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Discussing Low-Dose Naltrexone with Sajad Zalzala

This drug, known for curbing addictions, has shown other benefits in some patients.

Zalzala interviewZalzala interview
 

Dr. Sajad Zalzala, co-founder of AgelessRx, prescribes naltrexone for a variety of conditions and is currently enrolling patients in clinical trials for its effectiveness against the lingering effects of COVID-19 as well as for longevity. We caught up with him to discuss the progress in this area.

For the people who aren’t familiar with low-dose naltrexone, can you give us an overview of the history and how you’re using, why you’re using, low-dose naltrexone?

The regular-dose naltrexone was FDA approved for alcoholism back in the 80s or early 90s. It blocks the opioid receptors. For alcoholism, it seems to remove the euphoria that that some people get with drinking alcohol and therefore, people who have trouble with addiction with alcohol just no longer feel the need to drink anymore.

Obviously, if you’re on opioid medications, and the high dose of naltrexone or regular-dose naltrexone blocks the opioid receptors, so the Percocet and the morphine just can’t bind to the opioid receptors anymore, you don’t get that high or the addictive effects of the opioid drugs anymore.

In terms of how that got turned into low-dose naltrexone, from what I read, there was a physician by the name of Dr. Bihari. Based on what I understand from his research, he was looking for a way, I think he noticed that patients who had HIV, AIDS, had a low baseline, a low endorphin level.

He made that discovery, and this is back in the 80s, before we started getting any of the antiretrovirals and such, so they’re trying to find some solution. He scoured and found that naltrexone has some endorphin effect on it. From what I understand, he did some experimentation and found that a low dose of naltrexone can actually boost endorphin levels.

That led to the discovery of low-dose naltrexone. By trial and error, he found that the dose around, 3 milligrams, 4 1/2 milligrams, 5, tend to do give you all the benefits of naltrexone without many of the side effects that you get with the higher dose. That’s why we call it low-dose naltrexone, to differentiate it from from the high dose. I would go as far as saying that the high-dose naltrexone, the regular dose, doesn’t have the same therapeutic properties as low-dose.

Going back to some of the work from Dr. Bihari, he cites a case where a patient was on low-dose naltrexone, an HIV patient, it seemed to keep his cancer in remission. As the story goes, the pharmacy accidentally dispensed the 50-milligram dose, and that ended this patient’s remission and he passed away shortly thereafter from the progression of cancer. That’s an anecdote, but I think there’s a lot of reasons to believe why that could be potentially true given the mechanism of action of what I understand from LDN.

I came across a study on ovarian cancer where it suggested low-dose naltrexone was effective in dampening the growth of cancer. When you have higher doses of naltrexone, it can actually encourage cell growth and proliferation. There seems to be an opposite effect at the dosing extremes.

Exactly. I think there was a recent mouse study that that showed that naltrexone had some anti-tumor effects to it as well. I didn’t dig into the study to see what the dose was compared to humans, but it’s always hard to translate most of those to human doses anyway.

With this opioid growth factor, the naltrexone blocks the receptor site, and that causes a compensatory upswing in the number of OGF receptors and opioid growth factor as well. That’s where you get most of the effects that you see with low-dose naltrexone.

I believe so. There seems to be two mechanism of action responses for LDN. One is the rebound effects, it temporarily blocked the opioid receptor, and that causes a rebound upregulation of these growth factor receptors you’re talking about and probably other endorphin receptors as well. Endorphin receptors are in immune cells, everywhere that you look, not just related to pain.

There seems to be a lot of other functions. I’m not an immunologist, so I can’t really dive into the details there, but that’s my understanding. There’s endorphin receptors in a lot of different tissues, not just the brain, not just the spinal cord, things like that, where the pain is controlled. That’s one mechanism.

The other mechanism, some research suggests that it’s a direct inhibitor of toll-like receptor four, and then that seems to have a benefit when it comes to neuroinflammation, inflammation in the brain and the nerves, and that could account for some of the mechanism of action for things like Complex Regional Pain Syndrome and more interest in it for mood disorder, for PTSD, neuropathies. I’ve had a lot of patients, they read about LDN and they try it for neuropathy, and it almost clears up their neuropathy. A lot of times, the doctor says it’s idiopathic neuropathy, but they try LDN and it seems to help.

It’s hard to tell which of those two. Is it the rebound effect, or is it TLR4 that seems to be responsible? I suspect it’s probably a combination, and the reason is because I spoke to Jarred Younger, he did some of the studies on fibromyalgia at UCLA a few years ago.

He found that LDN was very helpful for fibromyalgia, and he helped elucidate some of the mechanism of action. He tried another drug called dextromethorphan on fibromyalgia patients, also supposed to help the TLR4 receptor, but he didn’t even get this. He didn’t seem to get the same clinical response. There seems to be something about LDN, that we need both for it to work properly.

You’ve treated people with a wide range of different disorders with low-dose naltrexone, from what I gather. Is there a common thread that ties most of these different disorders together? Are they all inflammatory in nature?

Inflammation seems to be the common thread among almost all these diseases that people seek treatment with LDN from. The #1 condition is probably fibromyalgia/chronic fatigue. That’s probably the main reason people seek a prescription for LDN, probably followed closely with Hashimoto’s thyroiditis, and then maybe things like rheumatoid arthritis, other autoimmune conditions, and increasingly for mood. It seems to benefit mood as well in some patients.

I understand depression is actually somewhat poorly understood, it’s a general constellation of symptoms. You can try a half a dozen different drugs on depression, and none of them may do the trick, but some people respond to very specific things. In this case, low-dose naltrexone may be one of them.

A lot of these diseases and symptoms are very complicated. When I prescribe to patients, I’m like, “Hey, look, there’s probably a lot of factors that lead to your symptoms. As good as LDN can be for some patients, it may or may not work for you.” I see that clinically as well. It doesn’t help everybody.

There’s a portion of the population that try it, and either they don’t tolerate it because of side effects, or they just don’t get any benefits out of it. I’m not quite sure why. Like I said, I suspect it just has to do with the diversity of mechanisms of action and causes of the various symptoms.

My understanding is that even in relatively high doses, serious side effects aren’t that common, but in low doses, it’s pretty safe. I’m sure there are exceptions.

It’s very low risk. If you look at the FDA, the FDA warnings on naltrexone, you’ll see something about liver toxicity. If you look at the literature, you’ll see that they’ve followed that up with trials, and there doesn’t seem to be any evidence that naltrexone has any liver toxicity whatsoever. In fact, there’s a case study, a 26 year old female was being treated for alcoholism, alcohol addiction, and she was given a prescription: 30 tablets of 50-milligram naltrexone, she got fed up, she swallowed the whole thing, and then she regretted it and she was at the hospital.

She was observed overnight. I think she had some mild symptoms, like nausea, dizziness, and things like that. None of her lab tests came back majorly abnormal. There was no indication of liver toxicity, no indication of renal toxicity. In fact, if you read the case study, she had struggled with opioid and alcohol addiction for so long, overdosing herself seemed to be the best thing she ever did, because it gave her two weeks of her life back. For two weeks, she had no cravings for drug or alcohol, and it was enough for her to get her life back together.

Again, I didn’t treat this patient. It’s just based on a case report, but they were saying that it gave her two weeks of regular life, enough to get her life back together. I highlight that as the safety. If you were to do that with other drugs, and I don’t want to mention any names or give any ideas, that would be a really toxic dose. If you took a bottle of a lot of over-the-counter, you would have some serious toxicity. It just highlights the fact that there’s there’s no known toxicity of naltrexone, even at a single dose of 1500 milligrams.

There seems to be an avalanche of positive accolades and applications for naltrexone across the web, but not as many clinical studies to back up those anecdotes. Naltrexone is generic now, isn’t it?

Yeah, it’s been generic for years.

That’s a disincentive for people to do clinical trials on things like fibromyalgia or Crohn’s disease?

Yes and no. I spoke to a physician in New Jersey. She was trying to patent a combination of naltrexone and acetaminophen for migraines, and so while she was willing to put in the the funds to do the clinical trial, she was hoping to get a patent at the end of it, which I have mixed feelings about.

A patent is great because it incentivizes people to do trials and things like that, but on the other hand, we all know what happens when you force a patent on a medication, all of a sudden it drives the price up. For example, there was a generic for colchicine, 0.6 milligrams, there’s some FDA dispute or something like that, and only the brand name could be available, and then all of a sudden one tablet went from pennies to dollars and dollars, ten dollars a tablet. The hidden thing about drug patents is that yes, they are beneficial to support clinical trials and things like that, but in some ways you actually lose access to medication if it’s patented.

On that note, for people who are interested or think they may benefit from taking low-dose naltrexone, it’s an affordable option compared to other options, potentially? Is that true? Relatively affordable because it’s generic.

It can be very affordable. The price varies. Some compounding pharmacies will give you a month’s supply of LDN for $20. Other compounding pharms, a little bit more. The price varies. Shop around the various compounding pharmacies, you can usually find a very, very good price for for it. Usually, the most expensive part is for the first few weeks, because that’s where you start a low dose, you ramp up. You tend to go through a lot of LDN, and it tends to be a little bit more costly up front, but then once somebody settles in on a maintenance, it’s very, very reasonable.

Do most insurance companies cover prescriptions for low-dose Naltrexone?

No. Part of it is because it’s compounded. Pharmacy benefits across the board just don’t don’t cover any component in general. People can use their HSA, FSA, I think some pharmacies accept that. We accept that at AgelessRx, we accept HSA, FSA, but that’s not really like an insurance coverage per se.

You actually have a couple clinical trials that you’re ramping up right now, isn’t that correct?

Yeah, our goal is to try to expand and enhance the understanding of LDN and its use.

Could you tell me a little bit more about the two? You have one for long COVID and one targeting longevity?

As an intervention trial, we have an IRB approval for long COVID. Post COVID, long COVID, depending on when you picked up on that term. We’re actually doing a combination of two therapies, a low-dose naltrexone and NAD patch. There’s some anecdotal evidence that each of them separately can definitely have a benefit for patients for long COVID, and I thought that if we did a clinical trial combining them, then you’d have the best chance of getting a positive outcome of the trial.

The reason why we selected LDN is because it’s thought that a lot of these idiopathic conditions, fibromyalgia, chronic fatigue syndrome, tend to follow viral infection. One of the proposed mechanisms or pathophysiology of these diseases is post-viral, Epstein-Barr virus, cytomegalovirus, other viruses, post-infections, and it’s very well known. There’s a lot of post-infectious disorders.

Based on my experience, some of those post-infectious disorders respond well to LDN. That’s why we decided on long COVID, it’s probably just another post-infectious disorder, but millions of people have it. It’s in the news, so let’s see if LDN will work as well for this post-viral disorder.

Have you worked with any long COVID patients as of yet? Have you had some coming into the clinic?

Before we launched the trial, we had some people read about long COVID and come to our telemedicine platform to ask for LDN, and we’ve gotten some anecdotal responses saying that it’s helped them. Again, not everybody. We’ve enrolled probably about 15, 20 people into our clinical trial. I don’t want to say anything until we actually do an analysis, but so far, it looks promising. We are continuing to enroll and hope to be able to get probably about 60 people on this pilot trial before we close it.

Do you have clinical endpoints for that trial?

The biggest one is fatigue. There are several symptoms that are common with long COVID; I felt fatigue was probably the the best one to target. We use the Chalder fatigue scale, a standardized scale for fatigue. Some people are fortunate that they recover from it pretty quickly. Others are still not recovered.

We actually had an IRB approval for an acute COVID trial using a combination of metformin and low-dose naltrexone, but we could never find the right way to enroll for that. We were hoping to work with some labs that could provide us access to patients who are testing right on the spot, but we never really found a channel for that, so we dropped it.

I was really hoping to see it, the primary endpoint would have been hospitalizations and symptoms, but what I was really interested in seeing is whether metformin and LDN would actually prevent long COVID. I guess we’ll never know. One of my regrets here is that we never got that one off the ground.

And then you have a longevity trial.

That’s an observational trial, a retrospective/cross sectional trial. I feel strongly that just given all the benefits I see from LDN, there must be some influence on aging, on the aging process, on inflammation and autoimmunity and all these other things that go along with aging. LDN seems to work so well on so many of those.

You’re investigating the hallmarks of aging, and I gave you some information about that as well. I don’t know if you had any more to add to that, but it seems like LDN can hit maybe a couple or more of the the nine hallmarks of aging, but there hasn’t really been anybody who has explored that or even asked that question.

We’re trying to enroll as many people who are on LDN as possible, anybody, if you’ve just started LDN or if you’ve been on it for just a short while, we want to enroll, and we’re really interested in people who have been on it for a long time. We want you enrolled to see if there’s any patterns that emerge.

I want to ask you about naltrexone and weight loss.

Naltrexone is FDA approved for weight loss in combination with another medication. The combination is called Contrave, approved probably 10 years ago or so. A lot of people, a lot of physicians and medical professionals, don’t realize that one of the barriers to LDN is guilt by association. A lot of physicians say “I can’t prescribe you naltrexone, I’m not a pain clinic. You’re not a drug addict. I don’t want to get in trouble with the medical board for prescribing a controlled substance.”

Those are all misconceptions. It’s not a controlled substance. It’s not addictive, and it’s not classified by the DEA. There’s no issue. I’ve looked, I’ve researched, I’ve asked pharmacies. You don’t need to provide your DEA number when you prescribe LDN or naltrexone at all. I tell patients, go ask your doctor, she’ll give you Contrave, that’s got naltrexone in it. What’s the big deal with LDN? It was FDA approved in combination, but it’s a different dose and it’s a different formula.

Is that a high dose, low dose, middle of the road dose?

I would probably put it more towards medium to high dose. The maintenance dose for Contrave is 32 milligrams of naltrexone, but it’s an extended release formulation.

How would that play into the low-dose Naltrexone mechanism where you’re blocking transiently and then you get an upswing as opposed to having a sort of long, slow blockade. Would you anticipate the same pharmacodynamics?

I would suspect that what we’re seeing with that combination is that Wellbutrin is a drug in there. When using it for smoking cessation, it’s called Zyban. The reason why it works for smoking cessation and FDA approved is because it seems to help curb cravings. If you couple that with the anti-addictive properties of naltrexone, then you’re capturing people who typically seem to have problems with weight loss when it comes to food cravings.

That’s where Contrave seems to shine. People just have strong cravings for food: instead of being addicted to alcohol, instead of being addicted to smoking, they’re addicted to food. In a lot of people, food gives them this high so that they’re always craving it. That combination seems pretty potent.

In that case, they’re using it more towards the high dose, the original intent of naltrexone, rather than the low dose, although it is at that dose where some people reported, when they first started out, they get some of the benefits of LDN. It’s hard to tell because LDN is supposed to be immediate release. It’s supposed to give you that temporary blockage and then a rebound.

I read an article that indicated that naltrexone can improve insulin resistance. Do you work with any diabetics, any observations you may have made in the clinic on improvements in glucose tolerance or anything along those lines?

We need to see more more of that study before we can draw any conclusions. Based on my recollection, it left some questions open, but it makes sense. Clinically, what I see for thyroid patients, sometimes I get patients who seek out LDN to help with Hashimoto’s and sometimes I see these patients on really high doses of thyroid medication, like 300 micrograms, 250 micrograms, and that’s like double, triple the dose that a patient will require. So I suspect that there’s some thyroid resistance going on, receptor resistance.

When I put patients on LDN, I’ve had several cases where they actually flip to become hyperthyroid. They get palpitations, they get insomnia, they get anxiety, and it seems their lab work flips and becomes hyper. I think what happens is the LDN seems to be helping to overcome that resistance. I don’t have any proof for that. That’s just my clinical suspicion. It definitely makes sense that LDN would help. If it helps with thyroid receptor resistance, it would make sense that it probably helps with other receptor resistance syndromes.

By the way, as far as I know, thyroid receptor resistance has not really been officially acknowledged, but I’m sure if you talk to an endocrinologist or other primary care doctors, everybody I think has a patient who has been on an ungodly dose of thyroid medication. The only way to explain why they’re able to tolerate that is because of resistance.

Is there anything you want to add that you think it’d be beneficial, anything I haven’t asked about?

Roughly, in my experience, about 10 to 20% of people do phenomenally on LDN. About 10 to 20% of people either don’t respond or don’t tolerate it and so they drop off. About 60% or so have some reaction in between where where they get some benefit to it, but it’s not as pronounced as some of the people who claim that it’s life changing.

Honestly, sometimes they don’t realize how well it’s working for them until they stop it. I can’t tell you the number of times I’ve had people, they don’t request a refill for a year, and then I hear from them a year later. I’m like, “Hey, where have you been?” It’s like, “Well, I took a break. I didn’t think it was working for me, but looking back, I think I felt a lot better on LDN. I want to try it again.”

It wasn’t life changing. Most people stick around, but sometimes it’s subtle. Some of the changes are subtle, because sometimes people forget how sick they feel until they start feeling better and then when they stop doing something. The other common question that people ask me is, “How long do we have to be on LDN?” And I’m like, “If you can’t find the reason why you’re sick, your reasons for your symptoms, and remediate all those reasons, you probably can’t get off.” For most people, we’re not quite sure, and so LDN seems to be a long-term thing for patients.

I’ve had patients stop LDN, it seems like their symptoms continue to be steadily improved from baseline. Other people, they stopped, then about two or three weeks later, symptoms start to creep back, not full force. The most common phenomenon is, they had this two-week honeymoon after stopping the LDN, and then it slowly started to come back.

As far as I know, there’s no withdrawals to it. People say “Hey, can I just stop if it’s not working?” and as far as I know, there’s no issue. Now, with every one of my statements, there’s an exception. I’ve treated enough LDN patients that there’s always an exception. There’s always exceptions to somebody having withdrawal symptoms.

There’s always exceptions, somebody having some crazy side effect to it. Those are the exceptions and definitely not the rule when it comes to LDN.

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About the author
Stephen Rose

Stephen Rose

Chris is one of the writers at Lifespan.io. His interest in regenerative medicine and aging emerged as his personal training client base grew older and their training priorities shifted. He started his masters work in Bioengineering at Harvard University in 2013 and is currently completing his PhD at SUNY Polytechnic University in Albany, NY. His dissertation is focused on the role of the senescent cell burden in the development of fibrotic disease. His many interests include working out, molecular gastronomy, architectural design, and herbology.
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