Experience with LDN?

ahhh! yes of course

Yes i would agree i was really responding to anecdotes of people (i read a few but only on this thread so i dont know how common it it) saying it helped their cognitive ability but nothing else.

Mainly because if it helped my cognitive function but nothing else, i think it would reduce my physical activity. Overall. Because i used to LOVE doing challenging sudoku puzzles, & reading things about art/philosophy/theology that are currently beyond me, even at my best, (so the reason i not able to do them isnt about battery draining, but simple inability).

So if it had some effect on my cognitive skills which enabled me to do those things, but didnt raise the overall activity capacity, it would appear on the actometer to have had no change/made me worse. LOL because i'd be just doing that stuff every chance i got instead of physical stuff. That wouldnt be natural fluctuation that would be drug-result-driven change in activity patterns - steps would go hugely downward, but not because it was making me worse overall.

What if that was the case for many/most participants?

Like someone who prefers computer gaming so does no exercise.

 

As has been suggested in other threads, what about the measurement of time spent upright versus horizontal?

 

Something as simple as that might be brilliant. A barely noticeable locket on a fine gold chain (that looked good if it showed) and just monitored how far away from the ground it was?

 

That would certainly have shown positive results for my trial of LDN. I went from occasional trudges (limited by pain) to multi-hour daily hikes. I did a lot of hiking the winter I first tried it. However, I'm one for whom LDN blocked pain, without any other noticeable effects.

I'm not sure what the point of the experiment would be though. I doubt that it will show that LDN at a certain dosage will benefit the majority of PWME; the dosage and effects vary too much between individuals. At best, I think it would allow more PWME to get prescriptions for it for self-experimentation.

 

Lots of evidence. Many of the Doctors who wrote the global consensus “2” use it. Dr Afrin, Dr Theoharides. Dr Deering who is a UK specialist is using it. He likes it very much.

Dr Leonard Weinstock uses LDN with his patients. He makes quite a few you tubes and appears most years at the LDN conferences. He’s a gastro so I guess that is how he got involved with MCAS. He has some case reports I will post further down. But mostly we have a lost of MCAS patients joining the group now.


“People know it as LDN. For some reason, I’ve seen it actually work. I don’t know why. It’s counterintuitive, because when we do skin test, morphine is a positive control, because you will cause mast cells to degranulate. Unless these patients have endorphins or enkephalins, something stimulating them, it doesn’t make sense that naltrexone will work, but it seems to do so. I’ll give it at least a month or so if nothing works.”
https://www.drkarafitzgerald.com/2018/11/20/mast-cell-clinical-researcher-dr-theoharides/

The Hoffman centre uses it. They’re a big supporter of LDN - https://hoffmancentre.com/natural-treatments-for-mcas/

“Can LDN help with Mast Cell Activation Syndrome (MCAS)?

This is Dr Weinstock, the question was; “Can LDN help Mast Cell Activation Syndrome” (MCAS)?

I treat many patients with Mast Cell Activation Syndrome, or MCAS, and a group of us study MCAS online with 160 physicians and the overwhelming number of us find that there is benefit for these patients because it’s commonly overlapping syndromes which are basically part and parcel of MCAS that often respond; such as Fibromyalgia like Syndrome symptoms, or Chronic Fatigue Syndrome like symptoms, or even Irritable Bowel Syndrome. So I actually looked at my ability to treat Mast Cell Activation Syndrome in 116 patients and 60% said that they had actually felt improvements in a variety of parts of their body and 20% had no impact and another 20% had to stop the medication because they were having side effects from it. Mast Cell Activation Syndrome patients often have symptoms related to intolerance to medications, so that’s not a big surprise.

So were did people find improvements? Well in the 70 patients of the 116 patients who found improvement there was a wide array of things; so when you think about the head down to the feet – depression, brain fog, anxiety, nausea, insomnia were improved. In 4, 3, 2, 2 patients respectively fatigue was improved in 11 patients, headache 4 patients, dizziness 1 and Autism 1 patient.

Abdominal pain was improved in 15 of the 70 patients, hives were improved in 2, rash improved in 2 and itch improved in 2. Just reducing Mast Cell Activation flares were improved in 4 patients. Allergies in 1, difficulty breathing in 1. Gastrointestinal symptoms also improved in the area of diarrhoea in 6, constipation in 5, bloating in 4 and stabilising the weight in 2. Restless Leg Syndrome improved in 5 of the 70 patients and joint pain improved in 11, patients muscle pain improved in 9, nerve pain improved in 2 and then finally when we get down to the feet; oedema improved in 1 and an inflammatory condition called erythromelalgia improved in 1. And that actually is reported in a recent publication.


So can LDN work for MCAS? Absolutely. And how does it work? Well, it’s thought that T-cell microparticles activate mast cells and we do know that LDN will reduce excessive T-cell dysfunction. There may be opioid nerve receptors on the mast cell, although that’s not clear. So you you can see that there’s another way for LDN to help MCAS.”
https://ldnresearchtrust.org/can-ldn-help-mast-cell-activation-syndrome-mcas

A combination here - Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment
https://casereports.bmj.com/content/2018/bcr-2017-221405

Erythromelalgia in a Patient with Mast Cell Activation Syndrome: Response to Low Dose Naltrexone
https://www.jofskin.org/index.php/skin/article/view/722/pdf

 

Sorry, not sure what you mean by that?

 

Top symptoms that are improved with LDN according to 1979 votes are;

Pain
Fatigue
Brain fog
Sleep
Immunity
Reduces PEM
Better Mood.

 

Re: anectodal attributing an improvement to a new pill, etc.

My story:

I woke up this morning with a nearly refreshed sleep feeling and the increase of upper body muscle pain of FM over the past two days, rather excruciating, was gone. To what do I attribute this improvement?

I had a big increase in FM muscle pain over the past 1-2 days from lifting and carrying a small box of groceries, and also vacuuming and moving something heavy.

Yesterday, pain had subsided a tiny bit but was till way above baseline. A friend had given me some (CBD, THC) gummies.
I ate one. An hour later my head felt heavy, I was talking out loud to myself without realizing it. No effect on pain.
Took my usual muscle relaxant (tizanidine) which does work on pain.

I have also been taking trazodone at double my previous dose for about a week (now at 50mg). I am sleeping without waking up as much; there may be residual am neurotransmitter activity more than at 25mg.

Yesterday i had a long conversation with a young neighbor/friend. I talked a lot (as though I hadn't talked to anyone in three years during the pandemic and also being older, have a huge stash of memories). She is a huge listener.

The sun came out today and I knew it was going to come out. We have a weather emergency due to the atmospheric river and so the sun coming out made me happy this morning. We have had rain and storms on/off since end of December.

What did I attribute my improvement to?

the gummy bear that did nothing for my pain.

This attribution is irrational. There is no way of knowing. Probably beneficial (untroubled) social contact was a prime factor.
Increase in trazodone dose. Sun coming out. Some other factor or combination of factors. Not just one is my point.

 

How are you in three months time?

 

This is not about LDN; I took a gummy bear of CBD/THC for the first time in years. I have never taken LDN. This is about attribution of improvement due to ingestion of a substance, a med for instance.

I have FM for 27 years now, and not ME/CFS by Institute of Medicine diagnostic criteria (I don't have orthostatic hypotension or cognitive dysfunction severely (ie more than half the time).

I wanted to add that my FM pain came back after I wrote the post along with the weather clouding up.

So, in my humble opinion, or at least for me, my mood (I would term how I feel as a form of mood) is like the weather (depending where on the planet you live).

For me, I could devise my personal objective outcome measures of improvement. (This would be leaving the house every day, driving to a trail for a walk, talking in person to someone for two hours without PEM, or flare up. Being able to do cognitive tasks after 2pm).

So, stratification of research subjects by levels of impairment and perhaps symptomatology for objective outcome of improvement is key.

Again, the fallacy of post hoc ergo...."after this therefore because of this" does not prove causality.

 

I am aware this wasn’t about LDN.

My ESR rate has significantly declined. This is true of others.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
https://link.springer.com/article/10.1007/s10067-014-2517-2

Association with general markers of inflammation
As clinical research of LDN is still in its infancy, we do not have studies in humans that parallel the work performed in animal models. However, some indirect evidence supports the concept of LDN as a novel anti-inflammatory. In the initial pilot study of LDN in fibromyalgia [15], baseline erythrocyte sedimentation rate (ESR) was a significant predictor of clinical response to LDN. ESR is a commonly employed clinical test that is sensitive to both chronic and acute inflammatory processes [33]. In our study, individuals with greater ESR at baseline experienced a greater drop in pain when taking LDN, despite that fact that FM is not considered to be a classic inflammatory disorder, and ESR values were in the normal to high-normal range.

We have now collected more data on the relationship between baseline ESR and LDN (38 individuals with fibromyalgia in total). Aggregating across studies (Fig. 2), we see that fibromyalgia patients with greater ESR levels at baseline tend to have greater pain reduction when taking LDN (left pane; r = 0.58, p = 0.0001). In contrast, there is no association between baseline ESR and pain reduction during placebo administration (right pane; r = 0.06, p = 0.744). Each participant received both LDN and placebo in a blinded fashion. The difference in correlations is significant (z = 2.52, p = 0.012), suggesting that the clinical effect of LDN may be physiologically associated with the reduction of inflammation. Unfortunately, as we collected ESR only as a screening blood test (to exclude major inflammatory disease), we did not measure ESR at the end of the LDN condition and therefore cannot determine if LDN responders had a significant decrease in their ESR.


Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489802/

3.2. Main Results
In our primary analyses, we found the following inflammatory plasma markers to be significantly reduced at Drug compared to BL: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, IFN-α, TGF-α, TGF-β, TNF-α, and G-CSF (Table 2). The concentrations of these cytokines are presented, for each two-week block, in Figure 1. In addition, as a demonstration of individual cytokine levels over the study period, we present each individual’s TNF-α concentrations for the entire study period in Figure 2. We also found a significant reduction of FM-associated pain (15%), and overall symptoms (18%) at Drug compared to BL.

4. Discussion
The goal of this study was to test if LDN administration is associated with reduced markers of inflammation in FM. We found that, after eight weeks of LDN administration, plasma levels of a range of broadly pro-inflammatory cytokines were decreased. In addition, we found that participants reported less pain and symptoms following LDN. Combined, these results support the hypothesis that LDN may help chronic pain conditions, such as fibromyalgia, by acting as an atypical anti-inflammatory medication.

FM is not a classical inflammatory or immune-mediated condition, but the immune system is thought to be a part of its complex pathophysiology [9,17]. However, existing literature on inflammatory abnormalities in FM was insufficient to allow us to predict which specific cytokines would respond to LDN [18]. Therefore, we examined a large array of cytokines. After correcting for multiple comparisons, we found that the cytokines most suppressed by LDN are known to promote nociception, allodynia, and hyperalgesia, including TNF-α, IL-1β, IL-2, IL-6, IL-15, and IL-17 [19,20].

 

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.

 

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.

 

Think OMF has a wearables expert and for something like this OMF may give (free) advice -
@ME/CFS Skeptic

 

Probably we are thwarting micro-organisms all day long, as that's what our immune system developed for.

So cytokine levels may be meaningless.

Just to add my n=1 re: primary FM. All my rule-out labs for immunologic disorders including lupus (I run a false positive ANA) have been normal.
Sed rate normal. Everything normal except PAIN, etc.

I have absolutely no signs nor symptoms of a systemic rheumatologic disorder, ie, no fevers, rashes, swollen joints.

 

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.