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Stephen Dickson, BSC (hons) MRPharmS - Using an Old Drug to Trick the Immune System into Healing Itself (2018 Conference) (LDN, low dose naltrexone)
Stephen Dickson, BSC (hons) MRPharmS - Using an Old Drug to Trick the Immune System into Healing Itself (2018 Conference) (LDN, low dose naltrexone)
Stephen Dickson: So basically this is about a bit of the history as part we're seeing and about how we're using the LDN at the moment to treat various diseases. So if you've seen one of my presentations before you recognize some of the slides, but I'll try and sort of add in some extra things that we haven't had before.
So the first patent for naltrexone came in about 1966. And in fact, it was Naloxone, which was still one of the most important drugs in the WHO essential medicine list. And it's used all over the world because of its properties of blocking opiates. The oralyl active, which is on the right-hand side, you'll see that Naltrexone has an extra little bit of a molecular group there which actually makes it more orally active bioavailable.
So Naloxone and Naltrexone are almost identical but Naltrexone actually has a little bit extra, which makes it more capable of surviving oral transit into the bloodstream. It's really interesting that naltrexone has very, very interesting pharmacology because it hits and attaches onto the G protein-coupled receptors.
Now, those are a very useful group of receptors because they have multiple outcomes depending on how the agonist or antagonist attaches onto them. G protein-coupled receptors can have more than one functional outcome based upon what type or what structure or how tightly the molecule bonds to each of the receptors.
So from just, if you look at the bottom part there in the trimeric receptor, you can actually have six possible outcomes from just the three different parts of the receptor. But it's quite a common quite common thing across in pharmacology that you have multiple different outcomes based upon how the agonists or antagonists attach onto them.
But this particular family, things like glucagon, the beta-agonists and beta-antagonists, opiate somatostatin and TLR receptors, which we'll talk about later on are all part of the same family. To understand how Naltrexone has been used for autoimmune disease and cancer it's useful to know what opioid receptors are. So opiate receptors basically are all over the body, and we know it because we use painkillers like morphine diamorphine, etc. Codeine, and the way that they work is that they are agonists, which fit and activate opiate receptors. You can also have partial agonists like buprenorphine, which sit on the receptor partially activate the receptor, but also block other endogenous and exogenous opiates from activating the receptor.
And then we have antagonists like naltrexone and Naloxone, which block the receptor and stop anything else from activating it. So the history and pharmacology of LDN are based upon how naltrexone works. So, but actually looking at how opiates work in the body. We all have inside our bodies a constant production of endorphins. Now endorphins are made by your brain, and your body uses it to create a homeostatic environment where the immune regulatory system regulates pain control. It regulates all sorts of systems throughout the body.
And when we take exogenous opiates like heroin, like codeine, like tramadol, for example, you are exposing the body to exogenous opiates. So what happens if you take lots and lots of, if you take any opiates, you get to sort of at the top, you see analgesia and euphoria. That's the typical things you would see for opiates, but over time you get a reduction in sensitivity to those opiates because your body gets used to being exposed to these exoginous opiates and receptors, internalize or deactivate, or become less sensitive.
So, and that's where we get this whole addiction problem that we treat like addiction to heroin addiction to do methadone. And actually one of the most interesting things the first uses of naltrexone was it was used for treating addiction. So what you find is you give a full dose of Naltrexone, it blocks these receptors, these opiate receptors, and it reduces this pharmacological addiction by allowing the receptors to re-express and grow back again.
So for addictions, and Naltrexone itself is licensed from 50 milligrams to 200 milligrams daily, and it is incredibly successful in stopping people from taking other opiates. So if you're addicted to heroin, and you're given naltrexone or Naloxone I don't know if anyone has seen any of those videos? There are quite good ones on YouTube. No it's quite sad, but it's interesting to watch because you'll see someone who's overdosed on fentanyl. They're lying there, about to die, you give them a shot of Naloxone and then suddenly they spring to life, like a zombie coming out of the grave.
And they're always very, very unhappy because what's happened is all of their opiate receptors have been blocked at once by Naloxone. But Naltrexone when you take it orally isn't actually terribly good for addictions because it's quite a short-acting. You have to take it every day, and if you're addicted to heroin, and you want to get a high from heroin, then why would you take a tablet every day? So that's a bit of an issue. But also when you're taking it in these doses of 50 to 300 milligrams, it blocks all of our opiate receptors. Now, as we talked about earlier on, opioid receptors are being used constantly by your body and by your brain to regulate all your other natural systems.
So what you can end up with is this thing called dysphoria, where patients feel very flat, they feel unable to have an ability to feel happiness, feel that they’re drifting through the world and it kind of sort of vague haze, and that's because all of the receptors that they're using, their natural endogenous endorphins are hitting normally have been blocked by big doses of naltrexone. Interestingly, we're actually finding that naltrexone is, in these doses, is having a resurgence for use in the treatment of alcohol addiction. We'll talk a bit about that later on.
But now on to the good stuff. I think if anyone has been involved in pharmacology and medicine for years, you'll know that drugs have side effects and most drugs are not 100% selective.
So it's almost impossible to create a drug that does exactly what you want it to do and doesn't do something else. And that's because of the way our bodies are made in multiple systems, interact homeostasis, you can change one system and something else tries to correct it. So drug that's called cell activity.
So Naltrexone is not a hundred per cent selective. And what we do find with most drugs is after they've been launched, they go through this course called an elucidation period where we discover that not only do they do what we licensed them for, but Oh, heyho they do something else? One of the most common examples of that is things like Amitriptyline, Gabapentin, which was originally licensed to be used as antidepressants but they’re more commonly used now as painkillers for nerve blocking and to help with pain. So drug companies look for this. So they look for a side effect happening here, is that useful? So, and actually, this is something that is a common process that goes through.
But we do find that drugs which affect homeostasis often have different effects in low and high doses. And there's a lot of examples of that through the literature, but I’m sure the Q&A can elucidate that. But looking at the immunological effects of naltrexone drugs are rarely - when they've manufactured the mechanism for making them and the way that you synthesize drugs you end up with a chiral mixture. So has anyone seen a sort of picture like this before? Yes. So we understand the concept of Chirality? So when you basically put all the building blocks together to make a drug you end up with two things that are identical. We've got all the same building blocks. Just like your hand one left-handed one right-handed. Then what we find is that levol drugs tend to be the ones that we find are used in humans that have the most effect. So you're looking at levo thyroxin you're looking at levo Cetirizine , which is the levo isomer of that. And drug companies have been trying recently just to produce the levo tablets are just unbelievable because often the Dextro the right-hand side has got side effects that are not beneficial to the patient because the levo mechanism is the one that the body is naturally designed, so the receptors are designed for levo, left-handed molecules instead of right-handed molecules. But that doesn't mean that the right-hand molecule doesn't do something because it often causes side effects. So different isomers of the same drug can have different pharmacological targets. Yes. Okay. Right. I've got there in the end.
Okay. So the various effects that we have for Low Dose Naltrexone (LDN) are that when we're using LDN rather than full dose naltrexone its used at a lower dose than we do for addiction. So we're using a kind of 0.5 to five milligrams. But you can still get the withdrawal effects because you are giving it a biologically understandable dose of naltrexone.
So even at the 4.5 milligrams, you can still precipitate withdrawal from opiates, but it does bind to the endorphin receptors, which are those opiate receptors we spoke about earlier on and it can interfere with homeostasis in the body by binding onto the receptors. But we've discovered recently also the dextro molecule binds onto TLR receptors. Now I’ll go into that in a minute, and that's part of the immune system. So you don't need to worry. But also has a much shorter duration of action, cause you're giving a much lower dose. So we've known that endorphins, that's these natural endogenous opiates that we spoke about at the start, those have been known to be immunomodulators since 1985. So most of what we are doing in this conference is talking about immunomodulation using naltrexone and these TLR receptors that I'm just about to talk about, are part of the innate immune system. What we know about the immunological effects of LDN, pretty much, most of the science started off came from Doctor Zagon. He's done about 30 years of research into this, and it's produced a plephora of incredibly beautiful papers that really, it would take forever to try and explain, but I've sort of summarized it here. If you want to go do a search in pubmed you can read all of the papers, they are very, very interesting, but quite dry.
And so basically if you summarize it in layman's terms, Many outward diseases are expressions of the malfunctioning immune system. So everything from arthritis to pain control, to chronic fatigue syndrome, to Lyme disease, to cancer, can all be traced back to its roots based on a malfunctioning immune system.
And what he says is the blocking opiate receptors briefly using Naltrexone causes an upregulation in the production of these natural endorphins that we know are to be immunomodulators and they can correct an immune system malfunction. But also what we discovered recently is these, the production of extra, or the dosing with LDN at the production of endorphins also seems to have a role in cell proliferation. So that's cell growth. So in the number of divisions that are cell makes, so for example, cancer where it grows really quickly and out of control, it seems to be that naltrexone, this natural endogenous opiate system has control, some control over that. So in experimental models, either in the lab or in animals, they've shown beneficial effects using naltrexone in diseases, it's speeding up wound healing has been really interesting. MS obviously we know here, pancreatic cancer, breast cancer, Crohn's disease. There have been some amazing studies recently. This list grows constantly. So I mean, everybody in this room can probably stick their hand up and see, you know, Haley-Haley disease, I had a patient that did amazingly well or, or Hashimoto's disease, and the patient was doing fairly well.
This list keeps getting bigger and bigger and bigger. And one of the reasons, as we said earlier on, Toll like receptors are part of this immune system and a lot of people who have got malfunctioning immune systems have that because there's something wrong with the way they're responding to stimuli from outside or something from internally. So they may be responding incorrectly to a natural protein in their body that's causing inflammation or in the case of Lyme disease that potentially the system has started to run away with itself. And you've got autoimmune disease where you're attacking yourself. So these TLR receptors are part of that process, the TLR receptors sits kind of at the top of the immune cascade, and they are what defend us from bacterial, viral invasion.
So when the TLR start to notice something that's not supposed to be there, it kicks off a whole cascade, immune cascade, of reactions that cause inflammation.
So what we think at the moment is that the levo naltrexone, as we said earlier on acts at the opiate receptors to block them and cause this escalation and extra production of endorphins, whereas the Dextro Naltrexone is an antagonist at some of these TLR subtypes, anybody following me.
So the dextro naltrexone is a potent antagonist at some of these subtypes, which means that basically what we're looking at doing is if the TLR receptor is incorrectly recognizing natural endogenous products in your body then by blocking those receptors, we can stop the inflammation that's produced by this system being activated inappropriately.
So basically we're looking at using naltrexone now for all these myriad of diseases, autoimmune diseases, cancer, CNS disorders, and chronic pain. I'm just going to run through some of these, just put some examples. So the chronic pain you'd be looking at the levo molecule, doing upregulation of endorphins, causing an increased CNS release of dopamine, which helps the pain control and also the levo molecule working through this endorphin system would cause a suppression of inflammatory cytokines whereas the Dextro naltrexone suppresses the cytokine-mediated immune system, but also it appears to suppress NF Kappa B and reduce inflammation. There's some evidence of glial cell activation as well, but I'm not sure on that one because the papers aren't incredibly well receipted yet, but this is, so this chronic pain scenario is where you would have CRP, that’s chronic regional pain, fibromyalgia, nerve damage, potentially ALS. And the dopaminergic mechanisms you're looking at again, the up-regulation of endorphins causing the extra release of dopamine. And that may be beneficial in patients with Parkinson's disease, who are, who have issues with dopamine centrally, but it does cause an improvement in mood.
And I think any of our patients would tell you that taking LDN does seem to make them feel better regardless of the disease state. Um, it's probably because of that, but also working with the endorphins system you can get an enhancement of the effect of GABA by reducing inflammation. So when depression, anxiety, Parkinson's disease, potentially Alzheimer's disease and maybe some sort of benefits from using Low Dose Naltrexone (LDN). In Parkinson's there’s a very recent upsurge in the use of LDN, but there doesn't appear to be an awful lot of benefit longterm to the disease state, but I seem to make the patients feel an awful lot better.
If anyone wants to correct me on that, please do. Cancer, I'm going to leave to professor Dalgleish to talk about, but basically, I've just summarized your last beautiful paper there in five lines, and he's laughing. So I think I'll leave you to talk about that at length. But in a more autoimmune disease, again, we're getting this upregulation of endorphins causing immunomodulation. Potentially through the OGF access in autoimmune disease, we can treat MS, Crohns, Hashimoto's plus the myriad of other autoimmune diseases that we're talking about. Again, the Dex molecule working through the TLR system would be downregulating the inappropriate immune responses, and it could work through NF Kappa B and inflammation.
There's quite a lot of recent research, which has worth talking about, this is from 2018. So Mitchell et all did a little study and showed that in IBD, we could get a clinical improvement of 70, almost 75% of patients. So the paper that was just published just a couple of months ago is actually very interesting.
One thing to talk about in a minute are the changes in the number of patients in the different groups and different disease groups that we see recently. Again, another paper from January, IBD patients showing the - basically, it looked to see if you put LDN and what else stops?
One of the problems with Crohn's Disease, IBD is that you get an awful lot of people will get flareups, tend to not do very well. So what you want to do is reduce the number of flareups that people have. And this study seemed to show that when you put LDN in the number of flareups was reduced, and they got that information by looking at the number, the amount of prednisone and internal corticosteroids et cetera and other drugs that were there would have been used in the event of flareups. So that's, that's a very interesting because that's clinically important than could be immediately used in clinical practice. One of the other things that have happened the last sort of year is the incredible paper published in Haley Haley disease.
Now it was case reports rather than actually a proper study, but that sparked off - Haley-Haley disease is a very unusual, very rare condition, but there really isn't anything to treat it. And, this paper shows that there were a couple of cases where people who had nothing else to try thought, why not try LDN? And lo and behold, two of them got better. So this paper is showing another three, there was a variation in the response, which is quite interesting. Another paper by Dr. Zagon in January this year basically again, he's just confirming from a different angle that the OGF axis, this production of endorphins, overproduction of endorphins does have an anti-inflammatory effect and it works through this OGF access.
But what he did this time was he looked at the markers for the sort of cytokines interleukin pathway, the amount of interleukin is a good way of seeing how much inflammation is in the body. So we actually looked at the very specific interleukins and was able to see that there was a difference when you treated with LDN.
And again, someone else, Jarred Younger, from April 2017, actually did a lot of this primary work, looking at a whole range of interleukins and was able to prove that you got a reduction in the plasma concentration of all of these markers for inflammation when you apply LDN.
So we’ll have a look at the total daily doses of LDN equivalent. And so we, this is just from data that we've seen mixed with some data that we had from the NHS courtesy of some pharma companies. Now the data point for this year is based upon half of this year dispensing basically for up to the end of June. And we're looking at we've extrapolated that basically looking at what's happening in the last few years. And you can see it's been pretty stable up until 2016 when there was, I think it was one of the first American conferences and then it sort of, it's kind of exploded.
So the number of disease groups that LDN has been used for is going up very rapidly and we're approaching, I think by this time next year, we're probably going to be looking at a million daily dose equivalents, annualized per patient in the UK. But also interestingly, the number of unique GMC numbers that we see prescribing it in the UK is going up very, very rapidly as well.
So what we're seeing is that we're going from over just 600 in 2014, where, you know, we're well into the approaching the 2000 Mark, I would say by this time. And that's very comforting for any prescriber and any pharmacist here that there's this incredible usage of LDN across the whole UK. A lot of prescribers just prescribe it for one patient because they just happen to have an MS patient who's interested, but that's a unique number as well, but that's, that's interesting that that's growing so quickly. It's becoming almost a mainstream therapy. So you can have a look at these signs but basically, the top 22 consultation requests since the start of the year that we've seen, Lyme is growing very, very quickly. And Crohn's IBS is also growing quickly. We see for the first time ever depression, the mental health have crept into the first 22, I see one of the prescribers over there going, Oh, yes, yes. I know. Psoriasis strangely is on there as well, that's not been at the top before. But Lupas, Haley-Haley diseases made it in there as well.
So it's quite interesting. Represented in a slightly different way here, looking at starting from the biggest one, which has always MS because that's the number of patients with MS is still very big. But after that, chronic fatigue and fibro are the, is the next one down followed closely by cancer and then Hashimoto's disease.
So that's the top four that we see on a regular basis, Some people are looking carefully. Yeah. So you ask questions of the QA later on. So in five minutes, I think that's all I've got left. I'm just going to run over some clinical practice guidelines for anybody who's looking to prescribe it or get involved in dispensing it.
So when patients have chronic pain, you have to think about carefully what you're going to do. You can't just sort of stick them on LDN and leave them on all the other medications. Cause there's no point in knowing you don't really know what's going on. You don't know. You have to have a holistic view.
So if you're going to withdraw opiates with which you really have to do before you put people on LDN, do it gently. Nefopam in the UK. I know it's not available in Canada or America, but that's been quite positive too, you can withdraw opiates and replace it with Nefopan quite well. And many patients, especially cancer patients, seem to do.
Okay. Um, so review the use of all the other types of pain killers, you know, that are suitable to use with LDN. So you can use things like Pregabalin and Gabapentin that we talked about earlier. Paracetamol quite often it's underused in people with chronic pain. They don't think they take paracetamol when they're in pain rather than regularly, two, four times a day, which is the baseline of pain control and almost every guideline in the world.
But then actually use some of the tools that are available to you. Things like they're provided by the government, the NHS like pain management diaries, you know, how are you today is it a five, is it a six, is it a 10? Talk about it, use it for review and just gradually do a gradual increase to the dosage. And so don't start on a straight on 4.5 milligrams.
We still see patients appearing with a script for 4.5 milligrams daily taking at night. You know, it's totally inappropriate to do that. Now we find that people respond on one milligram and one and a half milligrams, two milligrams. It's very independent of them. But if you're not getting any responses, no improvement in the pain after three months, then there's not really much point in continuing cause pain relief should be sort of resolving by that kind of the point.
So if they're not getting a response, it's not, not gonna do anything. But then that's where we find anyway. So nerve pain, chronic regional pain syndrome, spinal pain, neuralgia, ME and that kind of the whole group of diseases where you could find pain. As I said earlier on, we're getting an increasing number of people for psychiatric reasons of depression, anxiety, et cetera, who are asking for LDN.
And we have had some cases where people have sort of been stuck on LDN privately, but they haven't really talked about it with their mental health professionals and not talked about it with the GP. And actually, unless you have a full picture of the psychiatric profile of the patient it’s a bit inappropriate to stick them on LDN and hope for the best.
So I think it's one of those things which we're finding it certainly does seem to be useful. but don't stick them on it if there are currently having an episode, you know, you want to actually think that it's going to be useful to prescribe it when the patient already has a manic episode, or they're having an episode of serious depression, make sure they're stable first three months, and then you can use it as a mechanism to withdrawal some of the other medications.
But then again with the CNS disorders, manage their expectations. As I said earlier on your Parkinson's, there's a lot of forums saying, “Oh, it's a miracle. It's a miracle” there’s not really much evidence for that. And it does seem to make people feel better, but so manage the expectations as I said, can use a local tool to assess their mood and energy levels.
And again, increase gradually. And you can probably look at taking sort of six months to have an effect or to have the full effect.
And cancer, it's again, it's a sort of different profile, but we'll hear more about that. I'm sure in a minute, but talk to the oncologists. If you're going to be a private prescriber, make sure they know that it's happening, don't practice in isolation, make sure that you review the evidence for this specific disease, you know, maybe there's a potential that actually LDN, Okay. It might be an addition, but possibly you could point them towards a trial that might be more useful for them or some of the biologics. And I've been told I have two minutes left, so I'm going to keep going. The recent, the most recent sort of information, but talking about LDN in combination with other medications for cancer is using LDN with cannabis derivatives like CBD and do LDN constantly every day, every morning and take the cannabis for three days on and three days off. So, but do you consider if you're giving LDN privately. Why not look at some of the other information that's out there? The mTOR inhibitors, things like the doxycycline, metformins etc. there's quite a lot of information on those. Um, it's not really, if you're going to be treating someone privately for cancer, it's not really time to be conservative. So, you know, reach out, ask all the questions. Again, in autoimmune disease withdrawal the opiates first, if you possibly can replace as required and make sure you manage the expectations. In Hashimoto's disease do be very, very careful, start on the variable dose because we have seen thyrotoxicity because it has an effect that’s quite fast, and they've then got too much thyroid medication and then don't start withdrawing thyroxin or changing
too many things at once. We'll talk about that a bit more later on about how to deal with those patients. So and again, we're looking at autoimmune diseases. If you've got chronic fatigue and you start with LDN, you can expect to have flu symptoms.
And in MS worsening symptoms for the first few weeks are not surprising.
Nighttime dosage appears unimportant. So a lot of the forums will say, take it at night time. It doesn't seem to make much difference in practice.
And really don't apologize for prescribing LDN. I think at this point I would say don't apologize for being part of the community because actually we have these incredible patient groups of tens of thousands of people worldwide taking it and it seems to work for them.
So there's enough evidence now that we shouldn't be shying back and we should be talking to other colleagues about it and encouraging them to attend events like this. But in the UK, be very careful of prescribing for children and only do it in person if you can, rather than remotely because there's a lot of pushback against obviously treating children with unlicensed medications.
Finally, help us fight the nonsense. You see on all of these forums is it slow release so I can't have this type or it has to be this particular filler. It has to be this. So I'm chemosensitive - all the stuff that we hear every single day. People come to you with lots of misconceptions and it's worth trying to fix those before you see whether or not they're actually going to do well on LDN. If you are stage four dying of cancer, I don't know if it really is all that important that your capsules are vegan.
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