LDN calling: low-dose naltrexone could be just the ticket

Less is more when it comes to naltrexone and from boosting immunity to helping with inflammation, fibromyalgia and digestive issues, low dose naltrexone could be coming into its own.

Our immune systems have been thrown into the spotlight over the last year-and-a-half, and making sure they are as fit and responsive as possible seems a sensible approach. However, when people talk about longevity and healthspan supplements and prescriptions, low dose naltrexone – or LDN – doesn’t always come up. Is it time more people knew about it?

Longevity.Techology: Naltrexone has been FDA approved for over 30 years, first for alcohol and opiate dependence and later for obesity, but that is using regular dosages. However, the really interesting stuff happens at lower doses. Intrigued, we caught up with Dr Sajad Zalzala, Co-founder and Chief Medical Officer of AgelessRx, to get the lowdown on LDN.

It is thought that naltrexone temporarily binds and blocks the opioid (endorphin) receptors. When the blocking ends after a few hours, the endorphin levels climb higher than before, causing a “rebound effect” – but how did this discovery come about?

Discovering the effects of low dose naltrexone

“Using naltrexone in low doses is attributed to Dr Bernard Bihari who, in the late 1980s, discovered naltrexone’s use in patients who had really low endorphin levels [1],” explains Dr Zalzala. “Dr Bihari found that AIDS patients had much lower than normal endorphin levels and hypothesized that this had something to do with their lowered immunity. So he looked for medications that would raise endorphins and found naltrexone.

“He discovered naltrexone could significantly boost endorphin levels, which was thought could help AIDS patients stave off opportunistic infections and live longer. Dr Bihari tried different doses of naltrexone and found that doses as low as 3mg given at night had the same endorphin boosting effect as the regular dose (50mg), but with lower cost and far fewer side effects. From there, 4.5mg at bedtime became the most widely used and studied dose.”

Low dose naltrexone benefits

Since Bihari’s discovery, there have been many smaller scale trials in humans (and animals) evaluating LDN for all sorts of conditions – and a common theme seems to be immune dysregulation and inflammation.

In 2013, a Stanford-based study by Dr Jarred Younger showed a 28.8% reduction in pain in fibromyalgia patients taking 4.5mg daily. The next year, he published a paper that helped shed light on how LDN can have benefits on a wide range of symptoms and disorders. 
“Dr Bihari himself would joke that he worried people would think it was like snake oil because of this,” laughs Zalzala.

“Many of the benefits are thought to be because LDN stimulates the body to naturally produce more endogenous opioids,” he continues. “Endorphins are one of those opioids; met-enkephalin is another. There is a large body of evidence suggesting met-enkephalin’s positive impact on the immune system.

“In addition to the “endorphin rebound” phenomenon, which is thought to be one of the ways LDN exerts its action, Dr Younger found that LDN blocks Toll-like receptor 4 (TLR4) that are found on microglia cells in the brain, which causes the microglial cells to “calm down” and reduce their inflammatory response. Dr Younger once told me that he thought LDN was “the most powerful tool that he knew of ” to reduce glial cell (and therefore brain and central nervous system) inflammation.”

Dr Zalzala feels recent research supports the idea that LDN’s “magic” has to do with at least two mechanisms of action – and indeed is hopeful that more might be found.

Low dose naltrexone for mental health

Mood disorders, such as depression and anxiety, are thought to be driven, at least in part, by inflammation in the brain. Conditions such as post-concussive disorder and maybe even PTSD are also thought to be driven by brain inflammation.

“Unlike the rest of the body, where inflammation can be cleared fairly quickly, brain inflammation seems to be much harder to quench,” explains Zalzala. “This is why it is thought that LDN works where so many other therapies tend to fall short.”

More from Dr Zalzala – find out why sticking with glutathione could be a smart longevity choice

Low dose naltrexone can help with inflammation

LDN lowers chronic inflammation, in short, by blocking TLR4 and glial cell excitability. In some studies, LDN was show to lower proinflammatory cytokines (IL-6, for example), and LDN also stimulates the body to produce more met-enkephalin, which is linked to immune system modulation, thus benefiting inflammation. Inflammation is, of course, linked with aging.

How long does it take for low dose naltrexone to work?

A key question is how long – people are often keen to ‘feel’ a supplement or prescription getting to work. What is Dr Zalzala’s experience?

“It can vary person to person,” he says. “I have seen patients report improved symptoms after a single dose, and others who never experience any benefit. Both of these seem to be on the extreme end. In my experience of prescribing LDN to probably over 3,000 patients by now, most people will start to experience benefits after about two weeks of starting LDN, but sometimes it can take as long as three months.”

However, Zalzala stresses two major caveats.

There seem to be about 10-15% of people who either cannot tolerate LDN, or they just do not see any benefit with LDN. In addition, most people will respond best at 4.5mg per day (taken at night), but there is some variation – and some people will not see any benefit until they hit their “Goldilocks” dose (the dose that is just right for them).”

Is low dose naltrexone safe?

Dr Zalzala explains that from a toxicity perspective, LDN is very safe. “In fact I suspect that once a patient has blocked their opioid receptors fully, there is no room to block it more and, therefore, extra naltrexone gets metabolized and leaves the body,” he says. “This makes it safer than commonly used over-the-counter medications such as Tylenol or ibuprofen. LDN can have side effects, but I have never seen one that I would consider “dangerous”. We warn patients to expect side effects such as vivid dreams and sleep disturbance, mild increase in anxiety, headaches, and nausea.  However, we can reduce the risk of side effects by starting at a low-low dose of 1.5mg and asking patients to work up to 4.5mg over a few weeks, or as tolerated. Most side effects will subside after a few days of use. Melatonin seems to help with some of the sleep disturbance.”

[1] https://bit.ly/3Ajx0cZ

Images and videos courtesy of AgelesRX and Annie Spratt / Unsplash

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