arthritic inflammation and bone changes in the rat. This may be an alternative treatment for arthritis in humans.
The neurotropic murine coronavirus, MHV-JHM (JHMV) causes encephalitis and paralytic-demyelinating disease in susceptible strains of mice and rats, serving as a model for human demyelinating diseases such as multiple sclerosis. In this communication, we report that a single intracerebral administration of the naturally occurring neuropeptide, beta-endorphin, reduced the incidence of JHMV-induced paralytic-demyelinating disease 40-50% in C57Bl/6 mice. Protection from disease was accompanied by significantly reduced virus replication in the brain as early as 3 days post-infection and did not occur in irradiated, or immunoincompetent mice. The data suggest that beta-endorphin engages immune mechanisms of host resistance to JHMV infection to protect the mice from disease.
Background: This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. Objectives: The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. Search methods: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies. Selection criteria: Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. Data collection and analysis: The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used. Main results: Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX. Authors' conclusions: MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (˜12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.
In the present paper we demonstrate that one of the early effects of the opioid peptide β-endorphin on human peripheral blood mononuclear cells is the induction of a change in the intracellular cAMP level. However, the effect of β-endorphin on cAMP levels is not uniform; increases as well as decreases in cAMP level are observed. It appears that β-endorphin is a true modulator of intracellular cAMP level: the peptide will increase cAMP levels in cells with a low baseline level. In contrast, β-endorphin tends to decrease cAMP levels in cells with a high cAMP concentration. Moreover, β-endorphin modulates the rise in cAMP induced by β-adrenergic activation. The effect of β-endorphin on cAMP level correlates negatively with the magnitude of the change in cAMP level induced by β-adrenergic activation.
Twelve MS patients were treated with L-tryptophan with or without decarboxylase inhibitor for 30 days, and the daily dose was either 1.5 g or 8 g. Tryptophan, 5-HIAA and HVA were analysed from lumbar punctures before and during tryptophan treatment. Clinical evaluation of MS symptoms was performed before, during and at the end of the tryptophan treatment period as well as after a 30-day placebo period. Tryptophan and 5-HIAA levels were found to be elevated 10 hours after the last dose of L-tryptophan. HVA concentrations remained approximately constant. A slight alleviation of changeable MS symptoms was noticed during the first month. The best response was found in symptoms like motility and bladder disturbances as well as in the mood of patients. These findings are indicative of the neural transmission changes during the rapid functional disturbances in MS.