Low dose Naltrexone - How might it work biologically in ME/CFS?

LDN Tlr4 inhibition explanation

If LDN works via inhibit glia tlr4, does that mean tlr4 is being activated in the first place? So what was activating?
Or can inhibiting tlr4 inhibit the common pathways of other signals? For example il1.
Tldr, if glia is activated by il1, can inhibit tlr4 inhibit activation still

My guess is something about a common pathway called toll interleukin receptor

 

Yea nah I misunderstood. Inhibiting tlr4 means just that, if LDN works by this, then that's what it's doing something is activating TLR4, damps or pamps

 

Merged thread

TAK242, resatorvid, a tlr4 antagonist

Is a non competitive tlr4 antagonist. LDN slows my pem down by a factor of 10, if its working via tlr4 inhibition I assume its because agonist conc is still going up. But tak242 is no competitive, meaning even if agonist goes up blocking remains. Solution to pem? If LDN works for you and its neuroinflammation. Only thing is unclear if tak242 crosses bbb

 

There are a lot of hits for TAK-242, including this one https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-020-2097-2

I haven't got the brainpower to read it at the moment.

 

For others like me who lack the background biochemistry:

See https://www.frontiersin.org/articles/10.3389/fimmu.2020.00807/full

For more information see https://www.nature.com/articles/nrd3203

See https://pubmed.ncbi.nlm.nih.gov/20881006/

see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700752/

 

https://www.takeda.com/what-we-do/access-to-medicines/pre-approval-access

Either can get through this, or buy from dodgy research only supplier. Hmm

Woah hold on there are a lot of tlr4 antagonists. Amitriptyline and thalidomide apparently are tlr4 inhibitors!
Oh my god there are a lot of tlr4 antagonists, somebody should comb through the literature. Which ones cross the BBB and which ones are non competitive I wonder??

• The lipid A analog eritoran acts as a TLR4 antagonist. As of December 2009, it was being developed as a drug against severe sepsis.[62] However, in 2013, a news story said the results against sepsis were somewhat disappointing and that it was better used to treat certain cases of severe influenza. Although it does not treat the virus itself, it could be used against the massive immune reaction called cytokine storm which often occurs later in the infection and is a major cause of mortality from severe influenza.[63]

• Amitriptyline[56]
• Cyclobenzaprine[56]
• Ketotifen[56]
• Imipramine[56]
• Mianserin[56]
• Ibudilast[64]
• Pinocembrin[65]
• Resatorvid[66]
• M62812
• Naloxone[55]
• (+)-Naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)[49]
• Naltrexone[55]
• (+)-Naltrexone[55]
• LPS-RS[55]
• Propentofylline[citation needed]
• Pentoxifylline[67] (and downregulate TLR4 expression[68])
• Tapentadol (mixed agonist/antagonist)
• TLR4-IN-C34[69]
• Palmitoylethanolamide[70]
• Resveratrol
• Lithium
• Oxymatrine
• Minocycline
• Doxycycline
• Erythromycin
• Sulforaphane
• NI101
• CRX-526
• Avorstatin
• Aspirin?
• Curcumin?
• Artimesinin
• Carvedilol
• Ferulic acid
• Ursolic acid
• Pentamidine
• There are definitely more than this I've seen a few more antibiotics can't remember what they were. Some of these are not antagonists but regulators? Idk
• Levo naltrexone is a tlr4 antagonist too

 

Merged thread

Is low dose naltrexone effective in ME/CFS due to an effect on the vascular system?

https://www.ccjm.org/content/ccjom/48/2/283.full.pdf

My understanding is that naloxone and naltrexone are very similar in their effects.

Also at the time of writing this it hasn't yet been confirmed that low dose naltrexone is actually effective for ME/CFS but it sounds like it might be for a subset of patients.

Maybe there is a vicious circle with exertion being stressful for the body for some reason, which leads to release of opiods which worsen orthostatic symptoms and cause even more stress?

 

Hmmm on this note, researchers were trialling tlr4 antagonists for sepsis. They failed though bc there were other pathways

 

Merged thread

Naltrexone TLR9 Antagonist?

https://www.frontiersin.org/articles/10.3389/fimmu.2017.00809/full
This paper says naltrexone has tlr9 antagonism but not tlr4... Contradiction so I haven't seen this paper mentioned anywhere in regards to ldn, so ig it was wrong? Or...

'we hypothesized that naltrexone may affect the MyD88-dependent signaling pathway and that any effects of naltrexone on IL-6 secretion via TLR4 were compensated for by signaling through the MyD88-independent pathway.'

If I get this right then LDN has these properties, tlr7, tlr8, tlr9, tlr4 antagonism,
Nox inhibition, and opioid antagonism

 

We need a foundation like this. https://www.google.com/url?sa=t&sou...MQFnoECCcQAQ&usg=AOvVaw2z-WT9GLfZ01LIuttzZpHj
Alz drug discovery. Though we're still looking for the cause... So that's a long way way

 

When they LDN has properties different to Naltrexone, due to dosage, do they mean chemical/biological properties or do they mean different drug effects? Eg dextro-naltrexone only seems to have TLR4, 7,8,9? activity and maybe NOX? activity, does that mean at a higher dose it doesn't? And instead does something else? I think I've misunderstood LDN this whole time, that there's a bell curve for responding to this drug. I think for some people regular dose naltrexone may be helpful?

Originally LDN was discovered by chronic pain patients on naltrexone right? As they were tapering off. I imagine they felt better due to the endorphin rebound effect. And thus, a low dose is necessary if youre using the rebound effect because... At a high dose its completely blocked and not working no more.

But for the TLR effect, why would a low dose be necessary?? In fact a higher dose would be better. But preferably only using dextro naltrexone. Initially I thought that the tlr effect was dose dependant too, as I saw in a study. But I misunderstood. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395119/#!po=23.5577
Higher doses make cell viability go down I'm not sure why or what that means, but higher doses were more effective in inhibition.

So in essence, LDN may be beneficial if I understand correctly even with out the low dose.

Case in point my experience with fibro PEM the first time I took it, I was intesley keen on the idea of it only working at a low dose, I was afraid that even though it was slowing down my pem I was afraid when I stopped it the pem would still be there and I'd ended up going over my limits. No when I stopped LDN so long as I paced while still on it, I returned to baseline, I stopped it because it seemed to make it harder to pace though. When I was taking it at first I took it at night, and the next day I'd have slower pem, but then at some point I tried day time and I realised that the effects were immediate, and that 4 hours later there'd be another effect, doesn't reduce my symptoms by much but slows down pem. And then I had a severe relapse thanks to something in weed, directly making my symptoms worse but also because it had a pain killing effect and masked my symptoms so I couldn't pace. I had seen some people say they dosed twice a day but I was still worried about only the low dose working, but I was so severe because I couldn't sleep too, can't do anything but lie down all day and thus can't sleep at night without sleeping pills, which also was indirectly the cause of all this in the first place, I had developed tolerance to zopiclone and needed an alternative so I tried weed. But so there I was unable to sleep and unable to do anything so I started dosing more. Twice a day? It still worked. Every 6 hours I wait for the rebound and dose again when I'm desperate. And within the hour of every dose my symptoms reduce a little bit.

The most I've dosed is 4x in a day, every 4 hours. I am gonna try perhaps dosing it all in one go to see if it's still beneficial, but I'd end up losing the rebound effect I think. And the concentration will go down over the 4 hours is it? So I'd end up maybe needing another dose...

Perhaps also worth saying my therapeutic range started at 1.5,maybe it was lower though bc I only took that at night so ig the next day rebound effect happened. Perhaps even lower may be immediately therapeautic, but I just didn't notice because I took it at night and my pem wasn't so bad at the time. But my therapeautic dose at 6.5 also had an immediate benefit and rebound later. Thus I started dosing at 4.5 as my regular dose because I thought okay so if you increase the dose it gets less effective. I could not distinguish the effects of 1.5mg, 4.5 or 6.5mg though, but I could.

Anyway I know this is s4me, not s4fibropem not everybody will find LDN useful but maybe somebody who responds to ldn may find this useful someday.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634939/ 75x more powerful than dextro naltrexone tlr4 antagonist, based on naltrexone

Why would naltrexone reduce cell viability? Why would it be cytotoxic?

polymyxin b tlr4. Another tlr4 antagonist

 

Does anybody understand how Naltrexone inhibits TLR4? If I get this right, naltrexone competitively binds for md2, a protein needed by lps to dimerise whatever that means, but naltrexone only inhibits in a biased fashion, the trif pathway. The other pathway is the myd88 pathway. So naltrexone isn't particularly good at blocking tlr4 then, because the other pathway can compensate? Does this mean even if lps binds to tlr4 via the md2 complex or whatever and naltrexone is inhibiting it, lps can still activate MyD88 pathway. Or does naltrexone prevent dimersiation?

There is no Wikipedia to answer my questions, seems the knowledge is only available in the scientific literature and the scientists themselves, maybe chatgpt but I don't think so. Yea chatgpt gives me bollocks

And why do researchers think TLR 4 and not other TLRs in particular? Because Naltrexone also inhibits Tlr2, 7, 8,9 but nobody has ever talked about them. And nobody has seemed to test the other tlrs, tlr1, 3,5 or 6?? I saw that tlr share common structures

Also apparently making tak 242 is easy, which must be why so many commercial companies are selling it to researchers. Thanks chatgpt didn't think it possible

The synthesis of ethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate can be accomplished through several different routes. Here is one possible synthetic route:

Step 1: Synthesis of 2-chloro-4-fluoroaniline
2-chloro-4-fluoronitrobenzene can be reduced using a suitable reducing agent like Fe/HCl or Sn/HCl to yield 2-chloro-4-fluoroaniline.

Step 2: Synthesis of 2-chloro-4-fluorobenzenesulfonyl chloride
2-chloro-4-fluorobenzenesulfonic acid can be converted to its corresponding sulfonyl chloride using thionyl chloride (SOCl2).

Step 3: Synthesis of ethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate
In a separate reaction vessel, cyclohexene-1-carboxylic acid is reacted with ethyl diazoacetate in the presence of a copper catalyst to yield ethyl cyclohex-2-enecarboxylate. The resulting ester is then treated with sodium hydride (NaH) and 2-chloro-4-fluorobenzenesulfonyl chloride to yield the corresponding sulfonamide intermediate. The final step involves the addition of a base (e.g., triethylamine) and the amine intermediate from step 1 (2-chloro-4-fluoroaniline) to yield the desired product, ethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate.

It is worth noting that this is just one possible route for the synthesis of ethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate and other routes may be possible depending on the starting materials available and the desired synthetic pathway. Additionally, synthetic procedures involving hazardous or reactive chemicals should only be attempted by trained and experienced chemists in a properly equipped laboratory with appropriate safety measures in place

 

I'm starting to doubt the TLR4 hypothesis Dr Younger has, since LDN is only a LPS tlr4 antagonist at the md2 site, there are other ways to bind tlr4 without md2. So how would naltrexone be of help there. Unless there are DAMPS that need md2 as well. But naltrexone has other tlr antagonisms so maybe there are others. Edit so at least hmgb1 requires md2 so naltrexone can block that

 

Ah damn I've misunderstood LDN for a long time, I saw that it inhibited tlr4, so I thought it was a competitive antagonist. No it's non competitive and therefore changing the amount of tlr4 agonist won't change the inhibition. So high doses of naltrexone will only help little bc saturation but still help I think, this is reflected in my experience there seems to be a saturation point. Also, so not everything I've listed earlier as a tlr4 antagonist before is an antagonist, some seem to be more like pathway inhibitors

Had another realisation:high dose naltrexone eventually becomes low dose too, unless the endorphin rebound wears out before that. And the tlr inhibition effect should be mutually exclusive with the endorphin rebound effect because when the md2 antagonism disappears so does the opioid receptors antagonism bc of half life

 

Just had another thought, although naltrexone has tlr 7,8,9 antagonism, these are located within the cell, and therefore ligand must be able to cross... Cell membrane...? So unless your ligand is a virus... Hmmm. No nvm, rna DAMPS can cross cell membrane so naltrexone could still be working via tlr 7 8 9 antagonism

 

Naltrexone IC50 for LPS NO at 2microM
Naltrexone IC50 for LPS NO at 100microM

Why the huge discrpency? They used different cell lines?
https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-9-32
https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.13394

Tak242 IC50 FOR X? IS 1 TO 11NM
Naltrexone brain plasma ratio is like 8 to 1
TAK242 Blain plasma ratio is like 1 to 4

 

I was thinking along same lines of looking up Narcan and seeing what it actually does: undoes the effects of opioids not necessarily eg getting rid of the opiods. But the focus seems to be e.g. breathing, it doesn’t work on overdose with eg alcohol or other drugs. And isn't long-lasting ie 30-90 mins to get someone to emergency care. Those people will apparently have a horrific withdrawal because of the sudden stop.

Naltrexone also stated as an opioid antagonist, but: acts of the effects of opiods, alcohol (and maybe others - if that is to be trusted at all and I'm cynical given all the 'expectation effect god complex nonsense that we've seen' and it works for gambling or kleptomania - rather than other 'nudges or bias' that sort of blows out of the water its own claimed reason for effect to me) but this time only the 'high' part. e.g. it can make people more likely to die because their tolerance reduces to opioids when on it for even a short time, but it has no protective effect it seems to 'stopping these harmful effects' that I assume are what Narcan 'blocks short term'.

And as a longer-term medication interestingly does nothing for withdrawal and doesn't stop intoxication from occuring or withdrawal. Which puzzles me given I spent my youth watching soap-operas that taught me people ended up unable to get off heroin because the withdrawal was so horrendous (and end up taking it to get away from that). But you can see the political/ideological here.

Now that's actually quite a significant difference, even if they both are in the same 'class' even for their primary purpose. And apparently blocking activity (sceptical me has read the claims of this being seen on scans but until I've read the detail of it I'm still thinking about the 'antidepressants change the chemicals in your brain' bla) needs doses of 50-100mg to get near blocking most of the various receptors that are claimed to matter for these purposes.

Yes there are then claims of different doses acting on different things in the brain but I can't see how these could be seen or proven beyond guesses and so why it couldn't be something in another part of the body given blood-brain barrier and so on.

I found the following and done no more search so assuming there are more in other ‘lateral’ areas (to the usual assumptions) but could be wrong:
De Marinis L, Mancini A, De Luca AM, Fiumara C, Zuppi P, Sammartano L, Valle D. Naloxone effects on post-prandial glucose, insulin and C-peptide levels in obese subjects. Diabetes Res. 1993;23(2):83-91. PMID: 7712683.

in this instance it affects metabolism which also could be relevant in the area of ME/CFS just as much as the suggested brain or cytokine/immune possibilities.

What I’m not even up with enough is whether for those who do try LDN who is it that it works for and do they get improvements that are consistent’within themselves’ (ie sticks) and any pattern of where/how it improves them ‘across people’.

I say who it works in because of the types, downstream, upstream, interaction with different comorbidities or body types etc. but at least if we saw who it works in most definitively and from their insight in what way and area for them there is a potential work-back to mechanism.

I’m all for the things that definitively do work in only some being looked into as it might give us as many clues as a thing else I can imagine. And is better than trials for something across a heterogeneous group without any drill-down because it gives those ‘exploratory research’ (normally in market research you’d go qual exploratuvely first to inform design of qual to make sure you don’t just ‘lowest common denominator’ something that only works in subgroups’) research design clues.

 

About narcan vs naltrexone I had the same thought, wondering what the difference was. There are 3 opioid receptors, mu kappa beta or something like that, narcan binds strongly to all 3 I was told, while naltrexone strongly binds 2 weakly binds the third

The metabolism study u link states :By these data we can hypothesise a complex regulatory role of opioids in metabolic balance in obesity.
So it's still related to opioids. Also I wanna mention tak242 the drug earlier it's said to be highly selective, with little off target activity but they say there is always off target activity, and due to the presence of some chemical structure it causes methemoglobinemia

Interesting that you bring up naltrexone having other properties elsewhere, I guess there's always a lot going on with any drug isn't there. I didn't look deeply into it but there are links to hgh and fertility too somehow.

Re antidepressants, depression is related to inflammation too somehow, panadol apparently can relieve depression. I am not sure I believe in the lack of neurotransmitter theory for depression, even though I know nothing about it, because if it was true why are we not measuring it to diagnose?