Experience with LDN? low dose naltrexone

[bobbler]

Good points, Trish.

I have never been terribly attracted to crossover trials and tried to think why. (Presumably they may give more data from fewer subjects - each giving outcome for two or more trial arms.)

I think the problem is in knowing whether being on LDN first arm and placebo second is the same as vice versa. What if 6 months of LDN sets you up for a good run for a year? I guess my objection to crossover is that it introduces more unknowns.

The point about pain is crucial. If we want to see if LDN reduces pain we need a strictly blinded trial with a pain scale outcome. Cut and dried. Pain could also be included as a secondary measure in a trial with actimetry as primary outcome measure of 'total impact on ME'. But the pain result would have to be repeated if the primary measure came out negative and the secondary measure positive (at least if only without Bonferroni). This is where being picky about power is critical. Planning for more than one trial may be the right approach.

What I had not said is that actimetry looks the best option if the trial is designed to test the impact of LDN on ME as a whole. There seems a good consensus that the primary aim for patients for an ME drug is being able to do more of actitivites that make life worth living. Whether through helping pain or cognition or whatever, that means that a validated actimetry index should reflect the aim. Not everyone may be able to do more, even if feeling better, but with trials you allow for that. If a drug is capable of reaching the primary aim for some it should show statistically. Outcome measures do not need to pick up every case of improvement. It is more important that they are simple and robust. Actimetry is criticised for missing things or being misleading but if, as you say, it is done over extended periods, and validated against diaries in a calibration study, then it ought to pick up a drug benefit. As we have discussed, scepticism about actimetry may partly reflect the fact that so far nothing has shown a useful benefit on it - simply because nothing so far has been good enough.

The bit about optimal dose of LDN being reached begs the question of how you do that without losing blinding - I think we have covered that. It makes the case for an objective measure.

When you put it in those terms I’d say crossovers need to be out definitively in ME because of the way that PEM accumulates - then hits after 6mnths of just pushing your boundaries to the limit (and getting away with it … then not .. boom)

you can kid yourself a regime of whatever is making you better because you get the ‘ability to do’ or walk the tightrope but that’s not really ‘tackling ME’ but ‘IS ME’ (and I think where much of the medical profession is still stuck - because even patients need years of living doing this same false hope mistake to realise ).

to me what would/should be really accurate is the plain ‘a year on’ comparison of groups - with yes good measures to that.


Just as I think the public don’t get that PwME would have walked through hot coals of hell with GETs hurt doesn’t equal harm for the promise of that having an endpoint to their disability. Or even just a ‘chance’ of that being worth the effort. BUT Anyone voluntarily signing up would have asked from a medical professional one question alone: will/could it make me worse?

And I almost have to remind myself of that too when looking at measures.

 

[bobbler]

I think measuring upright time instead of steps would be more meaningful for a wider range of severities (though admittedly not the very severe). For those able an increase in steps would likely still be reflected to some degree in an increase in upright time but the reverse is less likely to be the case (a more severe pwME may have meaningful improvement by being able to sit up more without this translating into steps).

I find my step count is very consistent, it barely drops during PEM because I'm at the level where I only do 'essential' steps anyway, as in go from bed to fridge to sofa to bathroom to bed, that sort of thing. The steps feel harder to do during PEM but the actimeter can't measure that. What does change measurably is how much time I spend sitting vs lying down.

Bateman Horne were working on an ankle strap for measuring time with feet on the ground (gyrometer?). And there's a commercial company whose name I've forgotten who are working on something similar though I can't recall if it was a strap for the arm or the leg. Hexoskin vests may also be worth looking into though they look like devils to get into and probably not a good solution for longer study periods.

I wonder if the best data would come from 2 separate straps measuring body position, one on the ankle to measure if feet are on the ground and the other on the arm to measure if the upper body is upright or flat. If at least the ankle strap also measures movement or steps then, combining readings from the two straps, an algorithm could differentiate between time spent walking vs standing/sitting properly upright vs sitting up with feet up vs lying down/reclining with feet up. Then use some form of formula to turn those measurements into a single physical activity rating.

To overcome the problem of people doing more but feeling worse as a result the physical activity rating could be combined with a simple cognitive test just before bed (or maybe an hour before to reduce the risk of it interfering with sleep) to capture how much the day's activity wore you out. Again use an algorithm to churn out a final overall rating where increased activity with decreased cognitive ability cancel each other out but increases on both parameters rate as genuine improvement.

One complication with regular cognitive testing is the learning effect - doing something every day means you get better at it over time - so the type of test needs to be carefully considered. A memory test of nonsense words or a reaction speed test may work. Most of the learning effect for these would be right at the beginning (and that could be done pre-trial) with level of exhaustion being the biggest factor after that.

General placebo question: is there such a thing as a placebo that can induce mild side effects? A bit of a contradiction in terms as it would have to be a substance that isn't entirely inert. But they do sham surgery trials so is there a pill or an infusion equivalent of some harmless substance that may make some people a tiny bit nauseous or headachy? Not useful for assessing drug side effects, obviously, just for blinding treatment effects.

The difficult thing is that the weeks where I’m actually worse and going downhill from having overdone things by no choice aren’t necessarily’less active’ because PEM affects my ability to get good rest (I’m already severe and doing little do the next stage is pain and having to ‘rest to get good rest’.)

If sensible patterns were being used and looked at not just snapshot then maybe better but I’d also add in a function measure for essential things like showering (how often, what help, how long and how much rest needed after before dressing) or tooth brushing in order to triangulate - with a proviso that a decline in those latter 2functions is likely to mean decline even when simultaneously ‘activity data’ seems like their body is more ‘active’

 

[Hutan]

When you put it in those terms I’d say crossovers need to be out definitively in ME because of the way that PEM accumulates - then hits after 6mnths of just pushing your boundaries to the limit (and getting away with it … then not .. boom)

Arguably, this is actually the benefit of a crossover trial: comparisons between the set of participants that do the placebo first and the set of participants that do the treatment first gives you some idea as to whether there is any residual benefit or harm from the treatment.

It does make the trial more complicated, and certainly makes reporting results more complicated if the two placebo arms don't have similar results, so perhaps that's a reason to avoid it. In favour of the cross over design is that it guarantees all participants some time on the treatment, so it may make it easier to recruit people. I don't feel strongly about the design either way, but I don't think ME necessarily makes cross-over designs wrong.

 

[Arisoned]

I have not looked through that paper in detail yet but one thing looks to me to be glaringly missing. They talk of a correlation between fall in ESR and fall in symptoms. But so far I have not seen a figure that shows that patients on LDN showed a greater fall in ESR than controls? If not then the whole thing is meaningless. There was no effect on inflammation. The correlation simply shows that people feel crummy when their ESR is high, for whatever reason.

On reading further it seems that they didn't even measure the ESR after treatment - pretty weird if they thought it was relevant. The difference between the treated and placebo in figure 2 looks to be due to two people with anESR around 50. Anyone with an ESR of 50 cannot reasonably be said just to have FM I think.

I am afraid this looks very much like scratching around to find a few crumbs that fit a theory having failed to get a result from the obvious test (which it is claimed was not even done). The rest of the paper is mostly speculation about glia in animals as far as I can see. It may turn out to be relevant but it all looks very makeshift at present.

Yes, they say in the paper they didn’t measure ESR after treatment which is a huge error, so I guess which is why the follow up paper.

 

[hinterland]

The UK government working party on research strategy for ME has been discussing the value of setting up trials for drug repurposing. LDN is a contender. I would be interested in the range of experience - positive or negative - amongst members.

I've tried LDN and found it had a useful effect and seemed to work on a deeper level than other treatments I've tried, but it was only a temporary improvement in my case. Once I'd carefully worked up to a therapeutic dose, which started around the 2.5 mg range and above for me I noticed reduced inflammation and better cognitive function. This treatment response lasted for maybe 2 or 3 months before it tailed off. Eventually I started getting issues with dry skin and sinuses that I identified as side effects from the LDN, so I reluctantly stopped treatment. The side effects resolved and there was no loss of function from stopping, so I decided in my case I was overall better without it but I'd be willing to try it again at some point.

One point I'd like to make is that the form and supplier of LDN could be important. The syrupy liquid version made up by a pharmacy very experienced in compounding LDN worked best for me, see my post #3 here:
https://www.s4me.info/threads/trial...ens-hospital-health-centre.28368/#post-426494

 

[Arisoned]

I am afraid that doesn't look like evidence @Arisoned.

When a cluster of private physicians with a special interest in a diagnostic category that most other physicians doubt exist say they find something useful but have never done any proper trials that is a pretty good indication that there is likely nothing to it. Individual patients may be convinced they have benefited and nobody can prove them wrong but talk from physicians like this just makes me even more sceptical. If these physicians actually knew anything about gathering clinical evidence they would have done trials, as I did for my drugs. These physicians are the problem, not the solution, as I see it.

Here are the links to Prof Theoharides studies.

https://me-pedia.org/wiki/Theoharis_Theoharides

Prof Theoharides spoke at The IIMEC13 Anne Örtegren Memorial Lecture.

 

[Jonathan Edwards]

I cannot see any results for controls in the cytokine paper?

 

[Arisoned]

I had a look at that and was not impressed that there was anything other than speculation involved.

If we do not even know its a drug works it is premature to claim to know how it works!

There seems to be a suggestion that the effect might be due to a dextroisomer, rather than the levoisomer binding to endorphin receptors. If so, I would have thought it was worth finding something that was not quite so muddled as a racemic mixture of a tiny dose of a drug that has no very obvious reason to work (either isomer) in either FM or ME - since neither is know to involve the pathways mentioned.

I use these -
http://www.ldnnow.com/ - Jayne Crocker is from the UK and is contactable. I would think she would be very helpful.
https://www.ldnscience.org/

The other admin for the ME and Fibro facebook page is a PHD Medical Biologist. I have asked him if he would be happy to gather some evidence for you or talk with you if needed.

Jarred Younger has been trying to get funding for dextro for several years.

 

[FMMM1]

Jarred Younger has been trying to get funding for dextro for several years.

Googled "Jarred Younger + dextro" and found that --naltrexone ---- dextro naltrexone.

 

[Jonathan Edwards]

The ldnnow website says:

"LDN is not a miracle drug. It is a drug that implements the biotherapy approach to medicine, which is all about artificially stimulating the bodies own defences and systems in order to restore control over systemic diseases. This control is how most people remain clear of these diseases in normal health. The immune system we have has evolved over billions of years and does many jobs far better than our modern, symptom relief drug culture ever can." LDNNow

About Us:-
LDNNow are a political/pressure group of individuals dedicated to getting Low Dose Naltrexone (LDN) accepted into modern medicine and dedicated to the myriad of uses it is believed it shows benefit for. These uses include autoimmune diseases and many cancers (cell proliferative diseases).

This looks like quackery to me. I have never heard of a 'biotherapy approach'. The text is highly misleading and likely to make people turn to unproven therapies when they might get genuine help - particularly in the case of autoimmune disease and cancer. LDN has nothing to do with either as far as I am aware.

 

[Jonathan Edwards]

If the immune systems does things better than drugs, why offer a drug?

 

[Arisoned]

Yeah, post-hoc subsetting is another indication of treatments that don't really work and researchers desperate to find something to report. (Not to say that it is always wrong to report an interested subset result.) Here they are suggesting that LDN works for the people with fibromyalgia who have a high ESR (which Jonathan suggests is a result built on just a couple of people with high baseline ESRs). For what it's worth, and it may not be very much, there have been reports of people with ME/CFS tending to have low ESRs, so... maybe LDN can be expected to make ME/CFS worse?


From what I have seen, cytokine research tends to be a mess. I think levels may fluctuate a lot, even throughout a day, and they might be hard to measure reliably - I don't know, but it seems incredibly hard to get any sort of consistent results. Having a whole batch of cytokine measurements seems to me to be a hallmark of studies that are fishing for some positive result. If you measure enough, there is often something. Perhaps there is something in that study though, I'll make a thread for it and we can have a closer look.

Yeah, post-hoc subsetting is another indication of treatments that don't really work and researchers desperate to find something to report. (Not to say that it is always wrong to report an interested subset result.) Here they are suggesting that LDN works for the people with fibromyalgia who have a high ESR (which Jonathan suggests is a result built on just a couple of people with high baseline ESRs). For what it's worth, and it may not be very much, there have been reports of people with ME/CFS tending to have low ESRs, so... maybe LDN can be expected to make ME/CFS worse?


From what I have seen, cytokine research tends to be a mess. I think levels may fluctuate a lot, even throughout a day, and they might be hard to measure reliably - I don't know, but it seems incredibly hard to get any sort of consistent results. Having a whole batch of cytokine measurements seems to me to be a hallmark of studies that are fishing for some positive result. If you measure enough, there is often something. Perhaps there is something in that study though, I'll make a thread for it and we can have a closer look.

I don’t think that low ESR’s are necessarily the case. Cort’s report in HR in 2019 on “clumpers and sliders” discus Ron Davis and Dr Bella Chheda’s results, and the results of the biobank study -

“As an infectious disease doctor, Dr. Bela Chheda had run hundreds, probably thousands of ESR or sedimentation rate (SED) tests prior to working on ME/CFS. She ordinarily encountered increased sedimentation rates in her patients with infections, but then came ME/CFS – a disease triggered by infection which many people assume is inflammatory in nature. (ESR tests, it should be noted, do not pick up all kinds of inflammation.) The ESR or SED rates in many of her patients, though, were not just low but bottom of the barrel low (usually 2). (She thought the reason she didn’t see even lower numbers was that the test probably wasn’t sensitive enough.)

In fact, so many people with ME/CFS had very low sedimentation rates that she began to think of it as a kind of non-specific biomarker and wondered if something different might be going on in her patients with normal or higher ESR rates.

Chheda’s anecdotal reports appeared to jive with Ron Davis’s finding of reduced SED rates in his Stanford red blood cell deformability study.

But then came, surprise, surprise, a very large British Biobank study which found normal ESR rates (median=5) in more severely ill patients and slightly increased ESR rates (median=7) in less severely ill patients.

Another seemingly consistent finding in ME/CFS went to pot! Not able to explain the differences that are showing up and still hanging on to my consistently low SED rates (they must mean something), here’s a poll with a twist to add a another slice to the data. Using Dr. Natelson’s supposition that people with ME/CFS differ from people with ME/CFS and FM, the poll will be divided up into three categories”:

 

[Arisoned]

If the immune systems does things better than drugs, why offer a drug?

http://ldnnow.com/48501/90412.html

First off, it always helps to have an understanding of the disease we have been diagnosed with and how this disease affects our bodies. Once we understand this, can we start researching therapies gaining an insight as to how various treatments work. Then, we can make an informed decision with the therapy of our choice as to how we wish to manage our diseases.

When anyone asks ‘what is LDN?’ it is important to understand that LDN is a ‘cell growth regulator’ and through its actions we are able to tap into our body’s own chemistry to help control pain, inflammation and disease progression in a non-toxic manner.

The evidence that the body’s own chemistry can be used to heal itself introduces an entirely new paradigm and a breakthrough in understanding the pathophysiology of diseases. It also provides the opportunity for a biological-based strategy in the restoration of homeostasis. This discovery has already shown the capability to transition from bench to bedside, and the clinical studies to date provide exciting and provocative results that promise even greater rewards.

So how does LDN work

By regulating and controlling errant cell proliferation we are able to exert a modifying influence on the immune system and control inflammation. If it weren’t for the immune system – which is the human body’s natural defence against outside invaders – we would be sick all the time. This complex network of cells, organs and molecules (immune system) fights off things like hostile bacteria and viruses 24 hours a day. The immune system is a powerful protection when it’s working for us, but can also be a powerful threat when it turns against us.

Among the key players in the immune system are special white blood cells called B cells, which produce antibodies to coordinate the attack, and T cells, which carry out the attack – and, importantly, also signal when the attack should stop. When the immune system launches an aggressive attack on infected cells, healthy tissues and cells can be mistakenly killed or damaged in the process as it fails to shut off that attack. The type of disease that is diagnosed depends on the type of body tissue or organ that is affected. The more dysfunctional and out of balance the immune system is, the more voraciously it will attack the body’s tissues

When cells of the body at a particular site start to grow out of control, they may become cancerous. Cancer cell growth is different from normal cell growth. Cancer cells continue to grow and form new, abnormal cells. In addition, these cells can also invade other tissues. Large numbers of cancer cells build up because they multiply (proliferate) out of control, or because they live much longer than normal cells, or both.

For anyone living with a disease, our goal is to quench the inflammation of the autoimmune reaction – to allow the immune system to do its job while keeping it from doing further damage – and to “reset” the immune system so that it will work normally on its own.

This is where Low Dose Naltrexone (LDN) becomes relevant.

As Naltrexone is a cell growth regulator, research has shown that by taking a very low dose of Naltrexone and benefitting from the rebound effect (the upregulation and improved interaction between OGF - Opioid Growth Factor, chemically termed met-5-enkephalin and its receptor OGFr), we are able to control inflammationand repress the proliferation of these cells. The rebound effect is what happens when the medicine you have taken clears your system leaving you with the benefit of its action.

This action is dependent on the OGF-OGFr axis which serves to promote homeostasis. The OGF-OGFr axis is a biological system and operates as a tonically active negative regulator of cell proliferation. By taking LDN, we are able to modulate the OGF-OGFr axis allowing us to harness the body’s own chemistry to manipulate the immune-system response (improved cell interaction and immune function). Bringing our ‘systems’ back into balance by controlling inflammation and slowing down errant cell proliferation can only be beneficial to anyone living with chronic sickness.

LDN blocks your opioid receptors for a period of roughly 4 hours. During this time it tricks your body into believing it is not producing endorphins and enkephalins, specifically met-5-enkephalin known as Opioid Growth Factor, (OGF). As a result, the body compensates by stimulating an enhanced production of these opioids along with their receptors. Only when LDN has cleared your system does the rebound effect come into play where we are able to repress the proliferation of these cells in a non-toxic manner.

The rebound effect continues long after LDN is no longer in your system i.e. 1-5 days. The mechanism of action works just the same regardless of the time of day LDN is taken for the simple reason this effect acts for this amount of time. Dosing is very individual depending on how quick a patient metabolizes LDN and the length of time the rebound effect lasts. These are open questions.

In addition to repressing the proliferation of T cells, B cells, and some types of cancer cells from the rebound effect, an upregulation of OGF has also been found to regulate the growth of astrocytes that form scar tissue in neurological damage, suppress the action of microglia in neurodegenerative disorders, repress the ability of viruses and bacteria type infections to multiply quickly, and inhibit angiogenesis (blood vessel growth) in cancer. This is important for tumour control because tumours need to develop blood vessels fast to stay alive, so inhibiting this will block tumour growth and even cause parts of the tumour to die off if they outgrow their blood supply. OGF is often described as ‘cytostatic’ (cyto = cellular growth, static = halt).

Research has also shown that by combining LDN with standard-of-care chemotherapeutic agents, an enhanced anticancer action has been observed where, LDN may also serve as a protector of any possible adverse effects from chemotherapy. Clinical trials have also shown that LDN can be used as an adjunct therapy to the more conventional medicines.

There is also exciting new research being done with LDN to treat pain looking at a different mechanism. Dr Jarred Younger and colleagues at Stanford are reviewing the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system via the Toll Like Receptor 4’s (TLR4’s) action on microglial cells. This may represent LDN as being one of the first glial cell modulators to be used for the management of chronic pain disorders.

Having the ability to take a medication that inhibits cell proliferation for those cells that have only been activated to proliferate through the disease process, yet leaves the healthy cells alone is rapidly gaining the recognition it deserves.

It is simple to see why so many Drs and patients are opting for this affordable non-toxic biotherapy approach to medicine when treating ‘cell proliferative related diseases’ which are driven by inflammation, making it an attractive therapy for cancer, autoimmune, neurological and infectious disorders.

Naltrexone itself is a novel and innovative drug. When taken orally in high dose which provides a complete opioid receptor blockade, there can be increased cell proliferation. There have been many studies published using high doses for this effect in autism, fertility issues, brain diseases and compulsive addictive behavior disorders at doses of >50mg.

Other methods of delivery of Naltrexone are recently being studied in ophthalmology for treatment of ocular surface diseases such as impaired corneal wound healing and severe dry eye with ocular films (1) and eye drops (2). A Phase I clinical trial to test the tolerability of eye drops has also been published (3). For those living with complications in wound healing, topical Naltrexone cream in high concentration has also been studied because it encourages cell proliferation on the surface of the skin. This has been shown to enhance closure of epithelial, surgical, or full thickness cutaneous wounds in normal or diabetic individuals (4) (5).

In 1979 the effects of taking Naltrexone in low doses (LDN) was discovered. Two years of experimentation to clarify its mechanism were required to study the effects of LDN and were published in 1983 (6). LDN has been prescribed in doses <5mg in the clinical setting since the late 1980s (7).

There are a lot of questions surrounding what dose people should take with more and more people wanting to use this non toxic biotherapy approach to medicine for various illnesses. Here we will talk about how LDN modifies a biological system through the rebound effect.

In order to benefit from taking LDN to manage autoimmune/central nervous system disorders and cancer, understanding it’s mechanism (8) is important to make an informed decision about your dosing protocol.


What happens when you antagonize the receptors?

When used in low doses (<4.5mg) LDN antagonizes a sufficient percentage of the receptors for a short period of time on average for about 4 hours.

During this time, it tricks your body into believing it is not producing endorphins and enkephalins, specifically met-5-enkephalin known as Opioid Growth Factor, (OGF). As a result, the body compensates by stimulating an enhanced production of these opioids along with their receptors (9). OGF is a tonically active, inhibitory endogenous peptide which is made in the adrenal gland, by all proliferating cells, and the brain. LDN also upregulates the opioid receptors and the all too important nuclear-associated OGF receptor (OGFr) during the receptor blockade time.

What happens during the rebound effect?

Antagonizing the receptors for around 4 hours allows the upregulated levels of the body’s OGF and receptor to then interact and work long enough during the rebound effect in a non toxic manner to produce a positive outcome of suppressing the unwanted proliferation of cells (in autoimmune conditions and cancer).

Of importance, is the understanding that if there is not an adequate amount of receptors for OGF and endorphins to bind to and interact, the body is not able to utilize the endorphins and OGF efficiently. Only when LDN is no longer antagonizing or blocking the receptors, can the upregulated levels of endorphins and OGF interact with its receptor. It is this cell interaction during the rebound effect that is critical to one’s health with controlling errant cell proliferation, inhibiting inflammation, slowing down disease progression and promoting homeostasis/healing

As LDN does not need to be in your system in order for you to reap the benefits, an important question that needs to be asked, is how long will the rebound effect last after taking LDN? For some, the rebound effect can last longer than 24 hours in which case every other day dosing or three times a week (Mon, Wed, Fri) dosing is beneficial.

Pre-clinical studies with Head & Neck cancer have shown that the upregulated levels of OGF remain elevated for one week (10). The six-month clinical trial with MS done by Dr Gironi in Italy has shown that beta endorphins remain elevated one month after patients stopped LDN (11). This reiterates that it’s not just the upregulated levels of OGF and endorphins that are important, but the length of time they interact with the receptors which can only happen when LDN is no longer blocking or antagonizing them.


What dose is the correct dose?

It is worth noting that if you want to benefit from the rebound effect, taking too high of a dose of LDN or taking it too frequently will cancel out this effect.

Some Doctors prescribe more frequent dosing ie three times a day at higher doses for chronic pain relief. We cannot find any peer reviewed articles/studies to support this protocol. This is a different approach when using LDN to control errant cell proliferation and to slow down disease progression.

Dr Patricia J McLaughlin states “The clinical use of LDN for treatment of autoimmune disorders outpaced rigorous scientific research. Even today, many internet-originated rumors exist that warrant clarification. For example, ‘‘more is not better’’. The fallacy in this statement is obvious; LDN patients should not be encouraged to increase their dosage or take more than one tablet daily. At present, the timing of administration of LDN is a patient preference, and there are no basic science studies that conclude morning or evening consumption is either harmful or better.” (12).

Dr Jarred Younger states “Successful treatment of chronic pain with naltrexone may require low dosages. Theoretically, a complete blockade of endogenous opioid systems would not be a desirable outcome with a chronic pain patient. Basic science evidence supports that concept by showing that low- and high-dose opioid antagonists have quite different impacts on the physiologic system.” (13)

With responses to LDN being so varied it is proving challenging for both Doctors and patients to get the best effect with dosing. Some Doctors recommend starting at a low dose (1mg) increasing by 0.5mg-1mg every two weeks with a view to alleviating any potential side effects. In the six-month clinical trial with MS, participants started out at 2mg and worked their way up to 4mg throughout the first month. Participants in the trial were allowed to remain at a lower their dose if they felt that this dose was most suitable (14). Typically, the dose people take varies between 2mg-4.5mg, either once daily, every other day or three times a week. Again, the maximum daily dose for LDN effects if 4.5mg once a day.

When using LDN for cancer, it is important to understand that cell proliferation happens during the time the receptors are blocked. It is the upregulated levels of OGF and its receptor that suppresses cancer cell proliferation which happens during the rebound effect. (15). Pre-clinical studies with an aggressive cancer have shown that taking LDN every other day is also effective. LDN can be used on it’s own or as an adjunct therapy to chemotherapy (16)

By using LDN, we are modulating the OGF-OGFr axis which helps balance the immune system and works towards slowing down disease progression. While we are discovering that for some diseases there aren’t enough OGF receptors for the OGF to attach to and other diseases have too many receptors and not enough OGF. Either situation creates an imbalance which needs correcting.

We hope by explaining the above, this will help further your understanding with making an informed decision about dosing. To speed up cell proliferation (fertility, brain diseases etc.) studies show a higher dose of Naltrexone may be beneficial. To slow down cell proliferation (autoimmune diseases/cancer), a low enough dose (LDN <4.5mg) to create a rebound effect is required.

LDN is novel in the sense that you only need a specific amount of the med to get the benefits. The science behind LDN and clinical evidence of the OGF-OGFr axis as a homeostatic regulator of proliferation has shown support that modulation of the OGF-OGFr pathway is an effective therapeutic paradigm for maintaining human health and treatment of disease (17).

References: at the link
http://ldnnow.com/48501/90512.html

 

[Arisoned]

https://www.facebook.com/LDNNow

 

[Jonathan Edwards]

First off, it always helps to have an understanding of the disease we have been diagnosed with and how this disease affects our bodies. Once we understand this, can we start researching therapies gaining an insight as to how various treatments work. Then, we can make an informed decision with the therapy of our choice as to how we wish to manage our diseases.

Yes, but although I haven't read through all of the text put below that, the beginning bit is complete nonsense. Just make believe.

 

[Jonathan Edwards]

I have read through. The information is grossly misleading, as well as being incoherent in places. I would assume that if this was written in the context of any commercial venture it would be illegal on trades description grounds. I actually think it should be illegal to put out such misleading documents in any circumstance. We are not told who the author is, as far as I can see. I strongly recommend that it is removed, for the sake of patients who may be misled.

 

[bobbler]

Arguably, this is actually the benefit of a crossover trial: comparisons between the set of participants that do the placebo first and the set of participants that do the treatment first gives you some idea as to whether there is any residual benefit or harm from the treatment.

It does make the trial more complicated, and certainly makes reporting results more complicated if the two placebo arms don't have similar results, so perhaps that's a reason to avoid it. In favour of the cross over design is that it guarantees all participants some time on the treatment, so it may make it easier to recruit people. I don't feel strongly about the design either way, but I don't think ME necessarily makes cross-over designs wrong.

I think we are in agreement that the residual/longer term measures are needed - ie 1yr on. And that the 6mnths on from treatment is the black box. ie 'condition 4' is the most interesting of those listed below

I was under the impression in this instance placebo ergo double-blinded would be made hard by the side-effect/dosing issues for LDN. But we need a control. And objective measures in that context are vital.

It's just that condition 3 below only adds benefit if blinding to control for placebo possible/as a placebo? , and without that then if we are looking at how we could interpret the possibilities

But it still leaves questions/interpretation in a way having 3 straight groups of 1yr control, 1yr treatment, 6mnths treatment--> 6mnths control might elucidate more? With measures at start and finish of each 6mnths for all groups.

But then I guess any 'placebo' might be the other way in as far as one group stops treatment half-way through (which they would anyway) but at least we'd have the 'staying on/off the drug' graph to compare it to?

I can see why it gets really hard if you have things like abifily where people have to take breaks vs something that 'might fix upstream before work downstream or vice versa' ergo take time for real effect to work vs 'stimulant category' type treatment that focus on helping get thru fatigue and crashes short-medium but don't treat underlying issue.

My brain is hurting from trying to work out the possibilities, so I might have got it wrong below?


Maybe - if we are working on blinding/placebo (trial effect) being impossible and ergo focusing on objective measures, then switching to: control for 1yr, treatment for 1yr, treatment 6mnths-->no treatment 6mnths. Basically taking all the measures at 6months of below but swapping out the control--> treatment for

I'm trying to 'game out' the possibility of if say 80% of patients were 'performing' 20% higher on treatment you'd have measures of:

1. placebo/control 6mnths - no difference

2. treatment 6mnths - 20% more activity more activity between start and finish

3. treatment (after placebo/control) 6mnths - 20% more activity between start and finish

4. 6months on from stopping treatment/placebo 6mnths after treatment 6mnths: which to me isn't the same as placebo in the context of ME/CFS. Because it is 'after having: both had treatment for 6months and done 20% more activity for 6months' + 'stopping treatment'


The bit I'd be most interested in is that last group 4 - to be reassured it isn't like many other treatments which make you think it is helping because it allows you to 'perform' by pushing your boundaries more for a while. But people might be tempted to look at 'treatment arms' and their start-finish differences.

But does that group 4 - if people crash and is the least active group - tell us that stopping treatment doesn't work, or that the treatment leads to a crash around 6months, 7mnths, 8mnths?

Or as Jonathan mentioned - if it's a drug that works, but the benefits are more obvious over time for various reasons that might be possible with ME - then that is the most active 6months?

Or - if somewhere in-between half-life/effectiveness-wise - shows a decline in activity from start - finish, or some sort of bobbling pattern


Group 3 exists because it allows for double-blinding where this is possible.

 

[TigerLilea]

It should not be up to patients to work out what works - clinicians who prescribe these drugs, and especially drugs with significant side effects like Abilify, are irresponsible if they don't do what they can to get well-designed clinical trials underway.

We could be waiting forever if we wait for "well-designed clinical trials". I've had ME for 32 years now and I'm still waiting.

 

[Sid]

Tried it a long time ago, back when it was all the rage. It’s hard to recall the specifics. Some mild initial improvement in ME symptoms but it was coupled with worsening of sleep disturbance and gastroparesis so I had discontinue it.

 

[Hutan]

We could be waiting forever if we wait for "well-designed clinical trials". I've had ME for 32 years now and I'm still waiting.

I agree, I'm not criticising people with ME/CFS who try things. Trying things is an expression of our desire to get better, our 'fighting spirit', if you like. But I do think that part of that fight to get well can be applying pressure to clinicians who have been prescribing drugs/therapies for decades, without properly considering the existing evidence, and without pushing for those well-designed trials.