Low Dose Naltrexone (LDN): A Surprising Immunotherapy
Welcome back, friends! I’m just going to keep on banging out the best, but least talked about tools available to us in the war against cancer. We had the big, long overview, the deep dive on Mistletoe, and today we’re going to talk about a medication almost as old as I am - Naltrexone. That might be a word you’ve never heard before, but I bet if I used its brand name ‘Narcan’, it would ring a few bells.
What could fentanyl overdoses possibly have in common with cancer treatment?
Let’s get into it.
Naltrexone: The Tale of Two Doses
Before we jump into Naltrexone’s cancer-fighting capabilities, let’s discuss its origin story. Back in the 1960s, Naltrexone was developed to treat people with opioid addiction and to rescue people from opiate overdose. The U.S. Food and Drug Administration (FDA) went on to approve the medication for the treatment of opioid and alcohol dependence in 1984 and 1994, respectively. It works by binding to receptors called opioid growth factor receptors, or OGFr. Naltrexone binds to the same opiate receptors in the brain as fentanyl, for example, but doesn’t turn the receptor on. It just blocks it. It also binds tighter. Way tighter than an actual opiate can. If an opiate like fentanyl happens to already be there, sitting in the way, Naltrexone will literally bump it off and steal its seat. If a person taking Naltrexone decides to shoot heroin, they don’t get high. They might stop breathing, but all the alleged fun stuff related to abusing opiates is gone. In high doses, typically 50mg to 100mg per day, Naltrexone acts as a strict receptor binder and blocker, preventing opioids from exerting their effects and helping to curb addiction.
Low dose naltrexone (LDN) is a different situation entirely. The first person to study naltrexone in low doses for its off-label indications was a gentleman by the name of Dr. Bernard Bihari. Dr. Bihari, a New York-based physician, began investigating the effects of LDN in the mid-1980s. He discovered that at really low doses, typically 0.5 to 4.5mg per day, naltrexone had significant immunomodulatory effects. This led him to explore its potential benefits in treating conditions such as autoimmune diseases, cancer, and HIV/AIDS. In these really low doses, Naltrexone does this crazy shape shifting maneuver. Instead of being a playground level opiate receptor bully, it becomes a kind crossing guard lady, leading the immune system back to optimal function. This lower dosage taps into a whole new set of properties, making LDN a pretty fascinating subject of study – especially in cancer.
Naltrexone is a drug that exists as a combination of two molecules that are exact mirror images of one another. Not all medications are like this, but many are. I won't dwell on this but it will become important in a minute. This two molecule situation happens when a compound contains an asymmetric carbon atom, which means some of the molecules bend to the left and some bend to the right. They’re the same molecule, just mirror images of on another. Like a left hand and a right hand. This is called ‘chimera’. Chimeric medications often have two different agendas because the left-handed molecule does one thing, and the right-handed molecule does another. Got me?
When it comes to Naltrexone, the right hand is blocking opioid receptors, but the left hand is working on the immune system.
LDN’s Immune Modulating Powers
You didn’t come out of the womb with opioid receptors for the sole purpose of being able to enjoy a post-operative morphine pump one day. Your body makes opiates as well. This endogenous morphine production creates something called endorphins. Endorphins are natural pain-killing feel-good molecules floating around in your brain. Your body makes these in response to exercise, pain and stress, spicy foods, funny movies, listening to your favorite music, acupuncture, massage, and really good sex.
Right-handed molecules of LDN temporarily block opioid receptors for a few hours. This brief blockade tricks the body into thinking, ‘Hey, wait a minute, what happened to my morphine?’ So what does the brain do? Well, it makes more morphine - or endorphins. Your brain likes endorphins, but so does your immune system. They don’t feel all warm and tingly on the inside like your brain does after your first kiss with a really hot guy, but suffice it to say, they pay attention as well. This upregulation of endorphins that happens in the setting of low dose naltrexone helps your brain to feel happy and pain-free and gives your immune system a little spring in its step.
Left-handed molecules of LDN work more directly on the immune system. Immune system explanations always give me anxiety. I think its because it was so badly presented to me the first time. Or I just wasn’t paying attention. Anyway, I’ll do my best to keep this as vanilla as possible. So – certain cells in your immune system, like monocytes, dendritic cells, natural killer cells, macrophages, and microglial cells, have specific receptors on their surfaces that get activated in the setting of infections and damage to other cells. These receptors are called ‘toll-like receptors (TLR)’, specifically TLR4.
Let’s say you’re walking down the street minding your own business and suddenly bump into a guy with a cold who sneezes directly in your face. Yuck. Certain cells in your nose and the back of your mouth wake up. They’re like, this had better not be fricking Covid again. They feel around for any spikey proteins, and if they see them, their toll-like receptors become activated. And by activated, I mean, all bent out of shape. They start the inflammatory cascade by making something called ‘interleukin-6’ or IL-6.
IL-6 is extremely important when it comes to immune system function. Think of IL-6 like alcohol. A little is a fun time, a lot is a DUI, a bar fight, or a ride in the back of a police car. A little bit of IL-6 is a good thing. It gets the immune system ball rolling to clear out the infection that just sneezed all over you. Too much IL-6 is a complete mess of chronic inflammation. It causes increased platelet production, vascular inflammation, clotting, organ damage, autoimmune disease, swelling and pain. We see increased inflammatory proteins called acute phase reactants – hsCRP, fibrinogen, and amyloid. The number of TH17 and CD8 cells goes up, T regulatory cells go down, and antibody production and VEGF increase. All sorts of crazy shit and nonsensical sciency acronyms.
LDN is like a psychotherapist for your immune system. Talks it off the ledge. It binds to your toll-like receptors and blocks them from making too much IL-6. Too much IL-6 creates a vicious cycle. The inflammation it starts causes damage to cells. Damaged cells trigger the immune system to make more IL-6. Damaged cells release IL-6 all by themselves. By the time this storm is out of control, we have moved from a productive immune system response, like killing an infection, to a completely destructive immune system response like that seen in autoimmune disease and cancer. How can we fix this? We have a few options:
Steroids: Side effects include weight gain, bone loss, elevated blood pressure, elevated blood sugar, increased risk of infections, muscle weakness, mood changes, stomach ulcers, thinning of the skin, easy bruising, slower wound healing, cataracts and glaucoma.
Anti-inflammatory drugs: Side effects include stomach ulcers, gastrointestinal bleeding, increased risk of heart attack and stroke, impaired kidney function and kidney failure, increased blood pressure, rashes, itching, swelling, and liver disease.
Biologics or monoclonal antibodies: Side effects include increased risk of infections, skin rashes, itching, and in severe cases, anaphylaxis, nausea, vomiting, diarrhea, fatigue, and flu-like symptoms including fever, chills, and muscle aches.
Low dose naltrexone: Side effects include maybe some vivid dreams and temporary sleep disturbance.
You tell me what sounds safer.
How LDN Works Against Cancer
Recent clinical research has demonstrated that LDN may attack cancer cells using several mechanisms outside of its previously established mechanisms of action. Studies now show LDN can suppress tumor growth by inhibiting cell growth and inducing cancer cell death. LDN intermittently blocks the opioid growth factor receptors, resulting in the activation of anti-tumor properties causing dysregulation of cell growth and death. Current evidence suggests that the intrinsic pathway of apoptosis induced by LDN may play a significant role in inducing programmed cell death in cancer cells but not in that of healthy ones.
Studies conducted on mice with human ovarian cancer treated with LDN and Cisplatin, as well as LDN and Taxol, showed that the combination regimen of LDN with these chemotherapeutics was more effective than the use of each of these drugs alone. To verify the effectiveness of combination therapy involving LDN with carboplatin in malignant breast tumors, studies were conducted on female dogs of various breeds, diagnosed with malignant breast tumors. The results showed that healthy immune system function was preserved in animals treated with LDN and carboplatin compared to groups treated only with carboplatin or the control group. Bone marrow complications resulting from carboplatin, such as leukopenia and anemia, were lower in groups where LDN was used as adjuvant therapy. Moreover, the survival rate and quality of life improvement were significantly greater among patients treated with LDN with carboplatin than chemotherapy alone. The evidence collected to date allows us to conclude that LDN possesses numerous positive effects in the context of cancer therapy and can be applied as an adjuvant in cytostatic treatment, due to its potential synergistic effects in combination with these drugs.
Main properties of LDN:
Inhibits Cancer Growth: LDN temporarily blocks the opioid growth factor receptor (OGFr). This trickery leads the body to produce more opioid growth factor (OGF), which then inhibits the proliferation of cancer cells.
Boosts Immune Response: LDN enhances the immune system's ability to fight cancer by increasing the activity of natural killer (NK) cells, CD8+ T cells, and promoting the production of interferon-gamma (IFN-γ) and interleukin-2 (IL-2).
Reduces Inflammation: LDN blocks toll-like receptor 4, modulating the release of proinflammatory IL-6. Additionally, it shifts macrophage production from the M2 type, which supports tumor growth, to the M1 type, which attacks cancer cells.
LDN can be used alongside chemotherapy and immunotherapy, enhancing their effectiveness and potentially reducing side effects. Unlike traditional cancer treatments, LDN doesn’t harm normal cells – only cancer cells, making it completely non-toxic to healthy tissues. Studies in both laboratory settings and animal models have shown that LDN can inhibit cancer cell proliferation, reduce tumor size, and improve the immune system’s ability to fight cancer. Clinical trials are ongoing to confirm these benefits in humans. LDN offers a promising, non-toxic approach to cancer therapy by modulating the immune system and inhibiting cancer cell growth. While more research is needed, its potential as an adjunct to traditional treatments could revolutionize cancer care.
LDN For The Masses
I know this is a post in the cancer section, but LDN's utility is endless. The LDN Research Trust website has compiled thousands of studies demonstrating the benefit of this therapy for basically everything, including the kitchen sink.
Mood Disorders: Anxiety, Depression
Neurologic Conditions: Autism, Alzheimer's, Parkinson’s
Chronic Pain: Arthritis, Fibromyalgia, Diabetic Neuropathy
Autoimmune Diseases
Bone Marrow Disorders
Inflammatory Bowel Disease
Infertility, PCOS, Endometriosis
Hashimoto’s Hypothyroidism
Graves’ Disease
Multiple Sclerosis
Skin Disorders: Eczema, Psoriasis, Hair loss
Long Covid
Lyme Disease
Chronic Inflammatory Response Syndrome
Insomnia
Weight Loss
And a whole section on using LDN in your pets😊
How can a tiny dose of an ancient medication help with so many conditions that seemingly have nothing to do with one another? Well, they might seem unrelated on the surface, but they’re really not. Chronic inflammation is a troublemaker in the body, contributing to many diseases, including cancer. LDN has anti-inflammatory properties, reducing the production of pro-inflammatory cytokines and increasing anti-inflammatory ones. This shift helps create a more harmonious environment, reducing the risk of cancer progression and other inflammatory diseases.
Dosing
The dosing on LDN varies from person to person, but in general, most protocols start with 1.5mg at bedtime and then gradually increase to 4.5mg over the course of a few weeks. Some people do better at 3mg or 2mg or even at ultra-low doses like 0.5mg. Everyone is unique. Children metabolize naltrexone a little bit faster than adults, so dosing is managed differently in little people.
Regular-strength Naltrexone is FDA-approved in 50mg tablets, which are available at just about any pharmacy. Low-dose naltrexone, however, needs to be made on a patient-to-patient basis by a compounding pharmacy. LDN is available in capsules, tablets, liquid, and even topical formulations. It is not over-the-counter and is only available by prescription.
Most studies on LDN utilize it as an adjuvant therapy alongside other immunomodulatory interventions like high-dose vitamin D3 and cannabidiol (CBD).
Side Effects
No therapy is without the potential for side effects, but LDN is about as close as you can get.
Sleep Disturbances: Insomnia, vivid dreams.
Digestive Issues: Nausea, constipation, or abdominal pain.
Neurological Symptoms: Headaches, dizziness.
I’ve never had patients report anything other than vivid dreams and occasionally sleep disturbance that goes along with that. These aren’t night terrors, but people often tell me they remember their dreams more clearly in the first few weeks after starting LDN. Dreams are weird. Maybe that’s why we typically can’t remember them. This side effect almost always goes away on its own, but if it doesn’t, we have people change their dosing from bedtime to morning. Within a few weeks, most patients find they sleep better taking their LDN before bed than they did before starting it.
LDN is usually given at bedtime to take advantage of the body's natural rhythm of endorphin production. Blocking opioid receptors at night temporarily causes the body to produce more endorphins, which then peaks in the early morning hours. This timing helps to maximize the therapeutic benefits of endorphin release, such as improved immune function and modulation of pain and inflammation, which can contribute to the overall effectiveness of LDN therapy.
Contraindications
Because LDN blocks opiate receptors, it’s not given to patients taking opiates. That passes the reasonable test, no? It’s only blocking a few receptors, though, and only for a couple of hours. Imagine you have a million opiate receptors in your brain. LDN is going to block about a hundred. I get these questions all the time: ‘So I sometimes get migraines. What if I take LDN tonight and then need to take Vicodin tomorrow? Will it still work for pain?’ or – ‘What if I take LDN tonight and then my appendix ruptures tomorrow, and I need surgery – will the pain medications still work?’ Yes. Yes, they will. We are pissing in an ocean of receptors here, so to speak. But because opiate withdrawal is so unbelievably miserable, we don’t want to risk causing any of those symptoms by giving an opiate blocker to a chronic pain patient already on scheduled narcotic pain medications.
I will throw in a few other ‘special considerations' here: high-dose steroids, other immunotherapies, and thyroid medication. Because LDN is itself immune modulating, patients may need dose adjustments of other medications they might be taking that are specifically modulating the immune system. It’s not uncommon, for example, to need less steroid or chemotherapy when LDN is added to the mix. Thyroid medications are similar. Most low thyroid conditions are caused by an autoimmune disease called Hashimoto’s. Adding LDN will potentially improve the autoimmune condition, and patients will need a lower dose of replacement therapy so as not to develop symptoms of hyperthyroidism.
Cost
Unfortunately, most insurance companies do not cover the cost of compounded medications. Fortunately, Naltrexone has existed for a million years and is long off-patent. This isn’t going to break the bank for most people and pales in comparison to the cost of conventional immunotherapies. The cost of LDN can vary, but on average, it typically ranges from $30 to $60 per month.
Conclusion
In the grand saga of Naltrexone, LDN emerges as a versatile and promising therapeutic with unique immune-modulating powers. By boosting endorphins, balancing the immune response, reducing inflammation, and enhancing the activity of crucial immune cells, LDN offers a multifaceted approach to supporting the body’s natural defenses against cancer. While more research is always needed to fully understand and harness its potential, LDN stands out as a safe, inexpensive, and well-tolerated tool in the fight against cancer and other chronic conditions. So, here’s to our tiny but mighty hero, continuing to surprise and inspire us in the ever-evolving world of medicine.
References
Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization, 2018
Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy
Low Doses Naltrexone: The Potential Benefit Effects for its Use in Patients with Cancer
Effective Doses of Low-Dose Naltrexone for Chronic Pain – An Observational Study
LDN Research Trust