Younger has been focused on finding treatments from the beginning
From the beginning, Jarred Younger has always had his eyes peeled for potential treatments for fibromyalgia, ME/CFS – and now long COVID. Younger, in fact, maybe our most creative researchers when it comes to uncovering new treatments.
The one theme pervading Younger’s treatment work has been trying to tamp down neuroinflammation. Any treatment Younger takes on has to be able to cross the blood-brain barrier and knock down that central nervous system inflammation. In particular, anything that can tamp down the activity of a receptor called toll-like receptor 4 (TLR4), which activates the microglia, is of special interest to him.
Younger, along with noted pain researcher John Mackay at Stanford, produced the first LDN low-dose naltrexone study in fibromyalgia back in 2009. The study was notable, in part, because the fact that LDN is compounded means pharmaceutical companies have no interest in it; i.e., it required an academic like Younger or a doctor to get its usefulness across in these diseases.
Younger followed up that study with three more LDN studies and is in the midst of a fourth. Over time, Younger has also assessed the effectiveness of low-dose dextromethorphan (not effective at 20 mg), identified three botanicals (curcumin, stinging nettle, resveratrol) that can help in Gulf War Illness, and has, I believe, received enough funding to explore a potentially more powerful form of LDN called a dextro-naltrexone trial.
He also has a psilocybin fibromyalgia trial under way.
The Nalmefene Project
Talk about working on the cutting edge. Younger’s latest venture – to get funding to assess a drug called nalmefene- could end up being the best of them all. Younger talked about this new project in a recent video.
Low-dose nalmefene, it turns out, does something similar to LDN but more effectively. LDN’s effectiveness is hampered by the inability to take it in large doses – but not so with low-dose nalmafine. Nalmefene lasts longer in the body (8-10 hour half-life—so you need less), has a higher bioavailability (40-50%—so again you need less), does not affect the liver (LDN can), binds to more opioid receptors more effectively, and maybe 4xs better at blocking those nastyTLR4 receptors that turn on the microglia. Since Younger believes the microglial cells in these diseases have become spectacularly hypersensitive blocking the TLR4 receptors that turn those cells on could be a huge boon.
THE GIST
- Again and again, Jarred Younger has looked far and wide for treatments for ME/CFS, fibromyalgia (FM, and Gulf War Illness. His goal, always, is to find drugs that can tamp down the neuroinflammation he’s found in these illnesses.
- He’s assessed dextromethorphan, uncovered botanicals that may help in Gulf War Illness, discovered a more powerful form of LDN that (I believe) he’s currently testing, and has a psilocybin fibromyalgia trial underway.
- His greatest impact, though, may come from a drug called nalmefene, which he’s currently attempting to get funding for. Low-dose nalmefene does something similar to LDN but may be much more effective; it has increased bioavailability, hits more points in the brain, lasts longer in the body, and appears to be MUCH more effective at turning down the receptors that turn the microglial cells in the brain.
- Younger noted that only full-dose nalmefene is available in the US and elsewhere. He warned that the current dose of nalmefene offered is so high that it will probably block your endogenous opioid pain system and give you malaise and feelings of lowness (both of which we already have enough of!). He recommended waiting until the trial results – which will attempt to find the proper dose – are in.
- More and more treatment options are appearing. Recent possibilities include monoclonal antibodies, checkpoint inhibitors, baricitinib, new antivirals (ensitrelvir), multiple antivirals, nicotine patches, and stellate ganglion blockades. There’s the capnography machine Dr. Natelson recently found that patients can use to improve CO2 levels and relieve fatigue, and the recent successful inspiratory trial which provides an easy way to improve breathing and, potentially, oxygenation.
- Most of these are not game-changers, and we’re still not seeing interest from the big pharmaceutical companies or large clinical trials—except from the RECOVER Initiative—but we are seeing more possibilities pop up.
- An interesting one showed up in a case report that reported that a treatment-resistant woman with osteoporosis responded extraordinarily well to a combination of low-dose naltrexone and rapamycin. Given the increased rate of osteoporosis found in fibromyalgia and the strong likelihood that it’s increased in ME/CFS as well (given the lack of exercise possible), an easy way to improve bone density would be a big deal, indeed.
- On the long COVID low-dose naltrexone front, several methodologically challenged studies suggest that LDN may be helpful in long COVID, and a more rigorous one is underway.
While low dose nalmefene shows real possibility, Younger warned that the current dose nalmefene is offered at is so high that it will probably block your endogenous opioid pain system – and produce malaise and feelings of lowness. He recommended that patients wait for the results of his trial.
Should he get funding, Younger will focus on determining the best dose for conditions like ME/CFS, FM, and long COVID-19 and clear the way for a larger, placebo-controlled trial.
Treatment Possibilities Keep Showing Up
Treatment possibilities keep showing up.
Younger’s new project highlights an important factor—how more and more new possibilities for treatment are appearing. Yes, they’re showing up in a confusingly haphazard way, but if you take the time to look, more and more treatment options are appearing.
Recent possibilities include monoclonal antibodies, checkpoint inhibitors, baricitinib, new antivirals (ensitrelvir), multiple antivirals, nicotine patches, and stellate ganglion blockades, to name a few.
Take stellate ganglion blockades – they were used for 50 years before someone decided to try them in ME/CFS/FM and long COVID. Take the capnography machine Dr. Natelson recently found that patients can use to improve CO2 levels and relieve fatigue. Take the recent successful inspiratory trial, which provides an easy way to improve breathing and, potentially, oxygenation. Take an oldie – vagus nerve stimulation – which is about to get a 50-person trial in people with long COVID/ME/CFS (blog coming up).
It’s true that pharmaceutical companies are still not embracing long-term COVID or ME/CF and that we still don’t have the big clinical trials that could turn things upside down overnight. Without them, we’re still nibbling away at these diseases, but there are many more nibbles now, and new possibilities keep showing up.
A recent case study demonstrates how little we can predict will happen over the next few years. Who, after all, could have predicted that LDN + rapamycin might help with osteoporosis?
Low Dose Naltrexone (LDN) Plus Rapamycin Dramatically Improves Bone Density in Treatment Resistant Woman with Osteoporesis
We think in terms of LDN in fibromyalgia, ME/CFS, and long COVID, but LDN is being studied in many diseases, including vulvodynia, multiple sclerosis, Crohn’s disease, complex regional pain syndrome, and quite a few rheumatological and autoimmune diseases.
With more eyes than ever checking out this intriguing drug perhaps it’s not too surprising to see new possibilities show up. The latest, though, could have special significance for women with ME/CFS, FM, and/or long COVID if it pans out.
A recently published case report, “Unexpected Increase in Bone Mineral Density With Rapamycin and Low-Dose Naltrexone: A Case Report of a 52-Year-Old Woman With Osteopenia,” suggests that LDN plus rapamycin may safely improve bone mineral density in women for whom other treatments have failed.
Given the finding of increased rates of osteoporosis in fibromyalgia and the inability of many people with ME/CFS to engage in even close to normal amounts of exercise – an LDN/rapamycin boost in bone density – if it occurred in these conditions as well, would be a real boon.
Despite the known – and potentially devastating – risks of hip and vertebral fractures as we age, many people, as they get older, still do not get bone density tests.
Various therapies – from drugs to exercise to nutrition – can increase bone density on average from 2-10% over several years in some people, but many people do not respond; one drug is incompatible with fibromyalgia, and others can have significant side effects.
The Geroprotectors Show Up
Enter low-dose naltrexone and rapamycin—two drugs that the authors of the recent case study called “geroprotectors.” The case report concerned a 52-year-old woman with osteoporosis who, despite trying multiple interventions (hormone replacement therapy, a Mirena intrauterine device (IUD), weight-bearing cardiovascular exercise and resistance training, vitamin D3 supplementation, and high dietary calcium intake), failed to improve her bone density levels.
In 2022, she enrolled in a double-blinded, placebo-controlled, 12-month low-dose rapamycin longevity trial, increased her vitamin K levels (which enhance calcium binding to the bone), and a year later began taking compounded LDN (starting at 1.5 and progressing to 4.5mg). In November 2023, she also began oral progesterone supplementation (100 mg/nightly).
A DXA scan in 2024 revealed an astounding 15.9% increase in her lumbar bone density. (Her cervical bone density went up by about 4%). The authors wrote:
“These findings represent an unexpected and substantial improvement in the patient’s bone health, which was particularly notable given the typical challenges in achieving significant BMD increases in patients with osteopenia, especially post-menopausal women.”
While the effects of her nutritional supplementation and continued exercise regimen may have helped, the authors focused on rapamycin and LDN. They noted that the mTOR pathway that rapamycin affects “plays a crucial role in bone remodeling.” and believed LDN’s ability to combat the “low-level, sterile inflammation that is a driver of bone resorption and degeneration” improved her bone health.
More LDN Long COVID News
A methodologically strong LDN Long COVID study has not yet been published, but a retrospective Canadian study found that LDN was associated with “fewer number of symptoms, improved clinical symptoms (fatigue, post-exertional malaise, unrefreshing sleep, and abnormal sleep pattern), and better functional status.” Another study found improvement in recovery, limitations in activities of daily living, energy levels, pain levels, levels of concentration, and sleep disturbance.
An intriguing pilot study found that combining LDN and NAD+ produced a nice bounce in SF-36 scores and a significant drop in fatigue scores in approximately half of the group classified as responders.
The LDN dose climbed from 1mg for four days, 2 mg for the next four days, and the full 4.5 mg dose taken in the evening after that. Four hundred mg/ml iontophoresis patches (IontoPATCH™️ STAT, ST. Paul, MN; provided by Pharmacy Solutions, Ann Arbor, MI or Belmar Pharmacy, Golden, CO) employing electrodes were used. The patches (400 mg/mL NAD + solution) were worn for 4-6 hours once a week.
A more robust placebo-controlled, blinded LDN study (n=160) is underway in British Columbia. The study will start with 1 mg and work up to 4.5 mg (or whatever dose is tolerated).
Advances are being made—not at the pace anyone would want—but they are being steadily made. Now, however, a wild card has shown up. What the Trump administration decides to do with the National Institutes of Health, the FDA, and possibly the Social Security Administration in the U.S. has the potential to profoundly impact people with long COVID, ME/CFS, fibromyalgia, and dysautonomia. The next blog reviews where we’re at at this point.
