Low dose naltrexone therapy in multiple sclerosis
Low dose naltrexone therapy in multiple sclerosis
Y.P. Agrawal Department of Pathology, The University of Iowa, Iowa City, USA
(YP Agrawal, MD
Yash Pal Agrawal, MD PhD, Department of Pathology, University
of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City 52242, USA.
(e-m, FAX: 319-339-7148)
The use of low doses of naltrexone for the treatment of multiple sclerosis (MS) enjoys a
worldwide following amongst MS patients. There is overwhelming anecdotal evidence,
that in low doses naltrexone not only prevents relapses in MS but also reduces the
progression of the disease. It is proposed that naltrexone acts by reducing apoptosis of
oligodendrocytes. It does this by reducing inducible nitric oxide synthase activity. This
results in a decrease in the formation of peroxynitrites, which in turn prevent the
inhibition of the glutamate transporters. Thus, the excitatory neurotoxicity of glutamate
on neuronal cells and oligodendrocytes via activation of the α-amino-3-hydroxy-5-
methyl-isoxazole-4-propionic acid (AMPA) class of glutamate receptor (GluR) is
prevented. It is crucial that the medical community respond to patient needs and
investigate this drug in a clinical trial.
Multiple sclerosis (MS) affects thousands of sufferers worldwide. In many cases it is
characterized by the relentless progression of disease with increasing disability.
Treatment with interferons or with glatiramer acetate necessitates multiple weekly or
daily injections, and this can be associated with significant side effects. Furthermore, the
drugs are only moderately effective in reducing relapses, while the progression of disease
is not much affected (1-2). Thus there is a need for newer therapeutic or neuroprotective
agents in MS. The lack of highly effective drugs for MS, may in part reflect the
considerable debate regarding the etiology and pathogenesis of MS. There are
suggestions in the literature that the widely used animal model of experimental allergic
encephalitis may not fully reflect human MS (3-6).
Apoptosis and oxidative damage in multiple sclerosis
Recent work by Barnett and Prineas confirms previous reports and suggests that the
developing lesion in MS brains, lacks the inflammatory cells. Instead it shows apoptosis
of oligodendrocytes and microglial activation as the prominent pathological finding (4-7).
Multiple studies have implicated apoptotic pathway components in the pathogenesis of
MS (8-10). There is considerable evidence that the cause of the oligodendrocyte cell
apoptosis, demyelination and axonal damage in MS may reflect oxidative stress and or
excitatory amino-acid toxicity (11-13). Nitric oxide synthase, nitric oxide and
peroxynitrites are the key mediators of oxidative damage in MS lesions (14-18).
Low dose naltrexone in multiple sclerosis
While there are no scientific studies documenting the effects of low dose naltrexone
(LDN) therapy in MS, the related drug naloxone has been investigated in a variety of
neurodegenerative and inflammatory disorders such as septic shock, injuries to brain and
spinal cord, myocardial and cerebral stroke and Alzheimer’s disease (15). There is
however considerable anecdotal evidence supporting the use of LDN in MS by the lay
Anecdotal literature from the United Kingdom and the United States suggests that LDN
markedly reduces the frequency of MS relapses and halts the progression of multiple
sclerosis. The cult like following of LDN by the lay patient is reflected in the
approximately 15000 hits for “low dose naltrexone” on the Google search engine
(www.google.com), over 70,000 LDN capsules have been dispensed between Jan-Aug
2004 from just one pharmacy (Dr.Henry Lenz Pharm D, personal communication), an
international petition for a clinical trial of LDN in MS has over 5500 signatories
U.S.Patent office (#6,586,443) and one ongoing clinical trial of LDN in ulcerative colitis
an autoimmune disease (http://www.hmc.psu.edu/colorectal/research/naltrexone.htm).
Furthermore, MS patients who had been going downhill with conventional therapy have
reported their experiences with LDN in five newspaper reports in the British and
American press, as well as have organized and participated in a self reported web based
survey of 267 LDN users from 16 countries. This patient organized survey, reports an
average relapse rate of only 0.2/year in patients with MS. While the patient self-reported
survey cannot be equated with a physician organized clinical trial, it begs the question as
to why are there no clinicians investigating this. The patient initiated LDN surveys as
naltrexone has been approved by the US Federal Drug Administration at ten fold higher
doses, it has not been systematically investigated in MS.
Naltrexone is related to naloxone an opioid antagonist with no opioid agonist properties.
The activity of naltrexone is due to the parent drug as well as its metabolite 6-beta-
naltrexol. They have a short half-life of 4 and 13 hrs respectively. Naltrexone is used at
low doses (3-4.5 mg/day) in clinical practice by private physicians. At these doses, no
significant side effects have been reported in the anecdotal literature. Some patients have
reported increased stiffness, or increased wakefulness. The increased wakefulness
disappears within a few weeks of starting therapy, while decreasing the dose can reduce
The peroxynitrites produced by astrocytes and microglial cells inhibit the glutamate
transporters in synaptic clefts of neuronal cells and adjacent oligodendrocytes resulting in
excitatory glutamate neurotoxicity. I postulate that naltrexone acts by reducing nitric
oxide synthase activity. This results in a decrease in the formation of peroxynitrites,
which in turn prevents the inhibition of the glutamate transporters. Thus, the excitatory
neurotoxicity of glutamate on neuronal cells and oligodendrocytes via the activation of
the α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) class of glutamate
receptor (GluR) is prevented. The detailed evidence and reasoning for this hypothesis can
be broken down into several steps (Fig.1).
Inducible nitric oxide synthase (iNOS) activity is known to be increased in activated
astrocytes and microglia (14,17,18). While the mechanism of the increase in iNOS
activity is not the focus of this hypothesis, it could be due to an activation (step 2) of the
p38 mitogen activated protein kinase (p38 MAPK), a member of the stress activated
superkinase family. The activation of p38 MAPK occurs via opioid receptors or other
lipopolysaccharide binding proteins/receptors (step 1) (15,25). In step 1, naltrexone as a
mu receptor antagonist can block endogenous opioid receptors as well as prevent the
increase (Step3) in iNOS activity (15, 25-27). Significantly, CSF concentrations of
glutamate, hypoxanthine and xanthine are all increased in MS (16,28) Nitric oxide (NO)
produced by iNOS can combine with superoxide (O -
cells by xanthine oxidation to produce peroxynitrites (ONOO -).
The subsequent steps in the hypothesis have been proposed earlier (29). The
peroxynitrites inhibit glutamate transport by inhibiting the glutamate transporters (16,30).
As a result the accumulated glutamate stimulates excitotoxic death of the adjacent
oligodendrocytes by activating the AMPA GluR (12,13, 31). Excitotoxic death can also
occur in axons (12,31). Thus, by reducing peroxynitrite formation, LDN would prevent
excitotoxic death of oligodendrocytes and neuronal cells.
Testing the hypothesis
It is known that peroxynitrites as well as glutamic acid levels are elevated in the CSF of
patients with MS (16). The biochemical basis of LDN therapy can be tested by measuring
the decrease in the levels of these analytes in CSF after treatment with LDN. Since the
postulated biochemical mechanism may be more complex than envisioned in this
hypothesis, it is also crucial to do a clinical trial. This can be achieved by doing a trial of
LDN versus placebo in patients receiving glatiramer acetate or other MS frontline
therapy. The anecdotal literature suggests that glatiramer acetate but not interferons work
well with LDN. Progression of disease could be measured functionally by using the
Kurtzke expanded disability status scale and by serial MRI’s.
The use of LDN has gained widespread public acceptance, inspite of the lack of
enthusiasm from prescribing physicians. It is incumbent upon us to investigate this drug,
for it offers the potential of an oral therapy for MS with few side effects. At the very
least, by showing a lack of efficacy, patients can be persuaded from using LDN in lieu of
Munari L, Lovati R, Boiko A. Cochrane Database Syst Rev
Rice G PA, Incorvaia B, Munari L, et al. Cochrane Database Syst Rev
Chaudhuri A, Behan PO. Shared scheme for assessing drugs for multiple
sclerosis: why are eyes tightly shut to considering causes other than
Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology
of the newly forming lesion. Ann Neurol.
Behan PO CA, Roep BO. Pathogenesis of multiple sclerosis revisited. J R Coll
Trapp BD. Pathogenesis of multiple sclerosis: the eyes only see what the mind is
prepared to comprehend. Ann Neurol.
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H.
Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of
demyelination. Ann Neurol.
Mycko MP, Papoian R, Boschert U, Raine CS, Selmaj KW. Microarray gene
expression profiling of chronic active and inactive lesions in multiple sclerosis.
Clin Neurol Neurosurg
, 2004; 106:
Ethell DW, Buhler LA. Fas ligand-mediated apoptosis in degenerative disorders
of the brain. J Clin Immunol.
Zipp F. Apoptosis in multiple sclerosis. Cell Tissue Res.
Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the
pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J
Werner P, Pitt D, Raine CS. Glutamate excitotoxicity--a mechanism for axonal
damage and oligodendrocyte death in Multiple Sclerosis? J Neural Transm Suppl.
Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple
sclerosis. Nat Med.
Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK. Activated microglia
mediate neuronal cell injury via a nitric oxide mechanism. J Immunol.
Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS. Role of nitric oxide
in inflammation-mediated neurodegeneration. Ann NY Acad Sci.
Gurwitz D, Kloog Y. Peroxynitrite generation might explain elevated glutamate
and aspartate levels in multiple sclerosis cerebrospinal fluid. Eur J Clin Invest.
Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW. Inducible nitric oxide
synthase in chronic active multiple sclerosis plaques: distribution, cellular
expression and association with myelin damage. J Neuroimmunol.
Broholm H, Andersen B, Wanscher B, et al. Nitric oxide synthase expression and
enzymatic activity in multiple sclerosis. Acta Neurol Scand.
Nicholls M. MS sufferers campaign for drug aid. EDP24
2004 May 21.
Calls for the radical treatment. The Irish Times
2004 May 18.
Weiss-Tisman H. Drug offers hope for MS patients. Brattleboro Reformer
Carswell S. MS experimental drug 'could save state millions of euros'. The
Sunday Business Post Online
2003 Oct 5.
Puttick H. MS victim finds hope in heroin users drug. The Herald
2004 April 12.
Undergrad J. Coping with an unprofitable cure. Columbia Spectator Online
Singhal PC, Bhaskaran M, Patel J, et al. Role of p38 mitogen-activated protein
kinase phosphorylation and Fas-Fas ligand interaction in morphine-induced
macrophage apoptosis. J Immunol.
Lysle DT, How T. Heroin modulates the expression of inducible nitric oxide
Lysle DT, How T. Endogenous opioids regulate the expression of inducible nitric
oxide synthase by splenocytes. J Pharmacol Exp Ther.
Stover JF, Lowitzsch K, Kempski OS. Cerebrospinal fluid hypoxanthine,
xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in
different neurological diseases. Neurosci Lett.
Rose JW, Hill KE, Watt HE, Carlson NG. Inflammatory cell expression of
cyclooxygenase-2 in the multiple sclerosis lesion. J Neuroimmunol.
Trotti D, Rossi D, Gjesdal O, et al. Peroxynitrite inhibits glutamate transporter
subtypes. J Biol Chem.
Smith T, Groom A, Zhu B, Turski L. Autoimmune encephalomyelitis
ameliorated by AMPA antagonists. Nat Med.
Figure 1. Postulated mechanism of naltrexone mediated prevention of oxidative
damage to neuronal cells and oligodendrocytes. 1.
Astrocytes and microglial
cells are activated by opioids or other stress signals. 2.
The p38 mitogen activated
protein kinase (p38 MAPK) is activated, which increases inducible nitric oxide
synthase (iNOS) (15,25). 3.
Naltrexone inhibits the increase in iNOS activity(15,
25-27). This leads to a decrease in the formation of peroxynitrites (ONOO-). 4.
The peroxynitrites can inhibit the glutamate transport in synaptic clefts and
adjacent oligodendrocytes by inhibiting the glutamate transporters (16,30). As a
result, the glutamate does not cause excitotoxic death of neurons and
oligodendrocytes via activation of the α-amino-3-hydroxy-5-methyl-isoxazole-4-
propionic acid (AMPA) class of glutamate receptor (GluR).
SINGULAIR ™ - Local Prescribing Information SINGULAIR PAEDIATRIC 4 mg GRANULES Pharmacotherapeutic group: Anti-Asthmatics for systemic use, Leukotriene receptor antagonist ATC-code: R03D C03 1. NAME OF THE MEDICINAL PRODUCT The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. Th
GERMAN ECONOMIC TEAM IN BELARUS 76 Zakharova Str., 220088 Minsk, Belarus. Tel./fax: +375 (17) 210 0105 E-mail: [email protected] Internet: http://research.by/ Student Loans: An Effective Instrument for Financing Higher Education Summary Student loans are the instruments to increase investment in higher education. In- vestments in higher education are profitable for both, for