Microglial Inhibition by LDN.

[Jonathan Edwards]

I wonder whether @Jonathan Edwards could comment on whether blocking microglial action could have such a rapid effect, and whether it could reduce immune type symtoms in general?

I don't know much about this but I see no reason why the effect on brain cells should not be within about 20 minutes (less on an empty stomach?) through blocking endorphine receptors. I think paracetamol (tylenol) is supposed to reduce fever by acting on ongoing signalling in hypothalamic cells so why not. I think we may forget that a lot of signals between cells are being packaged, sent and broken down all within a matter of minutes or even less. As soon as you block the constant message sending the effect stops.

But I am very intrigued by the fact that an antagonist seems to make people feel better.

 

[Indigophoton]

I don't know much about this but I see no reason why the effect on brain cells should not be within about 20 minutes (less on an empty stomach?) .... I think we may forget that a lot of signals between cells are being packaged, sent and broken down all within a matter of minutes or even less. As soon as you block the constant message sending the effect stops..

Thanks for replying. I am taking the LDN in liquid form (tabs dissolved in distilled water) and have opted to hold the dose under my tongue until it is mostly all absorbed - doing it this way is supposed to lessen the risk of gastric effects, but I guess it also means the drug could start acting more quickly.

Good point about the signalling timeframe.

I have been looking around the interwebs, and found an interesting observation by Dr Tom Gilhooly, a GP in Glasgow with a lot of interest in LDN, originally in addiction and now in MS. At the 2nd European LDN conference he said the following, based on research by J Younger,

LDN is a “racemic mix” of mirror image right- and left-handed molecules. This is common in chemistry, and most drugs consist of such a natural mix. It is usual for only one of the sides to be biologically active, but in the case of LDN, both sides are active.

The right handed molecule blocks the opiate receptors, which confer the action the drug is licensed for i.e., blocking the action of heroin and other illicit opiates.

The more interesting part regards the left-handed molecule, which acts on the Toll-like 4 receptors on the surface of immune cells and acts as an immune modulator.

Dr Younger studied the effect on microglial cells, a type of immune cell important to the neurological system, which becomes active when the immune system is activated. ... The left-handed Naltrexone binds to these receptors and reduces the inflammatory chemicals that are pouring out of these cells. This idea makes great sense and fits very well with our findings in the clinic. If this is the mode of action, it fits with the hypothesis of Dr Agrawal and others… This is a big discovery…

This would suggest that the opiate-blocking effect of LDN is actually the limiting factor on dose and we should aim to get the highest dose possible that the patient can tolerate, to produce the greatest effect on the immune system.

So it seems he was thinking along the same sort of lines as we are here: increasing the dose of LDN, or taking small doses more often through the day, would block the TLR4 receptors for longer, yielding more benefit.

(If this proved to be as relevant as it seems it may be, then presumably the ideal would be if the isomers could be separated out, resulting in benefit from the TLR4 blocking without the opiate blockade.)

 

[Sushi]

When my LDN prescription ran out a few months ago I thought I see how I felt without it (after about 4 years on it). Within a week I was asking for a new prescription. Without it, sleep was disrupted and I just felt considerably worse.

But I am very intrigued by the fact that an antagonist seems to make people feel better.

I don't think anyone has figured this one out yet as LDN gives benefits to quite a range of illnesses and affects a variety of symptoms. Just by raising the dose or lowering it by a mg or so, I can control certain symptoms, and yes, for some reason I do need to adjust the dose every few months--with the blessing of my doctor!

Sushi

 

[Ninan]

For me LDN worked exactly the same way as Doxycycline and Famvir: Probably modulating my immune system in some way. Great energy for a week or two. Then my body seems to get used to it and the effect wears off. Same thing happens when I meet my parents' cat and become allergic. Maybe LDN would have worked longer if I had pulsed it.

About dosage: I know a patient in Finland who takes 1,5 mgs four times during the day and has great effect.

 

[Jonathan Edwards]

I have been looking around the interwebs, and found an interesting observation by Dr Tom Gilhooly, a GP in Glasgow with a lot of interest in LDN, originally in addiction and now in MS. At the 2nd European LDN conference he said the following, based on research by J Younger,

So it seems he was thinking along the same sort of lines as we are here: increasing the dose of LDN, or taking small doses more often through the day, would block the TLR4 receptors for longer, yielding more benefit.

(If this proved to be as relevant as it seems it may be, then presumably the ideal would be if the isomers could be separated out, resulting in benefit from the TLR4 blocking without the opiate blockade.)

So if they can separate the isomers to do the research, why can't they separate them to put in the pills I wonder? Maybe it would make them ten times more expensive I guess, but you would have thought that some small studies on the pure isomers in people who regularly use LDN with benefit would be worthwhile. Maybe that's what they are doing.

 

[NK17]

So if they can separate the isomers to do the research, why can't they separate them to put in the pills I wonder? Maybe it would make them ten times more expensive I guess, but you would have thought that some small studies on the pure isomers in people who regularly use LDN with benefit would be worthwhile. Maybe that's what they are doing.

From my complete non expert perspective I think that the kind of experiment that you're talking about might not have been undertaken yet because LDN is a generic drug and a pretty cheap one, therefore there are no financial incentives to "study" it more deeply and accurately.

I wouldn't mind to do a web based research on the subject, if it wasn't for my aches and pains and low functioning level in which I have been stagnating recently. I'd greatly appreciate if you could look into this.

I personally hope and think that Dr. Younger at Stanford will be looking and pursuing this line of research that will possibly bring out a practical pharmacological intervention for neuro-inflammation.
Time for my LDN micro dose now

 

[daisybell]

When my LDN prescription ran out a few months ago I thought I see how I felt without it (after about 4 years on it). Within a week I was asking for a new prescription. Without it, sleep was disrupted and I just felt considerably worse.

I don't think anyone has figured this one out yet as LDN gives benefits to quite a range of illnesses and affects a variety of symptoms. Just by raising the dose or lowering it by a mg or so, I can control certain symptoms, and yes, for some reason I do need to adjust the dose every few months--with the blessing of my doctor!

Sushi

Can I ask how much you vary your dose by?
I have been on it for about two months now. After the first week or so, I improved steadily but have been less good recently. That may be my thyroid meds, but if I could tweak my LDN dosage and feel better again, it would be great!

 

[melamine]

The worst has been increased anxiety though. I just feel edgy all the time.

Anxiety is part of my worst symptoms also.

I have been going back and forth as to whether to resume trialing after taking a break for about a week. Yesterday I took about .3mg -.5mg around 11am and started to feel worse - more anxious/excitoxic for several hours after it kicked in. By mid afternoon however, I was feeling more energized enough to start accomplishing a few things after weeks of not. The energy was subtle and motivational, but not a relaxed, comfortable kind - more like slightly wired and driven. I think later in the evening the edge had been wearing off and this morning feels a little more normal. This is the first time I've noticed any good effect from LDN.

I am experimenting (primarily) with small to moderate doses of taurine and with dosing b vitamins as well, and took a small dose of adrenal cortex yesterday morning, so there will be the potential for mistaken identities and synergisms, although I don't believe that's the case this time, and in fact B vitamins have caused me similar undesirable symptoms as the LDN.

Having experienced bad effects lasting for days or longer with both naltrexone and other drugs or supplements, I'm thinking that not taking it every day might be a better way for me to test my tolerance and it's ability to help. I don't plan on taking any today and plan on pulsing it in some manner when (probably) resuming tomorrow. I'm interested in whether it might work as a background, rather sub-clinical therapy.

 

[maddietod]

Anxiety is part of my worst symptoms also.

I have been going back and forth as to whether to resume trialing after taking a break for about a week. Yesterday I took about .3mg -.5mg around 11am and started to feel worse - more anxious/excitoxic for several hours after it kicked in....

I've failed with LDN numerous times, always starting at 0.5mg. I got compounded LDN 5-6 weeks ago and started at 0.1. I increased by 0.1 every 4-5 days, and when I got to 0.4 I got a profound shift in daytime energy and vastly increased mental function. Recently I experimented with a 0.43 dose, and I felt very 'excited,' overly 'happy,' and a little stressed, both days I did this. I'm back at 0.4mg and my gains have remained stable for a month.

It's important to note that my diet has a huge effect on brain fog and memory problems, and I'd started eating right-for-me a month before the LDN.

 

[melamine]

@madietodd - thanks for the input. I have been measuring imprecisely from 1.5mg capsules. You must be dissolving yours in solution? From what you say and what I've been reading elsewhere here, my eyeball measuring method could be one of the problems that will need to addressed to best evaluate LDN's potential.

I have tried various diets, some prescribed, and have invariably found that symptoms worsened or improved on a schedule entirely independent of diet changes, although I am still experimenting, particularly with regard to histamines and fermented (high glutamic acid/high histamine) foods.

 

[maddietod]

@madietodd - thanks for the input. I have been measuring imprecisely from 1.5mg capsules. You must be dissolving yours in solution? From what you say and what I've been reading elsewhere here, my eyeball measuring method could be one of the problems that will need to addressed to best evaluate LDN's potential.

I have tried various diets, some prescribed, and have invariably found that symptoms worsened or improved on a schedule entirely independent of diet changes, although I am still experimenting, particularly with regard to histamines and fermented (high glutamic acid/high histamine) foods.

I got drops from a local compounding pharmacy so I could be sure of the dose...since the whole point of this experiment is precise dose calibration. The naltrexone is mixed with medium chain triglycerides rather than water, so it keeps forever. This is important because at .4mg daily, my 30ml will last over 2 months.

My point about diet was only that I wouldn't have gotten the brain functionality just from LDN. I can easily confound that result with foods that I don't handle well.

 

[Ninan]

I got drops from a local compounding pharmacy so I could be sure of the dose...since the whole point of this experiment is precise dose calibration.

That sounds great. I have 4,5 mg capsules. Can we make our own LDN solutions? It'd be great to know that one drop is 0,1 mgs.

 

[Sushi]

From what you say and what I've been reading elsewhere here, my eyeball measuring method could be one of the problems that will need to addressed to best evaluate LDN's potential.

Yes, I think it is very important to have a precise way of measuring. I use liquid and a syringe.

Can I ask how much you vary your dose by?

About one mg.

I have 4,5 mg capsules. Can we make our own LDN solutions? It'd be great to know that one drop is 0,1 mgs.

Yes, you can. I used to do this when I had capsules. Dissolve it in the appropriate amount of distilled water and keep it in the fridge. Then measure out your dose with some kind of syringe.

Sushi

 

[Indigophoton]

...you would have thought that some small studies on the pure isomers in people who regularly use LDN with benefit would be worthwhile. Maybe that's what they are doing.

Unfortunately studies on LDN seem to be few and far between in general, and on the individual isomers pretty much non-existent.

The Clinical Trials website currently only has five open trials involving LDN.

I personally hope and think that Dr. Younger at Stanford will be looking and pursuing this line of research that will possibly bring out a practical pharmacological intervention for neuro-inflammation.

Jarred Younger has a trial running at the mo, due to complete in June 2015, looking at LDN Immune Monitoring:

Purpose
We have found that low dose naltrexone (LDN) can substantially reduce pain associated with fibromyalgia syndrome. We believe LDN may work via novel anti-inflammatory channels. The purpose of this study is to determine if LDN lowers inflammatory markers in individuals with fibromyalgia.

Otherwise most of the stuff seems still to be focused on addiction in one form or another, although there is one looking at LDN as a treatment for Gulf War Illness. They will be testing LDN against placebo (and Dextromethorphan against placebo). The trial description includes the following:

novel anti-inflammatory drugs may be of benefit in symptom-defined illnesses related to a cycle of inflammation. Dr. J. S. Hong's laboratory at the National Institute of Environmental Health Sciences has demonstrated that Morphine-related analogs, including Naltrexone and Dextromethorphan, have great potency in anti-inflammation and neuroprotective effects. ... Results from several clinical trials showed that Naltrexone is effective in several inflammation-related diseases, such as neurogenic pain, movement disorders, etc. In addition, there were no obvious side effects in patients taking this drug for six months. This project will conduct randomized double-blinded studies for treating ill Gulf war veterans with Naltrexone and Dextromethorphan. Laboratory tests for markers of inflammation including neurogenic inflammation will be performed pre- and post-treatment, to see if these markers are elevated and if so, to see if treatment modulates these markers.

On another note, Tom Gilhooly suggests taking LDN sublingually may be advantageous. The same site also carries a regularly updated list of the published research on LDN.

Finally, just thought I'd mention that there is an app for tracking one's progress with LDN. I've been using it from the start, because I thought the graphs might be fun. Also the data is being collected for use in research, so worth doing for those interested.

 

[NK17]

Thanks @Indigophoton for all the above informations. I appreciate it very much!

 

[Little Bluestem]

From my complete non expert perspective I think that the kind of experiment that you're talking about might not have been undertaken yet because LDN is a generic drug and a pretty cheap one, therefore there are no financial incentives to "study" it more deeply and accurately.

My equally non expert question is: If someone could produce a pure, single-isomer form, could the patent it? If so, there should be money in it.