Low-dose naltrexone for treatment of multiple sclerosis Are clinical trials needed. Will they happen?

Every time I talk about complementary/alternative medicine to MSers someone tells me of a good luck story about low dose naltrexone. Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. Naltrexone should not be confused with naloxone (which is used in emergency cases of opioid overdose) nor nalorphine. Using naloxone in place of naltrexone can cause acute opioid withdrawal symptoms; conversely, using naltrexone in place of naloxone in an overdose can lead to insufficient opioid antagonism and fail to reverse the overdose. Low Dose Naltrexone or LDN as it known has been hitting the news recently. However the problem is is that there is simple not enough good data to support this use. 

Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G.A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008;14(8):1076-83.

A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, Majdinasab N, Shalbafan B. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010;16(8):964-9.
BACKGROUND: Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire.
METHODS: A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups.
RESULTS: Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study.
CONCLUSION: The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

Cree BA, Kornyeyeva E, Goodin DS Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010;68(2):145-50. doi: 10.1002/ana.22006.OBJECTIVE: To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients.
METHODS: This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightlynaltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients.
RESULTS: Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial’s statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05).
INTERPRETATION: LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.

So the same odd addage…Further studies are warranted. 

However, this is the perennial problem…neuros and charities tend to fund small scale trials, which are invariably too small to give definitive answers and not large enough to make a compelling case for moving things forward

Pharma aren’t really interested cos they can’t make any money out of this in the present climate. 

Should we be doing small trials that need another in the hope that pharma will work out how to repurpose the drug or only support stuff that gives a definitive answer. Or should we keep the Status Quo going? often with false hope peddling.

Can pharma be incentivised to do these studies? 

Is it another fad treatment? 

What are your views?

About the author



  • I always find that the studies quoted ever seem to look at the OGF-OGFr effect.. This is why I use LDN and Dr Zagon and Dr McLaughlin who do the serious work on LDN have shown that this is where the therapeutic/clinically useful effect will come from, not beta endorphin! OGF is met encephalin and OGFr is the zeta receptor on the cell nucleus that interacts with OGF and effects blockage of cell proliferation, amongst other clinical outcomes of use. I think the biggest cause for LDN not getting recognition might be looking in the wrong places. Please, read Zagon/Mclaughlins papers.

  • After three years of reading what ms patients write about this and other treatments, it doesn't seem plausible re disease progression. Too many people write about new lesions and relapses while taking it.

    That said, based again on three years of stories from patients across the internet, it seems to help with at least sleep and well being, possibly pain. That would be worth assessing with proper trials.

  • There are duty of care and quality of life concerns that shouldn't be overlooked by an instrumental cost/benefit analysis. LDN has been trialled and approved, any repurposed use for MS should not carry the risk of toxicity – neuros should rest assured that they would be doing no harm.

    • In my wife's case progression, now for over 10 years. I think you need to understand that ultimately there is only one clinical trial that matters to the patient, trying it on themselves. Most in the UK are not even offered the licenced drugs so they can not experiment with those. When Evidence Based Medicine comes up with a safe effective treatment that is priced so that it is generally available then I am sure most will want it. Till that point I think it would get more respect by eliminating the wide spread fraud in the drug industry rather than trying to discourage people from using safe treatments like LDN
      David Taylor

  • Can pharma be incentivised to do these studies? Only if they can "repurpose" the price. Clearly, pharma will not perform clinical trials on a licensed drug if they cannot profit from its use, translation – set a new price. Regarding LDN, it is an opioid receptor antagonist, cannabidiol is an allosteric opioid receptor modulator. Are their pharmacologic effects similar? The pharmacology is a bit tricky.

    • I am writing a review about cannabidiol and was interested by your post however the data is based on 100 micromolar concentrations so a bit like putting cells in a load of chip fat. At this concentrations cannabinoids do al all sorts of funny things as they are killing or almost killing the cells they are incubated with so not compelling in my eyes

  • LDN is a ‘cell growth regulator’ and what we are now understanding by taking LDN is that we are taking advantage of the body’s own chemistry and discovering a new biological pathway that has been shown to be effective in the treatment of MS (and complications thereof). The biological pathway is the Opioid Growth Factor (OGF) – OGF receptor (OGF-OGFr axis).

    Blockade of the interaction between OGF and its receptor OGFr for 4-6 hours using LDN inhibits and controls cell proliferation and growth/activity of cells, specifically astrocytes, microglia/macrophages, inflammatory T and B lymphocytes when the opioid antagonist is no longer present (18-20 hours).

    By modulating the OGF-OGFr axis, we are prolonging periods of remission and diminishing the number and length of disease relapses. Pre-clinical studies have shown that areas of demyelination and neuronal damage are markedly reduced.

    As the benefits from taking LDN come from the ‘rebound effect’ (the rebound effect is what happens when the drug you have taken clears your system providing you with the benefits of its actions), it is going to be extremely difficult to conduct a proper clinical trial (double blind cross over). As shown in Dr Gironi’s clinical trial in Italy, the effects from taking LDN for six months continued as the increased levels of beta endorphin continued to rise even after stopping LDN for one month.

    Conducting long term clinical trials is going to be difficult for reasons you have outlined in your blog and because of the novel way LDN works through rebound effect. We know it’s safe, well tolerated and the fact it is nontoxic, inexpensive and can be delivered orally is very attractive to people living with such a chronic progressive disease where most of the alternatives are medications via injection with potential serious side effects.

    The key to LDN’s success is dosing and this is where I see the downfall in the clinical trials so far – all taking 4.5mg at night. After two decades of patients using LDN, it is now understood that 4.5mg is too high for a lot of people with MS (3mg being a more manageable dose especially for those who are living with terrible spasms), and that LDN interferes with many people’s sleep hence the dropout rate in these trials. For this reason (lack of sleep) many are now taking LDN in the morning very successfully. We also now know that after taking LDN for a couple of years, your body is able to start producing sufficient endorphins, enkephalins and receptors with very little help from LDN so there is no need to take as much LDN or as frequently. However further studies/trials are very much needed to get more answers to determine how to successfully use LDN long term.

    It’s a shame that those Drs who are addicted to prescribing LDN having seen their patients disease progress at a very slow pace have not kept real data to publish!

    • So here it is a DMT dealling with relapses, but there are drugs that are accepted to work on relapses…what is the advantage?

    • One has to ask why then only 12% of MS patients are using these 'approved' drugs. High toxicity with potential side effects makes it far too risky for some to even contemplate using. LDN being non-toxic, orally delivered and a therapy that can be used long term to slow down disease progression is surely a far safer option?

      We need to find a way for delivering better drugs to patients, sooner, and at a lower cost than the current system of a lengthy, costly clinical trial. The whole system for approving drugs needs to be looked at. LDN has been used in the UK for at least 14 years and what matters for individual patients is the opportunity to choose a medical treatment that meets their individual health status and risk tolerance and this doesn't often tie in with what NICE approves.

    • A therapy that can be used long term to slow down disease progression is surely a far safer option?

      I am sorry but where is the real evidence that it does anything real for disease progression, I am not sure I can see it what am I not seeing.

      I agree we need a way to see if there is anything real happening…maybe the best way is to sign up to the MS register in UK and fess-up to CAMS and maybe in time they can seen if the anecdote has legs.

    • Some of us are willing to bet our lives on the science before the clinical proof goes through a tortuous approval process (given the poor alternatives being offered). So we have to make good choices and that is why we need good science references (Zagon/McLaughlin).

      Research into LDN is vital to the progress of medicine which leverages the bodies' own systems to promote health and manage the disease. LDN is a therapy with minimal side effects and easy delivery methods, making it ideal for those with MS. People want medications that intervene in their independence as little as possible, and dependence on a drug is hard enough on its own.

      In a perfect world we would have already proven LDN to whatever level of efficacy is required. All said, LDN continues to need rigorous research. To ignore it and not fund research might be unwise especially when the science shows that this and targeted drug choices are the major axis of 21st century medicine.

    • Have just at a few of the references of Naltrexone and EAE highlighted. High dose naltrexone did nothing and in 70% of cases low dose did not stop disease and it was not that marked. The claim is that it should be useful for RRMS, but is this why people use it?
      Maybe when ProfG has time he can do a survey and so if it is symptomatic control, relapsing MS or progression that people want to take it.

    • I don't expect a cure, but my relapses stopped after I started using LDN. Read Dr Zagons papers on LDN and OGF and you might see the mechanism. MS has no cure so we need to live with it. OGF controls microglial activity which can control spasticity formation. It also reduces the proliferation of T and B cells which is what drives EAE and we believe MS and Dr Zagon has published the effect of OGF on EAE with good results. If ProfG could look at OGF we may see some progress from there too. Stopping MS is not possible as yet, so disease management is the way forward for us.

    • High dose naltrexone did nothing and yet in low doses it worked for 30% of the people – similar figure to the current highly toxic meds I believe. Wouldn’t this in itself justify further research? It doesn’t surprise me if the 30% figure is based on the “4.5mg dose to be taken every night” protocol.

      It would be refreshing to find researchers and neurologists who understand that the benefit comes from modulating the OGF-OGFr axis and it is this that is responsible for repressing the action of microglia, astrocytes and T lymphocytes. With LDN having been in use for two decades, we have now learnt that the 4.5mg dose does not have a very high success rate. A lower dose may give more favourable results for MS.

      Suggested reading:-
      “Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis”:-

      Astrocyte Proliferation is Regulated by the OGF-OGFr Axis In Vitro and in Experimental Autoimmune Encephalomyelitis:-

      It would be most welcome if Prof G did a comparison survey including what doses are being used that people are using to help slow down progression. Thank you for your blog and this opportunity.

    • Have read the links but to me, it is not particularly compelling. There appears to be a weak immunomodulatory effect and much of the astrocyte effects are secondary to there being an anti-inflammatory effect, I think it makes the right noises

  • Well (in general), if it does have an effect in a number of patients and it is relatively safe to prescribe, can't you just try it for those that want it and record the effects, slowly building up the numbers and data? It's not randomised and class one evidence and it might take longer, but surely it's a close second? There doesn't seem to be any progress on these sorts of drugs so surely it's about getting a body of evidence to say if the drug works or doesn't. There has to be some alternative to the pharma model for drugs already out there that are now genetic.

    Question: what would happen if the best efficiency MS drug so far discovered happened to be past it's patent lifetime, it was discovered through off label use, it is considered safe and it's definitely effective etc?

    • Who is collecting the data so that the effect is seen….I suspect no one so the efficacy is anecdote at best and may not be robust and do anything.

  • Yes, research please! Can LDN slow, or even stop, progression? I have SPMS and offered nothing, nada, nil by neuro's. Put myself on LDN and OMS. What is there to lose? Is there everything to gain? Research! Yay!!

  • Rollo Wednesday, July 30, 2014 2:01:00 am
    I personally know about a dozen MSers using LDN. I guess the most shocking thing isn't that a huge number of MSers are using it but that the medical community seems unaware of them doing so. Just for a hoot Google a pharmacy in FLORIDA [EDITED] and ask how many prescriptions they fill have filled for LDN. Hint… ask XXXXXXXX to round it off in the tens of thousands.

    Wonder if inexpensive, non-toxic, and satisfactory effectiveness have anything to do with LDN's popularity? Wonder how many want to stop taking it and wait on evidence from a Phase 3 trial (which everyone knows damn well is never going to happen)?

    Yes, we realize that in the research world there is not enough good data to support using LDN. But in the practical world where MSers have no choice but to be fully engaged 24-7 LDN has been tried and found to be beneficial. There will never be enough good data because there will never be adequate funding to compile it, IMO.

    Some MSers I know are very reluctant to talk about using LDN because they source it themselves and are afraid big pharma will pressure their legislative lap-dogs in Congress to cut off their supply. Some of the LDN users have no insurance and cannot afford the $4700 a month one family member pays for Tysabri. Dare I mention another family member getting 3 months supply of LDN from a certain pharmacy in FLORIDA [EDITED] for $53 total cost? Wow, if that doesn't get Biogen jumping nothing will. Gosh, I'd think they would be chomping at the bit to prove how ineffective LDN is compared to their drugs.

    Patients are miles (kilometers, perhaps) ahead of researchers regarding the use of LDN in MS. It is a shame that disease societies are as neglectful of LDN as the drug companies. But that's story for a different day. Bottom line… don't expect patients to wait while researchers play catch-up. Life is too short for MSers, anyway

    • Ask howmany people go to Wal Worths for Vit D and it is millions but where is the prove it works…sales alone dont proove worth…millions buy lottery tickets few are millionaires

    • True, sales do not prove worth. But trials do, and several small trials have demonstrated LDN effective enough to warrant a personal trial for thousands of MSers convinced of the futility in waiting for larger trials. Reoccurring sales of a medicine found beneficial by disease sufferers settles the question of worth individually, at least.

      Sales do not prove worth; practical experience does. Thousands of people taking LDN for multiple years are why one pharmacy alone has filled tens of thousands of prescriptions. Patients are more interested in what works personally than reading about a percentage from a trial.

      But why no one seems interested in funding follow-up to early promising trials is quite a mystery to MSers. Understandable the pharmas are not interested in an inexpensive competitor but what about disease societies who exist for the benefit of disease sufferers?
      My queries in that regard to the NMSS in New York brought this response: “We funded a pilot study that had some positive results and would have expected more grant applications to come in on the basis of that.” When I asked for more details the NMSS further clarified, “We have funded the one pilot study in EAE; we have received one additional research proposal on LDN in 2008 that wasn’t recommended for funding; we have received no other LDN proposals.” End Quote.

      Since several applications to the NMSS for studying LDN have been submitted by multiple researchers from one university alone (Penn State) I find the NMSS response lacking credibility. It begs the question… why ignore something they characterized as positive? Makes me wonder how many applications beyond the 9 I know about were submitted. Also makes me wonder if there is a conflict between MS sufferers and drug company interests or if a $100 million a year in donations organization is an abysmal record keeper relative to the 450 research applications they receive each year?

      If MSers are deluded about LDN wouldn’t it be worthwhile to prove them wrong? Wouldn’t that be the compassionate thing to do? Little chance we will ever see definitive studies about LDN. Pharma isn’t interested; disease societies refuse to acknowledge even receiving applications to study it and university researchers have surprisingly limited awareness.

      The reality is that many MSers who trial LDN on a personal level find it effective enough for them to continue. I get your point MouseDoctor, but most will view prescription renewals slightly more rigorous than lottery sales in determining value.

      I express my gratitude on behalf of all MSers and caregivers for the dissemination of knowledge through this blog. This blog is irreplaceable for providing lights of knowledge which assist our way. Thank You for all your work. It is very humbling to receive something which you have no ability to repay save gratitude.


By MouseDoctor



Recent Posts

Recent Comments