Reprinted with the kind permission of Cort Johnson and Health Rising 
This is the last of three blogs emanating from interviews with Jarred Younger at his Neuroinflammation, Fatigue and Pain lab at the University of Alabama at Birmingham and at the 2018 Stanford Symposium.
Younger wanted to know one thing from his post-doc group studying rheumatoid arthritis, osteoarthritis and fibromyalgia: which disease do you know the least about? They said “we have no idea what’s going on with fibromyalgia.” The idea of breaking new ground clearly makes Younger tick.
Big NIH Push for Better Pain Killers
Spurred by the problems caused by the opioid epidemic, the NIH is on a pain-killer drug creating push. Younger said the NIH wants no less than 15 FDA approved new drugs over the next five 5 years and is pouring money into the field like never before. Fifteen new drugs is an extraordinary goal given the difficulty of getting pain-killing drugs to market. (Two failed in phase III trials in fibromyalgia last year.)
Some of the new drugs will go to helping with opioid addiction but a big push is being made to provide new pain-killers. Among other things that push will include developing many new animal models for pain and developing a new clinical network that’s designed to speed up testing and reduce costs.
“I think all of us that are concerned about this worry sometimes that we talk about one without realizing the other requires intense attention. But what about the people with chronic pain—24 million of them—with daily pain? What are they supposed to have available? We all agree opioids are not a great solution. But what other solutions do we have for people with severe daily pain? Not nearly enough.” Francis Collins 
The NIH’s big push makes it likely that over the next five years we’re going to see potentially very powerful pain-killing drugs entering the market. There’s some good news on the chronic fatigue syndrome (ME/CFS) side as well.
Younger has also noted a distinct increase in drug company interest in chronic fatigue syndrome (ME/CFS). Five small drug companies or startups that have specific compounds that are in some stage of testing have contacted him in the past year or two. Younger doesn’t sit on commercial boards but he’s happy to look over their scientific protocols and provide advice.
On The Hunt For Microglial Inhibitors
Younger’s been on the hunt – searching the medical literature – for neuroinflammation busters for FM and ME/CFS for years. He’s looking for substances to tame what he believes is at the heart of these diseases: the over-active immune cells in the brain called the microglia that are pumping out inflammatory factors and causing pain, fatigue, sensitivity to stimuli and other symptoms.
This substance has to be safe for humans, has to be able to pass the BBB and has to be available. Younger’s search has thus far spawned a bevy of clinical trials – from the breakthrough fibromyalgia low dose naltrexone trials, to the ME/CFS LDN trial, to the dextromethorphan trial that’s just getting underway, the botanicals trial that just finished up and new trial he’s trying to get underway which just might put all the others in the dust.
Low Dose Naltrexone and Beyond
The first thing I heard about LDN is that it was effective and did not produce side effects. It can be very effective but the idea that it does not produce side-effects is just not true. Both my partner and I have been unable to tolerate it and reports of side-effects can easily be found.
In Younger’s experience sleep problems (insomnia, vivid dreams) early on are common and usually work themselves out in a couple of weeks. (Taking it in the morning can help with that.) Very rarely he’s heard of people getting jittery or anxious or even having signs of mini-withdrawals (pupils bigger, sweaty, goosebumps) which he attributes to their having a super sensitive opioid system.
There may be a better way to take naltrexone, though, a much better way – one that besides being side-effect free may be much more powerful. It’s called dextro-naltrexone and Younger’s been wanting to get at it for at least five years.
Younger’s studies basically started the LDN fibromyalgia craze. He gloomed onto LDN in the same way he’s did with dextromethorphan and the botanicals he’s been testing – by painstakingly searching through the medical literature to look for anything that might tamp down neuroinflammation.
Now he’s focused on a different form of naltrexone called dextro-naltrexone. (There are at least three forms of naltrexone; the higher dose form used to treat opioid addiction; the lower dose form used in FM, ME/CFS and other diseases to reduce pain and neuroinflammation and dextro-naltrexone – a different form of the drug altogether.
Both naltrexone and dextro-naltrexone block the TLR4 receptors from activating the microglia. Dextro-naltrexone probably never made to commercial development because naltrexone was first conceived as an anti-abuse opioid drug. Naltrexone’s ability to interact with the opioid receptors made it an enticing possibility for an anti-opioid drug.
When it became clear that low dose naltrexone causes an increase in an endogenous opioid called the opioid growth factor (OGF, [Met5]-enkephalin) and other parts of the opioid system the stage was set for LDN’s introduction as an anti-pain drug.
Younger always thought, though, that LDN’s usefulness in FM/ME/CFS is due to its ability to calm the microglia – not it’s interaction with the opioid receptors.
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Plus LDN’s interaction with the opioid system may, however, have come with a cost. LDN’s interaction with opioid receptors may be causing side-effects and limiting the dose and therefore the effectiveness of the drug in FM and ME/CFS.
Enter dextro-naltrexone. It has the same potent microglia inhibiting properties as LDN but without the opioid hit.
Dextro-naltrexone presents the decidedly enticing possibility of being able to use a potent microglial inhibiting in far higher doses than is possible with LDN. We won’t know until the trial is finished but that should translate into more microglia suppression, greater pain suppression and more people who tolerate the drug.
Plus unlike LDN which cannot be used with opioids, dextro-naltrexone should be able to be used with them and might even – by removing the TL4R activation problem – remove the side-effects often found with opioid pain-killer’s. (Studies suggest dextro-naltrexone might also be able to ameliorate the side-effects of stimulants.)
The problem with dextro-naltrexone, though, has been getting ahold of it. It’s not commercially available and as of 2104 Younger  knew of no source that could provide it but something, it appears, has changed. Younger talked of a collaboration with Mississippi researchers to bring the drug to trial in chronic pain patients.
It’s possible that Younger’s FM LDN trials which have done so much for so many may simply set the stage for the really effective form on naltrexone….
Stopping Multiple Sclerosis in its Tracks? With LDN
Multiple sclerosis (MS) is a neurodegenerative disease believed triggered by inflammation. Younger proposes to whack that inflammation with low dose naltrexone in people in the early stages of MS. If he can tame the inflammation before it impacts the nerves he might be able to slow the progress or even stop it in its track.
Gulf War Syndrome Botanicals Trial
Younger has finished up with a novel treatment trial involving no less than 9 botanical agents that demonstrates some considerable creativity. Younger has been pushing for ways to clinical cheaply more cheaply which includes testing multiple substances in them. He believes this may be the first time so many different treatment possibilities have been assessed in one clinical trial.
The botanicals include stinging nettle, curcumin, reishi mushroom, resveratrol, luteolin and others.
Some have been well-studied studied in the lab. For example extensive lab studies show that resveratrol has neuroprotective effects  and can inhibit microglia activity. Researchers even know the specific pathways (MAPKs, phosphoinositide3-kinase (PI3-K)/Akt, glycogen synthase kinase-3β (GSK-3β)) resveratrol uses to do this, yet it’s never been tested in diseases such as ME/CFS/FM or GWS, until now.
Curcumin has been even more well-studied. Animal studies indicated that curcumin inhibits the microglia, staves off damage to the neurons, and reduces oxidative stress. One review stated 
Further, the outstanding safety profile of curcumin and its… potential for neuroprotective efficacy including anti-inflammatory, antioxidant, and anti-protein-aggregate activities… make this compound a potential therapeutic agent in treating neuroinflammatory diseases.
Younger has begun to assess the data from the study.
Endotoxin Fibromyalgia Study
Younger had also just finished up his endotoxin FM study. Injecting someone with bacterial molecules  which are guaranteed to illicit an immune reaction (flu-like symptoms) was not anyone’s idea of fun, and it was not easy to recruit for the study. In fact, it ended up being the longest study he’s ever done; it took a year and a half to recruit 8 FM patients and 8 healthy controls.
The study actually used a low dose of endotoxin – which the healthy controls didn’t notice but which the FM patients did react to. That suggested, as Younger had hypothesized, that their immune systems were on a knifes-edge – ready to over-react to a stimulus. Next up are the results of the immune testing. If Younger finds anything, he can begin to reposition fibromyalgia more as the neuro-immune or rather immune-neuro disease he thinks it is rather than the neurological disease it’s mostly been characterized as.
Pioneering Researcher Making Good in ME/CFS and FM
It seems like it’s one first after another with Younger. The first LDN FM and ME/CFS studies. The first dextro-naltrexone study. The first dextromethorphan study. The first brain heat mapping study. The first study to determine if immune cells are invading the brains of ME/CFS patients. The first big multi-treatment study. The first botanicals study.
It’s good to see Younger concentrating on FM and ME/CFS and thriving doing it. Hopefully his success will spark other researchers to dive into these disorders.
About the Author: ProHealth is pleased to share information from Cort Johnson. Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising .