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UK: Low-dose naltrexone as a treatment for chronic fatigue syndrome (2020)

pattismith

Senior Member
Messages
3,926
I don't think anyone has figured out the exact mechanism, but LDN may work for ME/CFS because it:


Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone 01.21
Andrew J.


https://doi.org/10.1016/j.bbr.2020.112896

Abstract

Multiple sclerosis (MS) is associated with burdensome memory impairments and preclinical literature suggests that these impairments are linked to neuroinflammation.

Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats.

Here we extend these findings to first demonstrate that (+)-NTX blocks TLR2 in addition to TLR4. Additionally, we examined in two rat strains whether (+)-NTX could attenuate learning and memory disturbances and associated neuroinflammation using a low-dose experimental autoimmune encephalomyelitis (EAE) model of MS.

EAE is the most commonly used experimental model for the human inflammatory demyelinating disease, MS.

This low-dose model avoided motor impairments that would confound learning and memory measurements.

Fourteen days later, daily subcutaneous (+)-NTX or saline injections began and continued throughout the study.

Contextual and auditory-fear conditioning were conducted at day 21 to assess hippocampal and amygdalar function.

With this low-dose model, EAE impaired long-term, but not short-term, contextual fear memory; both long-term and short-term auditory-cued fear memory were spared.

This was associated with increased mRNA for hippocampal interleukin-1β (IL-1β), TLR2, TLR4, NLRP3, and IL-17 and elevated expression of the microglial marker Iba1 in CA1 and DG regions of the hippocampus, confirming the neuroinflammation observed in higher-dose EAE models.

Importantly, (+)-NTX completely prevented the EAE-induced memory impairments and robustly attenuated the associated proinflammatory effects.

These findings suggest that (+)-NTX may exert therapeutic effects on memory function by dampening the neuroinflammatory response in the hippocampus through blockade of TLR2/TLR4.

This study suggests that TLR2 and TLR4 antagonists may be effective at treating MS-related memory deficits.
 

Hip

Senior Member
Messages
17,785
the non-opioid TLR2/TLR4 antagonist (+)-naltrexone

That study stating naltrexone blocks TLR2 and TLR4 is referring to normal dose naltrexone.

When you look at the low-dose naltrexone (LDN) literature, they seem to talk more about LDN blocking TLR4 than TLR2.

So maybe the effect of LDN on TLR2 is negligible or not as important as its effect on TLR4.
 
Messages
246
@Wishful yep must thoughts also. I remember trying it for ages though. I'm sure it was over a month. Like you I thought it would be great for t cells.

To be honest I got more out of taking Andrographis. Or other traditional herbs combined together like lomatium, isatis, houtouynia, skullcap, redroot, milk thistle and dandelion. But I'm looking for a long term solution now. Currently high dose thiamine and hopefully ldn will do the trick. Plus it will work out cheaper than andrographis.

Have you looked into gumweed leaf, osha root, and desert parsley root? Your response to andrographis is interesting since that is also a first-line treatment in the buhner protocol against lyme disease.
 

godlovesatrier

Senior Member
Messages
2,491
Location
United Kingdom
It's no longer a first line treatment, he actually removed it from the protocol. He found that knotweed was first line and andro was pretty much a second in line thing. Besides much like cranial cervical instability can exist in ME patients but not be the root cause of the disease, I'm afraid lyme disease bacteria can likely exist in a persons body but not be the root cause of there issues either. At any rate my lyme disease tests from armin labs were highly inconclusive, as the more sensitive tests came back negative across the board. Also the armin lab tests are useless as they don't indicate past infection, or whether the infection is active, they just show you that your immune system once had an interaction with lyme bacteria. That could have been over within a few months through a naturally mediated immune response.

Andrographis is also a calcium channel and h2 blocker.

Lots of patients seem to do well or go into remission taking calcium channel blockers like nimodipine. I trialed this one unsuccessfully 2 months ago, but do need to try again with a different brand.

Also there's tagamet a h2 blocker which has gotten many patients feeling loads better within weeks. Dr Goldstein used to use this class of drugs a lot and they've also popped up now as a treatment for long covid. This stuff is contradicted in men, but it's another potential treatment.

Andro has both these properties, as backed up my various studies, I find that more noteworthy to be honest than any potential anti spirochete activity.
 

pattismith

Senior Member
Messages
3,926
That study stating naltrexone blocks TLR2 and TLR4 is referring to normal dose naltrexone.

When you look at the low-dose naltrexone (LDN) literature, they seem to talk more about LDN blocking TLR4 than TLR2.

So maybe the effect of LDN on TLR2 is negligible or not as important as its effect on TLR4.

anyway, blocking TLR4 may not be enough for most ME/CFS patients.
Virus activate TLR7 and TLR9, so I think most of us need TLR7 and TLR9 blockers.

Here some herbs and antibiotics that had shown some efficiency at blocking TLR7 in animal Psoriasis models

Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation | Phoenix Rising ME/CFS Forums

;;;;
 

godlovesatrier

Senior Member
Messages
2,491
Location
United Kingdom
by knotweed, your refering to japanese knotweed?

why do you think a different brand of nimodipine would give you different results?

Yes japanese knotweed. This stuff is meant to be highly toxic to spirochetes, but it just gave me abdominal cramps and diherrea. Even so I took it for 2-3 months as the scientific evidence convinced me.

I made the stupid mistake of cutting up enteric coated tablets, I read online you are never meant to do this because the drug is enteric coated because it doesn't react well with stomach acid. It might explain some of my shockingly bad side effects, 1. Extreme hunger at night and a little bit in the day 2. Insomnia 3. very bad sore throat. Other than that I felt some benefit initially. It's not water soluable so you can't just dilute it and take it like you can with LDN.
So that's why a new experiment with non enteric coated would be a good idea I reckon! Knowing me I'll just react the same way :rofl:
 

nerd

Senior Member
Messages
863
I would be very cautious with the interpretation of TLR measurements in studies and how they deduce TLR regulation. TLR activation is a complex topic for the pathophysiology of pathogens because they all use different ways to manipulate receptors for their needs. However, I tend to believe that a normalization of receptor activation is always preferable while the innate immune system allows for a more subtle and differentiated intervention in viral mechanisms. This is also the case for TLR-induced pathways.

I wish there was a simple answer to the TLR-MyD88-NFkB topic, but it's one of the most confusing areas I found for the role of antiviral vs. proviral potency. Especially in the context of repurposed and novel antivirals for the use in CFS/ME treatment, this makes me unconfident that, while treating one viral infection, we might not be opening the doors for another virus family.

That study stating naltrexone blocks TLR2 and TLR4 is referring to normal dose naltrexone.

When you look at the low-dose naltrexone (LDN) literature, they seem to talk more about LDN blocking TLR4 than TLR2.

This might be due to the same reason as I mentioned in the Dextro-Naltrexone post.

Chronic Fatigue Syndrome: Naltrexone as an Alternative Treatment

From their discussion:
The concept of having a paradoxical hyperalgesia effect produced at significantly reduced doses of medications has been demonstrated before. The most notable example is that of morphine. The hyperalgesia effect can be seen at roughly one-tenth of the dose than that would typically produce reduced pain. This suggests that there is a small window at which opioid analgesics produce the opposite effects than those typically expected.12 Therefore, this same principle may explain the effects as seen with the hyperalgesia nature of greatly reduced doses of naltrexone.

This means studies on LDN and Regular Dose Naltrexone (RDN) need to be differentiated and not every RDN study is translatable for LDN treatment.
 

godlovesatrier

Senior Member
Messages
2,491
Location
United Kingdom
Hmm you raise an interesting point here. I have been a bit baffled as to why I seem to get bacterial infections whenever I feel better on certain treatments. I do think it can weaken certain other areas of immune response.

Maybe not surprising when you augment one area and the others don't work so well..

LDN is next to try on my list, but currently still on the herpes veridai protocol.
 

nerd

Senior Member
Messages
863
Hmm you raise an interesting point here. I have been a bit baffled as to why I seem to get bacterial infections whenever I feel better on certain treatments. I do think it can weaken certain other areas of immune response.

It basically comes down to the key question of genetics and the original antigenic sin. The priming of the innate system isn't really a learning process, but rather an adaption to pathogens. And in this adaption process, only the cell survival counts, but not the survival of the whole organism in the long term, or even quality of life. Pathogens and some vaccines "program" the innate immune system and it's a controversial debate in the scientific realm if this is really helping or if it makes immune function worse when faced with pathogens that are unfamiliar to the immune system.
 

Pyrrhus

Senior Member
Messages
4,172
Location
U.S., Earth
That study stating naltrexone blocks TLR2 and TLR4 is referring to normal dose naltrexone.

When you look at the low-dose naltrexone (LDN) literature, they seem to talk more about LDN blocking TLR4 than TLR2.

I would be a little concerned about anything that blocked any intracellular TLR receptor.

Intracellular TLR receptors are essential for the intracellular branch of the immune system, and they are only activated if there is an intracellular threat.

Pathogens and some vaccines "program" the innate immune system and it's a controversial debate in the scientific realm if this is really helping or if it makes immune function worse when faced with pathogens that are unfamiliar to the immune system.

I think you may mean the adaptive immune response, not the innate immune response here...
 

pattismith

Senior Member
Messages
3,926

Ok, something in this article is difficult to understand:

At a much lower dosage of 3.0 mg to 4.5 mg per day, it is the non-opioid antagonist path that is more active, which is believed to exert the anti-inflammatory and hyperalgesia effects.2 In this path, naltrexone simultaneously has an antagonist effect on non-opioid receptors, including toll-like receptor 4 (TLR 4), that are found on macrophages such as microglia.

.....

Dextro-naltrexone has been shown to have no activity on opioid receptors but is active on microglia receptors.5 The analgesic, anti-inflammatory, and neuroprotective effects of naltrexone do not appear to be dependent on opioid receptors as dextro-naltrexone has analgesic effects.6


So LDN causes hyperalgesia by blocking non-opioid receptors.....and D-Naltrexone causes analgesia from non-opioid action....

This is not logical at all....What is logical is that LDN still have residual anti-opioid action which produces his hyperalgesic action.
 

nerd

Senior Member
Messages
863
So LDN causes hyperalgesia by blocking non-opioid receptors.....and D-Naltrexone causes analgesia from non-opioid action....

This is the inconsistency they point out, from the findings of a study showing that DN doesn't have opioid receptor affinity but analgesic effects (10.1016/j.jpain.2012.02.005). Maybe LDN has these effects for other reasons as well, maybe not, maybe both. But in the case of DN, it could be due to the inhibition of TLR4 (10.1155/2016/5238730).
 

pattismith

Senior Member
Messages
3,926
I don't think hyperalgesia with Naltrexone is a matter of dose,
Pain is a common recognized side effect of the drug (at normal dose), so it's likely to be the effect of blocking opioid receptors (thus blocking endorphin action)....
 

pattismith

Senior Member
Messages
3,926
I would be a little concerned about anything that blocked any intracellular TLR receptor.

Intracellular TLR receptors are essential for the intracellular branch of the immune system, and they are only activated if there is an intracellular threat.

I understand your concern about inhibiting TLR7/9, but these TLR may be over activated by endogenous intracellular ligands that may be detrimental to some of us, or they could be over expressed by some unknown mechanism.
So I tried to combine low dose Naltrexone + low dose propentofylline + low dose methylprednisolone + low dose azithromycin....

And after a few days, what you predicted actually happened :D:
I had a cold sore showing up, which is what always happens to me when my immune system is depleted...

My MBL deficiency probably doesn't help!

I think I may try to change something in my cocktail ...
 
Messages
52
@pattismith Naloxone pulls me out of PEM. I believe PEM is an inflammatory reaction in response to neuronal damage. Commonly, the damage is due to insufficient blood flow to the head for a certain metabolic load in the brain.

Inflammation is good during periods of time when injury is at its highest. Keeping it high all the time reduces healing when it's needed.

Endorphins are released by neuronal injury and shut down neurons. Traumatic head injuries also release endorphins and cause brain fog. The solution is to prevent neuronal injury and stimulate healing. Endorphins are just an emergency reaction. There are various things that help neurons recover.