Hypothetical mechanisms for efficacy of Low Dose Naltrexone?

[Snow Leopard]

Hi,

I am curious as to whether anyone has some developed hypotheses as to the mechanism of 'low-dose' Naltrexone?

Much of the discourse about Naltrexone is dominated by discussion of it being a competitive inhibitor of the function of of mu-opioid receptors.

But it is known that at lower doses the target is actually filamin A which is a Actin-binding protein that anchors transmembrane proteins (specifically G-protein coupled receptors, integrins and ion channels) to the cytoskeleton. It is fairly ubiquitously expressed in many different cell types.

This means it can play role in alteration (antagonism) of diverse extraceullular signals, from mechano transduction to other G-protein coupled receptor signals, including leading to structural reorganisation of mitochondria (such as mitochondrial fission).

Hence it's effects may be quite non-specific, with a broad desensitisation of receptors in certain tissue (and possibly compensationary upregulation of those receptors in certain cells as a result). Which also means a broader range of side effects, if the dosage is high enough to stimulate them.

 

[Creekside]

It's hard to hypothesize a mechanism when the effects vary so much. For me, it worked wonderfully for blocking pain, but had no other noticeable effects. Other people have completely different responses (brainfog, sleep, etc). There could be a number of different mechanisms, working on some people and not others.

If it is the filamin A pathway, that's probably too ubiquitous to be of much help in figuring out how it's affecting which symptom(s).

 

[ah86445]

Im debating on if I should make a stand alone post because this is an older thread but your question is relevant to mine. With my question basically being;

What if the general hypothesis for LDN making ~some few~ people worse??

I have read up where I can, but I am limited by energy and just general capacity to understand science. What I generally understand is
- LDN results vary greatly
- used across a huge variety of disorders
- fillers can cause adverse effects
- side effects can occur sometimes for the first few weeks but subside
- side effects can be mitigated by reducing dose to ULDN etc
- there is no real way of knowing how you might react personally
- severity of ME/CFS isn’t a predictor of LDN reaction
- everyone’s optimal dose is different

anyway, now I’ve covered the basics of what I understand about LDN use, I was wondering if there is any hypothesis on why some people are just really unable to handle it, as in, side effects don’t subside and baseline worsens even at tiny doses below 0.5mg.

For my question, I am mostly going to toss aside the common culprits like dose being too high, increasing too fast, comorbid conditions/ medications, and filler reactions.

Like I said earlier, i’m not science inclined in the slightest so maybe i’ll never know but I have been trialing LDN for 6 months ish. I have not been tolerating LDN which is fine, it happens. But when i’ve tried searching to see maybe why this occurs, there is no explanations (yet) or maybe they are just buried under the LDN making me worse posts lol.

I mostly ask because I didn’t expect to be sensitive to LDN, which yanno, I shouldn’t assume. But my doctors landed on ME through elimination so I assume I have that, for about 7 ish years now. I am mild ME, and I don’t have any comorbid conditions. I have no allergies, no intolerances to any food, no obvious immune issues, no inflammation on my bloods etc. I have never noticed any adverse reactions to medications before so this was a surprise.

I’m stuck at 0.25mg, and any increase makes me feel like I have PEM and extra crushing fatigue. Even if I push through the discomfort, pace and aggressively rest in bed for a few weeks, the worsening doesn’t subside so I drop back to my safe 0.25mg.

It’s weird, and I assume there is an underlying mechanism of action happening here but I have no idea what. I also have no idea what theories there are for why others with their own unique circumstances may have adverse reactions to LDN either.

I’d love to hear if you have any theories

 

[Snow Leopard]

I forgot about this thread.

One of the popular hypotheses (of efficacy) is around TLR4 antagonism which putatively can lead to pain sensing nerve densitisation.

I'm not sure why it makes some people worse, it may be the base opioid receptor antagonism

 

[BrightCandle]

Seemed to help my back pain, it reduced the pain in my body. But it didn't make a difference to anything important about the severity of the disease.