Two ME/CFS, yes, ME/CFS low dose naltrexone papers appear, one  fibromyalgia report attempts to turn dosing protocols on their head, one patient blows through normal dose levels with spectacular success, Jarred Younger hunts for a more powerful naltrexone, and then goes out on the skinny branches with the next treatments he wants to test in ME/CFS/FM…

Studies indicate that low dose naltrexone (LDN) is effective in about 60% of people with fibromyalgia but chronic fatigue syndrome (ME/CFS) is another matter. LDN was originally tried in FM because of its endorphin enhancing effects. By temporarily blocking the opioid receptors, LDN, in effect, unleashes them – causing a rebound effect and an increase in the production of the body’s endogenous opioids.

microglial cells

LDN appears to affect the activity of the drivers of neuroinflammation – the microglial cells.

Later research, however, which found that LDN also modulates the activity of the glial cells in the brain, pointed to LDN’s potential use as an anti-inflammatory agent.  Jarred Younger’s three FM studies bore this out: not only was the pain in approximately 60% of the trial subjects reduced but LDN was associated with reductions in an inflammatory marker, erythrocyte sedimentation rate (ESR), and a wide array of pro-inflammatory cytokines. None of Younger’s trials were large but they did suggest that LDN produced consistent, if moderate (@ 30%) reductions in pain as well as improvements in fatigue and sleep.

Chronic Fatigue Syndrome (ME/CFS)

“I want to make a plug for Low Dose Naltrexone”  Dr. Nancy Klimas – Simmaron Roundtable Meeting

But what about ME/CFS – another apparently neuroinflammatory disease associated with extreme fatigue but less pain? The first clinical assessment of LDN’s affects on ME/CFS, “Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)”, was recently published.

Notably, it came from an unexpected source – a clinic in Finland. With this study, the recent intracranial hypertension study out of Sweden, the Norwegian Rituximab trial and the fecal transplant study under way, the Nordic countries contributions have been impressive, indeed.

The participants were given a fairly common protocol: start with 1.5 mg/day for the first week, double it the second week, and after six weeks increase it to 4.5 mg/day if they wished.

Two positive aspects of the study were the large size (218 people) and the long follow-up time – an average of almost 2 years. On the other hand, there was no placebo group, the effectiveness assessments were crude, and no validated fatigue or other symptom assessments were used.

When the patients came back into the office or needed to re-up their prescription, they were to assess things like increased alertness, improved physical performance, improved cognition, improved pain. This was a retrospective analysis based on patient charts.

Squirrel image

Fifty percent of the participants reported an increase in alertness. (Image by Image-by-Gerhard-Gellinger-from-Pixabay)

Fifty percent of the ME/CFS patients reported improvements of at least one point in alertness/vigilance, 23% in physical performance, 21% in cognition. Surprisingly only 16% cited an improvement in pain. About half reported at least a one point improvement in two or more areas. Overall, almost 75% reported “some degree of alleviation of ME/CFS symptoms”.

While the results were moderate, the authors noted that some patients were able to return to gainful employment and that even small symptom improvements can improve quality of life.

Most patients tolerated the treatment well with most adverse side effects (insomnia, nausea, dizziness and headaches) occurring early and dropping off over time. They noted that for those who continued the treatment, “long-term adverse symptoms were practically absent.” About 8% of the patients dropped out because of side-effects.

While the most severely ill patients experienced the highest number of adverse effects, the treatment protocol – starting from a fairly high level and ramping up quickly – was pretty challenging. A less aggressive start could have benefited these patients.

The authors hoped that this preliminary study would encourage others in producing placebo-controlled studies of LDN in ME/CFS. Many ME/CFS/FM doctors, including Dr. Klimas, Dr. Liptan and Dr. Chheda, support the use of this drug for their patients.


In conclusion, this study is full of holes! We don’t know if LDN was actually responsible for the symptom improvement and the lack of validated questionnaires doesn’t help.  Perhaps the most positive outcome of the study that most of the people that started LDN stayed on it.

While the study protocols weren’t impressive, the study is yet another example, though, of this field lifting itself up by its bootstraps – a process that is going to be a little messy. Congratulations to the Finnish doctors for taking the time to assess and publish their results – and for being the first to get an ME/CFS study out. Congrats as well, to the patients and researchers who took the time and trouble to publish their valuable case reports.

Recent Case Reports

Then came another evidence of “bootstraping” – two patients and a researcher working together to get some case reports published. As Utah researcher Alan Light noted, case reports can be crucial in giving researchers the validation to get treatment trials underway. We have far too few of them.

Three case reports including, “Low-dose naltrexone as a treatment for chronic fatigue syndrome“,  flesh out three ME/CFS patients’ experiences with LDN. As always, these case reports provide fascinating overviews of actual experiences. What they lack in statistics, they sometimes more than make up for in detail. They’re also a reminder that studies provide crucial assessments of groups of patients but don’t necessarily relate to individual patients.


One person was a healthy general practitioner until, at age 33, she developed viral meningitis and became bedbound, unable to care for herself, and experienced dizziness, widespread pain and anxiety. Over time she slowly improved and was able to return to work – only on a part-time basis – but suffered from headaches, fatigue, postexertional malaise and migraines.  After extensive testing proved futile, she was diagnosed with chronic fatigue syndrome (ME/CFS) in 1989.

A stomach flu 10 years later left her bedbound again, unable to tolerate many foods, dependent on a wheelchair to get around and on caregivers for support. Various treatments provided little help.

After decades being severely disabled, one patient recovered completely – by taking very high doses of LDN!

Twenty-one years after becoming ill, she was treated with low dose naltrexone (LDN) (1.5 mg). She slowly ramped up the dose, noticed only slightly increased energy at 4.5 mg/day – but then had to cut back to 3 mg/day because of headaches. Ten months later, she made what turned out to be a momentous decision and over time successfully ramped the dose up enormously.

At 9 mg/day her abdominal pain disappeared and she was able to resume a full diet for the first time in years. She continued to experiment with dosage and for the past 8 years has taken 6mg/day two times a day — or almost three times the highest normal dose.

Remarkably, after several decades of atrocious health and a full decade of being bedbound, she’s returned to near full health and has been off disability for several years.

She wrote:

“For me, low-dose naltrexone was truly life changing. From being virtually house bound, always limited by a multitude of symptoms, pain and low energy, I found my life returning. Every treatment or therapy I had tried previously involved effort— pacing myself, training myself, coping with symptoms. With low-dose naltrexone, the improvement just happened—I didn’t have to try, I just got better.


I went for walks and started cycling again. The first time I ate out when I was no longer limited by food allergies, I could select from the whole menu—the shock of all that choice! My husband commented I was no longer a shadow of a person but a genuine companion again. From being unable to string sentences together coherently for much of my adult life, I returned to university and gained a distinction in a Master of Research degree, when aged 62!”

Treatment Takeaways

  • Despite having a long and severe illness, this person completely recovered (!)
  • If you have a bad reaction, don’t give up on dosing. Her body clearly needed time to adjust to the drug but once it did, she responded very positively to far larger amounts of the drug than she had been able to tolerate before.
  • In the end, far higher than normal doses worked in spades for her.

Monica Bolton – one of the authors of the case study report and the patient who did so well on the higher dose – reported that her doctor, Dr. Gilhooly, told his patients to experiment with dosing, and that most of his patients ended up taking more than the 4.5 mg/day that most patients stop at.

Gilhooly was quite an advocate for LDN until the Scottish General Medical Council slapped him on the wrist. He’s no longer able to prescribe it.


Following a possible viral infection, early pregnancy and exposure to ticks, a 29-year old woman in the U.S. came down with ME/CFS, and was diagnosed two years later. Despite seeing many specialists and trying of many things including antivirals, her symptoms (pain, periodic muscle weakness, flu-like symptoms, orthostatic intolerance and unrefreshing sleep) continued unabated.

Then, 25 years after coming down with ME/CFS, she tried LDN.

Due to her immune hypersensitivity, she started at a lower dose than normal – just .25 mg/day. Even at that dose, her sleep was initially disturbed by vivid dreaming, but six months later, at 1 mg/day she began to notice some positive effects. She continued slowly ramping up the dose until she was taking 4 mg/day.

She didn’t receive the miracle outcome that the first patient did. Her pain and sleep issues improved but her functionality did not. Nevertheless, she reported:

“While the dreaming was at times disturbing, the positive changes gave me a hope for improvement I had not had in many years. The subsequent improvements have led to a much higher quality of life.”

Treatment Takeaways

  • It also took this woman over 20 years to try LDN.
  • Despite suffering from side effects at a very small dose, she was able to slowly increase her dose up to 4 mg/day.
  • She didn’t achieve the recovery the first patient did, but she did report improved sleep and pain.


A British man who came down with infectious mononucleosis at 10 and severe tonsillitis at 14 eventually became bed-ridden, suffering from severe fatigue, headaches, sleep issues and light and sound sensitivity. He gradually improved, though, and by using pacing and similar techniques was working in his mid-twenties at a full-time in a job with flexible hours. Still, he had trouble sleeping, recurrent colds and, particularly during those colds, suffered from depression.

Some 20 years or so after coming down with ME/CFS at age 37, he started taking LDN (1 mg/day) and slowly worked his way to 4.5 mg/day. His sleep improved, depression and anxiety lifted, and he went from a 6-7 on a functional scale to 8-9 (!).

He reported:

“Since I was 14 (when I had my first chronic fatigue episode), whenever I have had any form of illness I have suffered from depressive episodes, including needing to withdraw socially and becoming very insular. This included the period prior to any illness, where I have felt run down or could tell a cold etc was forming. I started taking low-dose naltrexone when I was 37 and for the first time in 23 years, I have not had a depressive episode linked to colds or any other illness. Low-dose naltrexone has really helped improve my quality of life and also helped in social situations where I am not withdrawing and being insular like I had been previously.”

Treatment Takeaways

  • It also took this man two decades to get to LDN.
  • Despite being bed-ridden initially, he improved enough to work full-time.
  • This man’s functionality, while high for an ME/CFS patient, still went up about 30% on LDN; i.e. LDN can clearly help the less severely ill as well.
  • The disappearance of his depressive episodes during colds indicated that the immune system can, indeed, sometimes cause depression.
  • His improvement during colds suggested that LDN, as Jarred Younger suspects, is affecting the immune cells (microglia) in the brain.

Treatment Takeaways

  • Finland shows up big with a big retrospective study which, while not rigorously done, nevertheless suggested that LDN had at least moderate effects on alertness and sleep in ME/CFS. Oddly, enough – not so much with pain.
  • Three published case reports were highlighted by one woman who, after taking over double the suggested top dose, fully recovered from a severe case of ME/CFS. When taking the typical dose (4.5 mgs/day) her progress was minimal.
  • That woman seemed to have topped out at 3 mg/day but successfully raised the dose greatly when she tried months later.
  • Other case reports highlighted the fact that even patients who can tolerate only minimal amounts of the drug at first can often work their way to full doses.
  • Another report out of Norway suggests that taking more LDN at first rather than less may be helpful for people having trouble taking the drug.
  • Despite the fact that people with ME/CFS have no FDA approved treatment options, and LDN presents the possibility of being a cheap, readily available option, Jarred Younger’s attempt to get two naltrexone trials, an ME/CFS LDN one and a dextro-naltrexone funded at the NIH failed.

Skip Lenz, a pharmacist, suggests that if you’re not taking a lot of tramadol that you can take it with LDN.



More on LDN, ME/CFS and FM

Now For Something Completely Different (!!!)

Another group has gone even further, though. Bolton provided a pdf (see link, below) “Alternative Dose Strategy” created by Steinar Hauge of the Norweigian LDN site www.ldn.no. LDN use in Norway apparently spiked after a 2013 TV documentary was shown.

In this protocol, which Hauge asserts produces fewer side effects, patients start at 6 mg/day and then drop down to 4.5 or 3mg/day or stay at 6mg/day if they wish.

Could some patients benefit from a radically different dosing regimen?

Hauge reports that “many patients with fibromyalgia (and possibly ME) … report good, and for many, immediate effects”. Hauge believes that lower doses of LDN are more immune stimulative while higher doses are more immunosuppressive.

Hauge, who is not a doctor, recommends patients try the typical dosing regimen first – starting at lower doses – but if that doesn’t work, then to try the high initial dose regimen instead.

LDN Clinical Trials

A parallel randomized (1:1) double-blind, placebo-controlled, 100 person, Danish FM Study just got underway.

Unfortunately, Jarred Younger was unable, despite numerous attempts, to get NIH funding for an LDN ME/CFS trial. The NIH, he said, just does not fund LDN. Despite his success with FM and the lack of drug opportunities for ME/CFS – the NIH wouldn’t go for it.

NIH stops LDN Trials

Twice the NIH refused to fund a clinical trial that could have benefited ME/CFS and FM

Then the same thing happened with dextro-naltrexone, which Younger believes has the potential to blow the pants off LDN in terms of effectiveness. Younger reported that he was able to find the materials needed to manufacture the drug and even had the infrastructure in place for production and testing, but once again, the NIH didn’t fund it.

Because this would be such an expensive trial (>$1 million), Younger said NIH or DOD funding would probably be necessary. They’re currently looking at the HEAL (Helping to End Addition Long-Term) initiative to see if a grant there could fit. The NIH Is currently funding over 160 clinical trials and research.

Younger is still jazzed about the compound but its rarity does present real challenges.

“I still think it is the best next compound to test, but the fact that it doesn’t exist anywhere in the world currently is a huge obstacle!”

Jarred Younger III : Treatments – A Better LDN and the Hunt for Microglia Inhibitors

The NIH – the “Not Interested in Health” Institute was just not interested. “Not Interested in Health” is too harsh, of course, but it’s amazing how many roadblocks the huge and hugely bureaucratic National Institutes of Health puts in the way of clinical trials.

No one should confuse themselves with the idea that whatever the institute’s name is, though, that its primary focus is on improving health of this country. Its primary focus is funding research –  the kind of research that enhances researcher’s career goals.

Check out the LDN situation. If any drug needs and should receive federal support it’s LDN. Because it’s compounded (and cheap) no drug company will ever fund a trial – meaning that the only available option is the feds.  Studies suggest LDN works in FM and ME/CFS – two disorders that get paltry funding and lack effective treatment options.

The NIH has said ME/CFS, in particular, is a priority; yet it refused to fund a trial of a substance which could not only help ME/CFS patients but could do so cheaply -something one would hope the NIH would be interested in. It’s hard to understand.

The fact that Younger – who knows something about NIH grants – tried multiple times to get funded suggests he bent himself and his study into a pretzel in an attempt to make the NIH happy. The only conclusion Younger could draw was that the “The NIH will not fund LDN trials”. Too bad they didn’t just come out with it and tell him that at the onset.

Next Up for Younger

Younger – one of our most creative and courageous researchers – is always beating the bushes for new treatment opportunities for ME/CFS and FM. His dextromethorphan and botanicals studies have wound up or are winding up, and when that happens, he hopes to go out on the skinny branches again with trials of noninvasive vagus nerve stimulation, cannabidiol (Epidiolex), and get this, psilocybin!


Younger hopes to do a cannabis and a psilocybin trial. (Image by SvgArtStock from Pixabay)

Talk about rewiring the brain. Psilocybin – a mushroom extract associated with psychedelic experiences – has been going mainstream. Johns Hopkins has been assessing psilocybin’s effects in a controlled environment for decades, and the drug’s effectiveness is now being assessed in depression, anxiety, migraine, cluster headaches, early Alzheimer’s and PTSD.  In 2019, psilocybin received “breakthrough therapy designation” from the FDA – which basically indicates that the FDA will do all it can on its end to support drug trials.

It should be noted that alleviating depression and anxiety may be no small matter for someone with an immune disease, as both are associated with increased pro-inflammatory cytokines.  Psilocybin appears to rewire the brain by temporarily kicking it out of the rut it’s in – and allowing new neural pathways to be formed. Michael Pollan’s book, “How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence“, is a good introduction to this subject.

LDN and Tramadol

LDN cannot be taken with opiates, but Skip Lenz, a pharmacist, (who does not consider tramadol an opiate), reported in “The LDN Book” by Linda Elsegood that he has not found that LDN doses in the range of 50 mg taken 2-3 times a day, cause problems.

Check out Health Rising’s Low Dose Naltrexone Resource Center for more on LDN

Low Dose Naltrexone (LDN) Fibromyalgia and Chronic Fatigue Syndrome Resource Center


With one retrospective trial and three case reports recently hitting the medical journals, ME/CFS has finally got some LDN love. The results were not earth-shattering but they were decent, and will hopefully open the door for bigger, more rigorous studies.

Mixed in them were some real surprises, including one patient who returned to health using a dose few even dream about, and a report from Norway suggesting a different dosing regimen may help those having problems with the drug.

Plus, the case reports suggested that efforts to increase the dose can take six months or more to bear fruit, and patients who need to start very, (very) low can still work themselves up to full doses if they take the time.

The feds are just about the only group able to fund an LDN trial but the NIH, in another disappointing decision, turned down several attempts by Jarred Younger – including one that could potentially have blasted the next, more powerful iteration of LDN into existence.

Next up, Younger – a man clearly determined to turn over every stone possible – wants to assess the effects of several more potential treatments including a cannabis drug and psilocybin – a mushroom derivative and “brain rewirer extraordinaire” which is now being studied in a variety of diseases.


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