History, Pharmacology and Mechanism - Stephen Dickson, BSC (hons) MRPharmS (2021 Conference) (LDN, low dose naltrexone)

 

History, Pharmacology and Mechanism - Stephen Dickson, BSC (hons) MRPharmS (2021 Conference) (LDN, low dose naltrexone)

LDN Research Trust 2021 Conference - Friday Morning

Stephen Dickson, a pharmacist in the United Kingdom, has been working with the LDN Research Trust for a great number of years as prescribing advisor, and also as a dispenser of LDN into a very large number of patients. 

Dickson’s presentation is on the pharmacology and the mechanism of action for LDN, including some practical usage of how it can be used in patients. He speaks from his personal viewpoint and years of experience and learning. He asks that any patients who watch this presentation that they don't take any actions based upon this presentation without consulting a medical professional.

So the history and pharmacology of LDN really are dependent upon where it came from. Naloxone, the parent drug of LDN, was discovered purely by accident in 1961 when chemists were attempting to modify a potent morphine analog called hydromorphone. And what they were trying to do was to make it less potent to reduce the side effects, but also possibly come up with a morphine-based or a morphine analog, which can be used to treat constipation or diarrhea. 

They were very successful with making a new molecule, but what they made had absolutely none of the properties they were looking for. The scientists who, although they were unsuccessful in doing what they intended to do, serendipitously, they created something which they realized very quickly, could solve an awful lot of problems. 

At the time, general anesthesia was done by adding quite an awful lot of morphine to an IV drip. In fact, it was quite common that during general anesthesia, people were given overdoses of morphine, and they often stopped breathing or died. Doctors had no way of reversing the effects of morphine or morphine analogs once they had been administered. What the scientists realized was that this Naloxone that they had created, was actually able to save these patients.

The first patent for Naloxone was filed in 1966. It was then added to the WHO’s (World Health Organization) list of essential medicines in 1970 when the FDA approved it to treat morphine overdose. Over the last 50 years, the Naloxone molecule has been slightly modified from an injectable called Narcan which contains Naloxone, into Naltrexone, which can be taken orally.

Dickson goes on to explain the body’s opiate system, the endorphin system. Opiates mimic the effects of endorphins. Endorphins are the brain’s happy chemicals, which are released in response to pain, happiness, various disease states, etc. These are passed through the brain’s neurotransmitters. 

This G-protein coupled receptor pathway is very important because it is responsible for a great number of immunological and also biological functions. One can get multitudes of outcomes from these receptors based upon the amount of drug that is given, how long it’s given, and what it's given alongside. This ends up being quite enlightening as to why LDN has shown to have very different effects from what we expect from the licensed form of Naltrexone.

Stephen Dickson explains opiate receptors,  endorphin receptors, and how the three main classes of drugs act upon these receptors. Viewing the receptors as locks, each of these drugs has a different effect. 

1. Agonists work a bit like a key to the receptor because they fit completely into the receptor, and it fully activates the receptor. An example of this is morphine which is a full agonist. 

2. Partial agonists are keys that fit into the lock, but only turn halfway. They don’t fully activate the receptor. 

3. An antagonist, like Naltrexone, is a key that fully fits into the lock, but it doesn't turn; instead, it blocks other molecules from being able to attach (such as Morphine). 

Thus, Naltrexone blocks the effects of morphine overdose by preventing the drug from accessing the receptors. 

Dickson discusses how the classical use of opiates causes somewhat of a contradiction. When a patient is taking extra opiates, on top of the natural endorphins that their brain produces in response to the stimuli, you get analgesia, and you get euphoria. But we all know that people become addicted to opiates because, over time, it'll take more and more and more of the opiates to get the same effect. This is called the down-regulation of receptors. Regular exposure to natural opiates plus exogenous opiates, like morphine, gradually causes all of these G-protein-coupled opiate receptors to become less sensitive to natural stimuli and also external exogenous opiates; And that happens because these receptors stop responding in the same way as they did.  What that means is the patient can form pharmacological addiction, where the baseline and release of endorphins aren’t enough anymore, and they have to have exogenous opiates added into the system in order to function normally.

An interesting part of Naltrexone is that it blocks the pathway between exposure to exogenous opiates and natural versions, which actually stops those drugs from activating the receptors by blocking the opiate receptors. And that actually causes a reversal of this pharmacological addiction, as well as causing an up-regulation of the natural receptors. 

Naltrexone has quite a number of immunological effects. This is interesting because drugs, such as Naltrexone, are very rarely 100% selective. For example, when a drug is made, it tends to be focused on managing one thing such as headaches. That drug does show through a clinical trial to treat headaches. However the drug can, through all sorts of various mechanisms work on treating headaches, but probably has other effects as well. So the headache drug isn’t not completely selective for one purpose.

Dickson explains that this is called an elucidation period, where unknown effects are discovered.  Quite often drugs end up being used for quite a few other issues. A good example of that is something called Amitriptyline, which was developed in the 60s to be used as an antidepressant drug; however, it wasn't terribly good as an antidepressant. But what they did discover is it's phenomenally good at treating neuropathic pain. As science improves over the years, it generally assists with the repurposing of these drugs from years earlier. Today you will find that the most common use of Amitriptyline today is for neuropathic pain, and rarely as an antidepressant.

Another discovery scientists have made is that expected effects from drugs can also affect the homeostasis of the body. Homeostasis is how everything works to stay in balance throughout the systems of the body. When a drug interferes with this system of homeostasis, deliberately or not, there can be very different results with higher and lower doses of the drug, because they’re affecting a natural system that will either rebound, decompensate or compensate.

Naltrexone is a chiral drug, meaning it can have compositions that are mirror opposites to one another all though they have the same molecular parts.  Look at your hands.  While they are identical, with the same parts of thumb and four fingers, they are in fact mirror opposites.  With chiral drugs, there is a  50/50 chance of how the molecules are going to come together. They have exactly the same makeup, yet they're structurally different, making them different isomers, just like your hands. And because they have are different isomers, they can have very different pharmacological targets. This is important to understand with Low Dose Naltrexone.

Low dose naltrexone, with a dose generally at 0.1 to 5mg, functions similarly to naltrexone dosed at 50-200mg. It fully blocks the endorphin receptors; however,  at a low dosage, it interferes for a much shorter time frame, causing the brain to upregulate the production of natural endorphins. Even though LDN is comparably a very small dosage, it can still precipitate withdrawal in someone using an opiate every day, such as morphine, regularly every single day. You must make sure the person doesn’t have any strong opiates in their system before taking LDN. 

An interesting function of the dextral isomer of LDN is that it binds to the TLR receptors. The TLR receptors are part of the innate immune system. And they're part of the body's beginnings of defense against external stimuli like bacteria or viruses. Endorphins are known immunomodulators. So the fact that LDN binds endorphin receptors, which then interferes with the homeostasis of the body causing an upregulation of the production of endorphins, it is logical that LDN could have a very powerful immunological effect. 

Dr. Ian Zagon has worked on the endorphin system for a great number of years, since 1986. Through his years of research, he's proven that endorphins are involved in every part of the immune system. Thus, for people who have malfunctioning immune systems, giving LDN, which increases the production of endorphins and how they are processed, could potentially have a very strong effect on the immune system. Dickson lists the many research papers Zagon has done, showing how autoimmune diseases like MS, ocular surface disease, and Crohn’s, are responding to LDN and its immunological effects, probably mediated through the endorphin system.

This list of diseases that respond to LDN  is growing quickly. The LDN Research Trust does a wonderful job of keeping an up-to-date list. He also suggests that those who want more details really should look into the work done by Dr. Ian Zagon, which is very thorough. 

Dickson states LDN has been used in treating everything from chronic pain to cancer. Many doctors believe that cancer, for example, is an autoimmune disease, or an inflamed inflammatory disease. So, by changing the inflammatory response of the patient, you can improve the outcomes. 

For chronic pain, LDN is causing an upregulation of the happy chemicals, endorphins, being released by the brain. This causes a central nervous system release of dopamine, which is a happy transmitter, which then suppresses the production of inflammatory cytokines, reducing overall inflammation in the body. Some of the types of chronic pain that have been treated with LDN are complex regional pain syndrome, fibromyalgia, nerve damage, Graves’ disease, and ALS. 

For diseases like Parkinson's (which tend to be deficient in dopamine), it's possible that using LDN could again cause an upregulation of endorphins. This release of dopamine improves the patient's mood and potentially enhances the GABA response. And that would be the general mechanism that we're talking about. In that same vein, LDN potentially can help with depression, anxiety, Parkinson's, and Alzheimer's.

There will be a couple of trials done with LDN in Parkinson's, and it does appear that it improves the quality of life, but Dickson states that he doesn’t think it does anything against the progression of the disease. In cancer, LDN has a great number of different effects. When you give LDN to patients with cancer, you get upregulation of immunoregulatory genes. So the immune system starts looking for cancer cells more, and there is a down-regulation of some of the origins (direct inhibition of growth of some cancer cells that's been observed). 

In autoimmune disease, LDN is causing an upregulation of endorphins (the immunomodulation), but also potentially,  it releases something called an opiate growth factor. But it does appear to work as an atypical anti-inflammatory or potentially disease-modifying, antirheumatic drug. LDN seems to cause the downregulation of the autoimmune response, helping those with MS, chronic fatigue, Crohn’s, Hashimotos, and a myriad of other autoimmune diseases.

Recent Studies

In 2021, there have been three excellent papers using LDN:  one showing an improvement in pain in fibromyalgia, one showing a reduction in progression of cervical cancer, and one showing incredible improvement in neuropathic corneal pain. These come just after recent studies for a year or two before, showing that there was clinical improvement in IBD, ulcerative colitis, and also patients who were having problems with their general health

From 2017 to 2018, Dr. Ian Zagon published an incredible paper showing how LDN could work. In addition, there was a great paper from Jared Younger, 2017, which showed how LDN reduces inflammation.

Stephen Dickson shows a list of the top 22 condition requests for LDN in the last three years. The top two are MS and fibromyalgia, closely followed by cancer and Hashimoto’s disease. However,  there are a great number of other conditions that are being treated with LDN, including infertility and Lyme. 

LDN Hot Topics

1. Long COVID: Dickson acknowledges that there is a need for clinical practice LDN guidelines for long COVID, one of the fastest-growing areas for consultation requests; however, it’s still in its infancy.

• Treat as you would for Chronic Fatigue.
• Expect results in 4-weeks (if not, you probably won’t)
• After 3 months, stop LDN to see if they have improved permanently.
• There haven’t been any negative reactions 

2.  Chronic pain 

• First, withdraw from opioids gently. Replace with Nefopam if required
• Require the use of a pain diary to monitor results
• Try it for 3 months and if nothing has happened, then it's not going to work
• Start dosing at 1mg, increasing every week until 3mg, then review
• Increase to 4.5mg if it's successful

3. Central nervous system disorders like depression, Parkinson’s, etc

• Only start LDN after the patient has been stable on the current therapy for at least 3 months
• Manage their expectations
• Again, use a symptom recording tool to assess how they're doing before and after
• Dosing, the same as chronic pain, 1mg with increases weekly to 3mg. Then meet for a review
• Increase to 4.5mg if successful

4. Cancer

• Work/communicate with patient’s oncologists (avoid working in isolation)
• Review the protocols for their specific form of cancer and any LDN trials
• 1mg titrating quickly (advise the patient of headache side-effects)
• If using CBD, LDN every day but 3 days on and 3 days off of maximum tolerated dose of CBD or cannabinoids
• Consider repo and synergistic drugs 

5. Autoimmune Diseases

• Suggest people use LDN forums (such as FB) to help decide for themselves
• Withdraw the opiates gently first
• Start at 1mg and increase each week by 1mg; except for CFS and Hashimoto’s, which you start at 0.5mg and very gradually over 1 - 2 weeks, go up by 0.5mg (high risk of them becoming hyperthyroid in Hashimoto’s patients & flu-like symptoms in CFS patients) 
• LDN often makes MS symptoms worse for the first three months
• Either nighttime or morning dosage is fine; both work equally.
• Try to avoid prescribing LDN for children if you can, because of the legal language they can get into. 

When not to prescribe/use LDN:

• If another therapy was started,  wait until the patient is stable
• Patients wanting prophylaxis (disease prevention)
• In patients with bipolar &/or depression, if you're not in a position to monitor them
• No to all organ transplants, just because of the way it works. it could interfere with some of the other drugs and potentially cause a problem 
• If a patient is on, and will not come off, of long-acting opiates. You could consider ultra-low-dose LDN 
• If a patient cannot give consent, ie children

KEYWORDS: LDN, opiates, endorphins, morphine, naltrexone, Crohns, fibromyalgia, chronic pain, IBS, MS, Parkinsons, depression, autoimmune diseases, chronic fatigue, Hashimoto’s, long covid, cancer, opioids, low dose naltrexone, Lyme disease, infertility, Alzheimer’s