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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 breathing 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.
Nalmefene is available on prescription in my country. Surely it would be safe to have it compounded into liquid form like Low Dose Naltrexone and start with one drop every other day, and build slowly from there?
I tried Low Dose Naltrexone on two occasions and stuck it out for 3 months but it caused insomnia.
Hi, you need to use ldn regular, yr insomnia is because of the endorphins, the same will apply to the Nalmefene IMHO. See my post here.
I would like to read your post, where can it be found?
LDN helped me greatly until I had my last really really big crash and since then it doesn’t seem like it helps me anymore. I have stopped it and restarted it more than once, to no avail. Thank goodness rapamycin has given me life back, but I do still take the LDN just because I’m concerned that possibly it’s doing something that’s helping me that I’m just not noticing. Maybe that’s silly and I will get my guts up to fully stop it. Why waste the money if it’s not helping.
Same thing happened to me with LDN!
Which is exactly why I take a low dose of naltrexone every 2 hours, not only dose it block the opiod receptor, therefore opening the calcium ion channel , but you also get the endorphin high for the second to third hour, depending on yr activity, just dose again to keep active! anyways I’m so bloody Thankful for the life it gives me!
Stops cfs symptoms like fatigue, pem, pain and pots, yet no one seems to want to trial it, Which is just Maddness!
Been using for 3 yrs, liver test every 6 months, completely Fine! It’s a myth, ldn is a Wonder drug!
What is the dose you take during the day every 2 hour. Thanks so much.
that would be interesting for me as well-how often do you take it and how high is your dosage? I`ve been taking it once a day, before bed. thank you 🙂
They are still missing the crucial factor and that is that it’s in the blockade time that the real magic happens, it can be a low time ,but not always, it’s the best time for movement, that’s when the calcium ion channels are opened and gligal cells are soothed etc, the next stage is the endorphin stage and you can still get stuff done but more carefully and enjoy the endorphin high, I currently get a blockade for the 1st hour on 4.5mls of naltrexone then endorphin stage for the 1 to 2 hours, this is not the best time fof heavy activity anyway, anyway, some clever person will work it out one day, oh wait that was me! Lol
Hi Vanessa,
Love to try your protocol for LDN, since I struggled with insomnia for 25 years and take hardcore meds for it. Tried LDN, but maybe try it as you recommended
Hi Bibi, yes great for insomnia through the night, I make up doses to keep near the bed.
Cort has said he will publish my protocol soon, but if you want it asap, email me at vgray1221@gmail.com
When I trialed LDN for three months, I took a tiny 0.05mg dose in the morning and it still caused me to only get about 4 hours sleep. I don’t see how taking more throughout the day and night would do anything but make my insomnia worse.
Thanks Vanessa. Will do. I need help with so many things, the fibromyalgia pain, CFS, back pain from stenosis etc., fatigue and severe insomnia. Autoimmune issues.I tried to take it at night which did not work, tried lower dose as well. So your way of taking seems different and worth a try. And that opening of the calcium ion channels makes a lot of sense, since I seem to never be able to get rid of my viruses and trauma is a major issue as well. Intriguing for sure. And I could use some sense of happy endorphins.
Don’t take LDN every two hours whatever you do. You will completely block your opioid receptors.
Of importance is this information which is why we take no more than 4.5mg in most cases until we have research that says otherwise –
“However, much to our surprise, we discovered that the animals getting the 10 mg/kg each day were coming down with tumors far earlier than the controls. Yet there were no tumors in the group of mice receiving 0.1 mg/kg! One month after tumor injection all of the mice in the 10 mg/kg group and control group had tumors, but none of the mice in the 0.1 mg/kg group. By two and a half months, still only one-third of the mice in the 0.1 mg/kg group had a tumor. Mice receiving 10 mg/kg survived for a significantly shorter time than control animals.”
https://www.ldnscience.org/resources/interviews/interview-ian-zagon
I’m doing fine thanks, fitter than ever, have dropped 32 kgs, and can walk and swim, I also have the endorphins too don’t forget in the second hour, All good!
That’s how caffeine works Vanessa. Anymore MCAS symptoms?
My mcas is great now im off the caffiene.
The mice that got cancer were given 10 mg PER kg which is a HUGE amount and many orders of magnitude greater than a 4.5 mg dose in a human. A 10 mg/kg in a 150 pound human is something like 750 mg.
may i ask how much 1 ml is in mg please?
thanks!!!
Same, I dilute a 50mg tablet in 50mls of water
sorry, my brain, just to be shure. 1 ml is 1 mg?
Yes, correct.
Hi Vanessa,
I have been experimenting with LDN dosing as well. How many mls of the 1mg/ml solution are you taking every 2 hrs? Thank you!
Hi MWhit, I’m currently taking 4.2 mls every 2 to 5 hrs.
Good luck.
I just use it as I need it.
Thanks Vanessa, Is there a resource where we can find your presentation at the conference you mentioned? My Dr’s are interested. I also had great success using a bone stimulator to heal from a very complex foot surgery, while carrying a Dx of osteopenia, borderline osteoporosis.
Hi Mwhit, happy to email it to you, vgray1221@gmail.com
I think Cort is publishing soon.
That’s Awesome!
Well they are wrong there, ldn simply opens calcium ion channels, without calcium a body cannot function properly!!!!
I’ve even met a women who used a bone stimulator for a year for a big fracture and she remained cfs free the entire time, until she stopped using it, and didn’t have access to it
I had never heard of a bone stimulator. Is it possible to know a little more please Vanessa?
Otherwise, I just received the LND, the pharmacy prepared capsules of 0.25 mg. I would have preferred in cash, but I did not find it in France.
Hi, they are not cheap, google them. Good luck with the ldn.
may i ask how much 1 ml is in mg please?
thanks!!!
the strength of the medication is measured in milligrams per milliliter, so it would vary.
Sorry I forgot to say bone stimulator open calcium ion channels.
My GP in the UK cannot prescribe LDN for fibromyalgia, because the research that was made about it as a treatment for fibromyalgia was not done in the UK. That means the NHS cannot support that kind of treatment.
It saddens me every time I see people in the US saying how much LDN helps them with fibromyalgia while it’s out of reach for me, and when I see treament research being done outside the UK I can’t help but wonder if it’s going to end up the same way: changing the lives of people in some countries, but inaccessible in others.
Research should be celebrated, but it comes with so many “yes but”s that it’s become increasingly difficult to feel unconditional optimism when I hear about it.
I wish scientific and medical research were a global effort, but I realise that’s a bit on an unrealistic utopia.
My daughter and I both get ours prescribed privately in the UK via private doctors. However I think Dickson chemist in Glasgow have a system where the pharmacist can prescribe it. I don’t know the cost of doing it that way but may be worth investigating if you can afford to.
I have recently lost my job so it’s not an option at the moment, but I’ll keep that in mind and give it a try as soon as I find a new one. Thank you very much for the tip 🙂
I’m pretty sure you can be prescribed LDN in UK easy enough, you may need to see another doctor or an ME consultant
Yes LDN can be prescribed by Dickson Chemist in Scotland and they post out to England etc. It was around £20 per bottle. The first night I tried it I got up and my legs collapsed from under me. I felt very strange. I persevered though and titrated up slowly. Legs were fine thereafter! However I started getting GI symptoms after the first week. These never let up. I was determined it would work though so convinced myself it wasn’t the LDN when it definitely was. Ended up with severe IBS and Irritable Bladder Syndrome (both of which I had spells of before but not to this degree). Couldn’t continue. I only managed to get up to 4ml per night at which point insomnia was creeping in as well. Can’t imagine taking 4.5ml every 2 hours?! Everyone is different though!
Did you take LDN in cash or in capsule, Beck? Some people do not support it in cash, but supports it very well in capsule.
Hi Claudie, it was liquid form…
I had a similar awful time when I started LDN. Diarrhoea every day from the liquid form. Moved over to sublingual drops & have no problems. I find LDN helpful in a subtle way, sometimes I stop using it as it’s boring having to remember but then I notice symptoms returning so I go back on to it.
Thanks Sue, I hadn’t realised you could take sublingual drops. Great to hear that these can be better tolerated. Will look into. Much appreciated.
It’s easy to access LDN in the Uk. Though it has to be paid for. I don’t think it’s expensive. I’ve used it successfully for Fibro for years. Check out clinic158.com. They will provide a phone consultation with a prescriber. It’s helpful to have any blood test results available if you have them. If you’re suitable you pay for a prescription which is passed to a pharmacy in Glasgow, which posts out your medication, again this has to be paid for, about £30 for a month to 6 weeks supply.
That is much cheaper than I expected! Thank you for all this info 😀
Dr Wier I thought did. I’m in US but thought I heard that. He’s in London. Heard of pharmacy that compounds it too.
Slightly off subject but because Stinging Nettle was briefly mentioned as one of the botanicals, it’s important to mention that it is known on occasions to cause breast growth in men, as can increase oestrogen (estrogen) levels. (Note only some people have this issue)
But where my concern lies is that higher oestrogen levels in males are actually linked to higher incidence of ME/CFS.
High oestrogen levels in females may affect their testosterone levels too (I don’t know which way but the hormone levels affect each other). And low testosterone levels in females are linked to ME/CFS also.
So although Stinging Nettle may reduce pain and inflammation. People need get their oestrogen and testosterone levels checked if using it regularly.
There’s a case study in New Zealand in which a man started growing breasts in (from memory) in around 2 to 3 months of daily use. Breast growth in males from what I understand is permanent. They don’t shrink back to nothing afterwards
Interesting to read your comments about stinging nettle. I’m a post-menopausal woman with me/cfs, fibro and allodynia who has been taking nettle supplements for years, for nasal congestion and postnasal drip. I’ve noticed the dosages of stinging nettle vary tremendously between different nettle supplements. The only side effect I’ve experienced is more dry mouth at the highest dose. The benefit for me includes better sleep and thus lessened fatigue, due to improved breathing when asleep and awake. In addition to nettle leaf extract 225mg twice or three times a day, I take quercetin/bromelain 800/200 mg twice a day, for the nasal congestion. All of the above have some anti-inflammatory effect, which allows me to decrease NSAID intake.
Unfortunately, in my experience US doctors are unwilling to test hormone levels, even for people taking hormone replacement. My husband has gynecomastia, which prompted his doctor to give him a testosterone test and prescribe testosterone. He’s been taking T for about 30 years (which didn’t decrease gynecomastia) and still docs rarely want to test him again. I’m on HRT and mainstream docs won’t test me, even though they adjust my dosage based on perceived cancer risk. Very odd. It seems there’s controversy about how reliable hormone tests are, but it makes no sense to me to avoid testing at all. A functional medicine practitioner who was my primary care doc at a university clinic actually was let go because she insisted upon doing saliva tests for hormone levels. She ended up opening a private clinic for hormone management. Like many such clinics here these days, they don’t accept health insurance and charge an access fee (due to prohibitive overhead costs). So hormone testing may only be available for people who can find and afford functional medicine care.
Best wishes, everyone!
None of these treatments will ever be available. I am 59. If they are avail one day, I’ll have long been gone. Very frustrating. I just started LDN about 1.5 months ago. I started on 1.5 mg. Increasing dose by .5 mg every two weeks until I reach 4.5 mg. I am praying I can stay on it with no serious adverse effects. Most side effects will go away by ver time. I would recommend staying on a med if it is helping. My muscle pain I night had gotten unbearable.
Glad to hear it’s helping! Nicotine patches scored better than most in our polls. Have you tried them yet?
I haven’t tried them. Do they need a prescription? What about the nicotine gum?
I will give Zyn, On or Velo. I assume they can be purchased without a prescription.
The upside of searching for a “silver bullet”, in terms of a medication, it might improve symptoms and daily functioning – but only while one continues to take this medication.
While this is understandable, but ultimately misses addressing (A) underlying causal factors and (B) encourages patient’s false hope and (C) passivity.
Hi Cort,
hope this works.
I saw, was it yesterday the youtube from Jarred younger. but thought he said that LDN with neuroinflammation was especially for FM, not so for ME/cfs or Long covid. What do you think?
It did! LDN was originally prescribed to reduce pain not for fatigue and it’s always been a question how helpful it was going to be for fatigue. I don’t know if any ME/CFS studies have been published. Younger’s statement – that it especially works for pain – certainly makes sense – although I would think it would help for ME/CFS or long COVID patients more on the FM’ey pain spectrum.
Fatigue without pain is another question.
Thanks!!!
Hi Cort, I am interested in the upcoming blog on vagal nerve stimulation. At least there is some reasonable scientific basis for it, with ANS etc. Related to this, have you heard of Newcastle University’s (UK) trial? I contacted the lead researcher, they are expecting to publish the results later this year. I am weighing up the idea of getting my daughter to try it. Her sleep is quite and issue
Attention – Cort!
Cambridge University study out finding high levels of interferon in long covid patients. And in those who recovered, levels returned to normal.
Seems to jive with the idea of persistent covid virus, or reactivation of other viruses.
Remember, studies show immune activation in the early years of ME/CFS, before levels fall below normal.
Maybe occam’s razor here – the simplest and best explanation is viral, or viral reactivation.
If this is correct, then one must hope and pray that PolyBio’s antiviral studies are successful.
Maybe there is hope after all
https://www.science.org/doi/10.1126/sciadv.adi9379?fbclid=IwY2xjawIoy2RleHRuA2FlbQIxMQABHQvbuzAikEzv3A12Yv5Mi332eOQlbjAZJOYCyA5qhJW9OoKs0STvIGPasw_aem_BSUVZIZE5nvvvryMa88Zzw
Here is how LDN SHOULD be dosed until we have science saying other wise, and Griffith and Jarred younger agree.
I hope Cort isn’t thinking of posting an experiment of =N1 without speaking to Griffith first who stick by once a day dosing. It would be incredibly reckless to publish an experiment without knowing a history and without proper research.
A reminder on cell proliferation (cancer) from LDN NOW –
Dosing information from LDN Now –
Naltrexone itself is a novel and innovative drug. When taken orally in high dose which provides a complete opioid receptor blockade, there can be increased cell proliferation. There have been many studies published using high doses for this effect in autism, fertility issues, brain diseases and compulsive addictive behavior disorders at doses of >50mg.
Other methods of delivery of Naltrexone are recently being studied in ophthalmology for treatment of ocular surface diseases such as impaired corneal wound healing and severe dry eye with ocular films (1) and eye drops (2). A Phase I clinical trial to test the tolerability of eye drops has also been published (3). For those living with complications in wound healing, topical Naltrexone cream in high concentration has also been studied because it encourages cell proliferation on the surface of the skin. This has been shown to enhance closure of epithelial, surgical, or full thickness cutaneous wounds in normal or diabetic individuals (4) (5).
In 1979 the effects of taking Naltrexone in low doses (LDN) was discovered. Two years of experimentation to clarify its mechanism were required to study the effects of LDN and were published in 1983 (6). LDN has been prescribed in doses <5mg in the clinical setting since the late 1980s (7).
There are a lot of questions surrounding what dose people should take with more and more people wanting to use this non toxic biotherapy approach to medicine for various illnesses. Here we will talk about how LDN modifies a biological system through the rebound effect.
In order to benefit from taking LDN to manage autoimmune/central nervous system disorders and cancer, understanding it’s mechanism (It is important to make an informed decision about your dosing protocol.)
What happens when you antagonize the receptors?
When used in low doses (<4.5mg) LDN antagonizes a sufficient percentage of the receptors for a short period of time on average for about 4 hours.
During this time, it tricks your body into believing it is not producing endorphins and enkephalins, specifically met-5-enkephalin known as Opioid Growth Factor, (OGF). As a result, the body compensates by stimulating an enhanced production of these opioids along with their receptors (9). OGF is a tonically active, inhibitory endogenous peptide which is made in the adrenal gland, by all proliferating cells, and the brain. LDN also upregulates the opioid receptors and the all too important nuclear-associated OGF receptor (OGFr) during the receptor blockade time.
What happens during the rebound effect?
Antagonizing the receptors for around 4 hours allows the upregulated levels of the body’s OGF and receptor to then interact and work long enough during the rebound effect in a non toxic manner to produce a positive outcome of suppressing the unwanted proliferation of cells (in autoimmune conditions and cancer).
Of importance, is the understanding that if there is not an adequate amount of receptors for OGF and endorphins to bind to and interact, the body is not able to utilize the endorphins and OGF efficiently. Only when LDN is no longer antagonizing or blocking the receptors, can the upregulated levels of endorphins and OGF interact with its receptor. It is this cell interaction during the rebound effect that is critical to one’s health with controlling errant cell proliferation, inhibiting inflammation, slowing down disease progression and promoting homeostasis/healing
As LDN does not need to be in your system in order for you to reap the benefits, an important question that needs to be asked, is how long will the rebound effect last after taking LDN? For some, the rebound effect can last longer than 24 hours in which case every other day dosing or three times a week (Mon, Wed, Fri) dosing is beneficial.
Pre-clinical studies with Head & Neck cancer have shown that the upregulated levels of OGF remain elevated for one week (10). The six-month clinical trial with MS done by Dr Gironi in Italy has shown that beta endorphins remain elevated one month after patients stopped LDN (11). This reiterates that it’s not just the upregulated levels of OGF and endorphins that are important, but the length of time they interact with the receptors which can only happen when LDN is no longer blocking or antagonizing them.
What dose is the correct dose?
It is worth noting that if you want to benefit from the rebound effect, taking too high of a dose of LDN or taking it too frequently will cancel out this effect.
Some Doctors prescribe more frequent dosing ie three times a day at higher doses for chronic pain relief. We cannot find any peer reviewed articles/studies to support this protocol. This is a different approach when using LDN to control errant cell proliferation and to slow down disease progression.
Dr Patricia J McLaughlin states “The clinical use of LDN for treatment of autoimmune disorders outpaced rigorous scientific research. Even today, many internet-originated rumors exist that warrant clarification. For example, ‘‘more is not better’’. The fallacy in this statement is obvious; LDN patients should not be encouraged to increase their dosage or take more than one tablet daily. At present, the timing of administration of LDN is a patient preference, and there are no basic science studies that conclude morning or evening consumption is either harmful or better.” (12).
Dr Jarred Younger states “Successful treatment of chronic pain with naltrexone may require low dosages. Theoretically, a complete blockade of endogenous opioid systems would not be a desirable outcome with a chronic pain patient. Basic science evidence supports that concept by showing that low- and high-dose opioid antagonists have quite different impacts on the physiologic system.” (13)
With responses to LDN being so varied it is proving challenging for both Doctors and patients to get the best effect with dosing. Some Doctors recommend starting at a low dose (1mg) increasing by 0.5mg-1mg every two weeks with a view to alleviating any potential side effects. In the six-month clinical trial with MS, participants started out at 2mg and worked their way up to 4mg throughout the first month. Participants in the trial were allowed to remain at a lower their dose if they felt that this dose was most suitable (14). Typically, the dose people take varies between 2mg-4.5mg, either once daily, every other day or three times a week. Again, the maximum daily dose for LDN effects if 4.5mg once a day.
When using LDN for cancer, it is important to understand that cell proliferation happens during the time the receptors are blocked. It is the upregulated levels of OGF and its receptor that suppresses cancer cell proliferation which happens during the rebound effect. (15). Pre-clinical studies with an aggressive cancer have shown that taking LDN every other day is also effective. LDN can be used on it’s own or as an adjunct therapy to chemotherapy (16)
By using LDN, we are modulating the OGF-OGFr axis which helps balance the immune system and works towards slowing down disease progression. While we are discovering that for some diseases there aren’t enough OGF receptors for the OGF to attach to and other diseases have too many receptors and not enough OGF. Either situation creates an imbalance which needs correcting.
http://www.ldnnow.com/48501/90512.html?fbclid=IwAR1KQj5u_t60Bn8IGGwhwTtr8HBu_53uTAxRAiOT8iezEr33NTOk0L4mEHk
Griffith need to pull there finger out and do the multi dosing trial, they know it works, I’m in regular contact with the head scientist there for 3 yrs, I presented my protocol at the ME International conference in Australia a year ago, with there help. There were doctors from all over the world there, That had NOTHING!!! What you are neglecting to acknowledge is that in the blockade stage, calcium ion channels are opened, this is cfses problem!!!! Viruses, Trauma etc close these channels, when the opiod receptor is blocked the calcium ion channels are opened. Anyways it works. If yr wise you can use it to function and ride the endorphins too.
I have zero pain. My legs were so bad before it was a 11 out of 10, a body needs magnesium, potassium, sodium and CALCIUM.