Low Dose Naltrexone (LDN) is increasingly used by clinicians for management of challenging medical conditions such as chronic pain or autoimmune disorders.  Even though research on LDN as a treatment modality for certain diseases remains sparse, there are several clinical studies conducted to evaluate the effect of LDN for treatment of these conditions and they have shown beneficial effects on symptom improvement.  LDN is known to be extremely safe and well tolerated, especially when compared to the drugs typically used to treat these conditions. That is why LDN is considered as a valuable option for clinicians and is an important focus of ongoing research.

 It has recently been found that the addition of LDN to treatment regimens for mental illness can help reduce symptoms.  However, the evidence showing efficacy of LDN use in treating mental illness is still lacking but the research is ongoing.  I am going to review several clinical trials that focused on LDN and psychological disorders and then discuss the beneficial effects and how LDN can be promising for patients with mental illness.

Naltrexone is a reversible competitive antagonist at the mu and kappa receptors and to a lesser extent is a delta receptor antagonist.  At oral doses of 50–150mg, it can reverse opioid overdoses and treat alcohol addiction.  Paradoxically, LDN enhances the effects of opioid agonists by blocking the opioid receptor transiently which causes a positive feedback mechanism that increases the production of endogenous peptides.  Increased levels of endogenous opioids peptides are known to promote healing, inhibit cell growth, and reduce inflammation.  Naltrexone works by binding to the C-terminal pentapeptide of the scaffolding filamin A with strong affinity. Filamin A is also found on dopaminergic D2 and D3 receptors which might explain the effect of LDN on prevention of desensitization to D2/D3 agonists.  This potential LDN mechanism on dopaminergic receptors led researchers, Bear and Kessler, to propose a study to evaluate for beneficial effects of LDN on restless leg syndrome (RLS)5. The study showed that RLS symptoms had improved with the use of LDN.  RLS is typically treated with D2/D3 agonists such as pramipexole or ropinirole. Thus, the researchers suggested that the LDN use would effective in RLS possibly due to facilitated sensitization of D2/3 agonists.

The pathophysiology of depression is thought to involve abnormal dopaminergic D2 receptor function which is possibly associated with D2 receptor desensitization4.  An observation study has demonstrated that patients had a relapse with depressive symptoms when a D2 antagonist was given following successful treatment with SSRI.  The result was similar in an animal model of depression in which the symptoms were reversed by tricyclic antidepressants4.  Therefore, the prevention of D2 receptor desensitization may be essential to effectively treat depression when combined with antidepressants such as SSRIs or SNRIs.  Antidepressants may foster the sensitization of D2 receptors and LDN may exert antidepressant effects by preventing D2 receptor desensitization and thus enhancing dopaminergic signaling.

In addition, there has been anecdotal evidence in multiple trials showing that LDN has beneficial mood effects in different conditions.  Following the RLS study, a randomized, double blind pilot trial was initiated based on this background information.  The study was conducted to evaluate the hypothesis that patients experiencing depressive breakthroughs would demonstrate greater improvement in their depression when supplementing their current antidepressant regimen with LDN versus placebo, with no significant difference in side effects5. In the study, 12 adults with recurrent major depressive disorder (MDD) on dopaminergic antidepressant regimens (stimulants, dopamine agonists, bupropion, aripiprazole, or sertraline) were randomized to naltrexone 1 mg b.i.d. (n=6) or placebo (n=6) augmentation for 3 weeks. The study found that LDN augmentation reduced the severity of depression symptoms in 12 depressed patients who had relapsed on dopamine-enhancing antidepressants. The key finding of the study is that if a patient has depression and has experienced a relapse while taking a previously effective antidepressant that works primarily by dopaminergic mechanisms, the addition of LDN could potentially reduce the depressive symptoms when combined with the original antidepressant. However, a major limitation with this study is that the patient sample is small.  It may be necessary to reconduct this study with a larger sample size to confirm the significant difference between the LDN and placebo group.  Also, the study included only antidepressants that work by dopaminergic mechanisms.  Thus, additional studies should be conducted to determine how effectively it would work with other types of antidepressants.

A retrospective case study, performed by the Department of Psychiatry at the UCLA Kern Medical Center in California, had investigated the efficacy of LDN on a comorbid depressive disorder6.  In the report, 5 patients received at least one month of LDN, 2 patients had a diagnosis of MDD, and 2 patients had Bipolar Type II and 1 patient had Bipolar Type I.  The results from this study showed that of these patients, 2 patients with fibromyalgia only had minimal improvement, 1 patient with lumbar discopathy had no improvement, and 1 patient with Lupus had much improvement with liquid LDN.  At the conclusion of this case study, 80% of patients experienced some degree of improvement with LDN at week 4.  Another study conducted by a German Research Group in 2015 found that patients with severe trauma-related dissociative disorders had positive effects after treatment with LDN at doses ranging from 2 - 6 mg daily7.  In this study, 11 out of 15 patients reported immediate positive effects and 7 patients described a lasting beneficial effect.  Although it is not known how LDN positively affects patients with depression or posttraumatic psychotic disorders, it seems that LDN has some association with beneficial effects on depressive or psychotic symptoms in those patients. However, these studies remain limited due to their small sample sizes. These studies need to be replicated with a larger patient population to validate the positive efficacy of LDN on those mental health problems.

As mentioned earlier, it is well known that LDN has beneficial effects on chronic pain and autoimmune disorders.  This knowledge led researchers to conduct clinical studies evaluating the effect of LDN on certain medical conditions such as multiple sclerosis (MS), fibromyalgia, or Crohn’s disease1. LDN has been the subject of many debates and despite there being few clinical studies performed, these studies are key clinical trials demonstrating how LDN results in significant improvement of symptoms.

            Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, and mood issues. Thus, patients with fibromyalgia are sometimes treated with antidepressants. There is a single-blind crossover pilot study that investigated the effectiveness of LDN in treating fibromyalgia symptoms8.  The study was conducted based on the hypothesis that LDN may reduce fibromyalgia symptoms by inhibiting the activity of microglia and thus reversing central and peripheral inflammation. In this trial, 10 women with fibromyalgia participated and completed daily reports of symptom severity during baseline (2 weeks), placebo (2 weeks), LDN (8 weeks), and washout phases (2 weeks).  In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity.  This study results showed that LDN reduced fibromyalgia symptoms in the entire cohort with greater than 30% reduction over placebo.  In addition, participants showed improvement in mechanical and heat pain thresholds during the laboratory visits.  Also, participants reported that side effects including insomnia and vivid dreams were rare, or minor and transient. The study concluded that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.   The mood changes in fibromyalgia patients may be associated with the severity of pain that the patients are experiencing.  Therefore, it can be suggested that improvement in pain symptoms may contribute to reduction of depressive symptoms in patients with chronic pain.  In other words, LDN may have beneficial effects on mood disorders by exerting positive effects that lower the severity of pain experienced.

            Prescribers are becoming increasingly interested in LDN use for various medical conditions since it is well tolerated, safe, and inexpensive.  Also, several key clinical trials have shown that LDN may be promising for the management of recurrent or hard to treat mental illnesses, but further research is needed to ensure the efficacy of LDN for those medical conditions.  However, researchers emphasize that LDN should not be used alone for the treatment of mental illnesses, but it can be added to enhance the therapeutic effects of existing regimens.  In conclusion, LDN can be effective in treating mood disorders when combined with current regimens but additional studies with larger sample sizes are needed  to generate more reliable data.

The Medicine Center Pharmacy in New Philadelphia specializes in custom compounded medications in custom dosage forms. The pharmacists are trained experts in low dose naltrexone therapy. LDN therapies can be customized across 23 different dosage forms for 15 different disease state protocols. If you would like to learn more about low dose naltrexone or would like to schedule a phone call or video conference please contact us.

 References

1.     Low Dose Naltrexone. Provider Guide.

2.     Chopra, Pradeep. Mechanism of Action of LDN, Low Dose Naltrexone. Provider Guide.

3.     Wang, H.Y., Frankfurt, M., Burns, L.H., 2008. High-affinity naloxone binding to filamin a prevents mu opioid receptor-gs coupling underlying opioid tolerance and dependence. PloS One 3, e1554.

4.     Willner, P., 2002. Dopamine and depression. In: Di Chiara, G. (Ed.), Handbook of Physiology: Dopamine in the CNS. Springer, Berlin, 387–416.

5.     Mischoulon D, Hylek L, Yeung AS, Clain AJ, Baer L, Cusin C, Ionescu DF, Alpert JE, Soskin DP, Fava M. Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. J Affect Disord. 2017 Jan 15;208:6-14. doi: 10.1016/j.jad.2016.08.029. Epub 2016 Oct 1. Erratum in: J Affect Disord. 2017 Oct 27;227:198.

6.     The 15th Pacific Rim College of Psychiatrists Scientific Meeting. (https://onlinelibrary.wiley.com/doi/pdf/10.1111/appy.12002)

7.     Pape, W., Wöller, W. Low dose naltrexone in the treatment of dissociative symptoms Nervenarzt 86, 346–351 (2015). https://doi.org/10.1007/s00115-014-4015-9

8.     Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009 May-Jun;10(4):663-72. doi: 10.1111/j.1526-4637.2009.00613.x. Epub 2009 Apr 22. PMID: 19453963; PMCID: PMC2891387.

Physiology of the Disease

Cancer is a condition in which cells within your body divide at an uncontrolled rate. Our body's natural defense against these cells are known as tumor suppressor genes. However, mutations can occur leading to the formation of oncogenes that promote cell growth and reproduction, or suppression of tumor suppressor genes. When this occurs, the cells divide rapidly leading to tumors or large masses and cause your bodies other healthy cells to die. These cancerous cells can then travel to other parts of your body through the bloodstream via a process known as metastasis. When this occurs, the cancer can continue to grow in these areas making it much more difficult to treat.

LDN – How it Works

At its intended doses of 50-100 mg, naltrexone is an opioid antagonist used in the treatment of addiction. However, when used at much lower doses, naltrexone is known to act as an anti-inflammatory agent. As we used LDN more and more, and involve it in animal and human studies, we have found it to be useful in many other conditions such as cancer. Although we do not know the full mechanism of action for benefit in cancer patients, here are some proposed mechanisms:

●      Intermittent dosing significantly reduced cancer cell development, in contrast to a constant blockade that accelerated tumor growth

●      May enhance natural killer cells, T-Cell, IL-2, and TH-2 activity via the mu receptor and also by binding to receptors on cancer cells themselves. These cells are the major players in our body’s natural immune system

●      LDN causes increased cell death in certain cancers and potentially increases patient response to chemotherapy agents

●      Cells that are treated with LDN up-regulate BAD and BIK1 genes that aid in cell death

●      Some cancer patients treated with intermittent LDN, experienced greater benefit by chemotherapy drugs

o   Example: Priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell ki

Effectiveness

            Naltrexone’s potential for cancer prevention and treatment began mainly from the work of Penn State investigators Ian Zagon and his colleagues. They initially studied and published evidence that a dose of 0.1mg/kg in mice reduced neuroblastoma tumor incidence by 66%, slowed tumor growth by 98% and increased survival by 36% over controls.

            More recent publications include that from Liu et al in 2016 who published that cells treated with LDN followed by chemotherapy always resulted in a greater reduction in cell number and viability when compared to cells cultured with LDN after chemotherapy treatment. However, in cells treated with standard NTX, treatment with any of the cytotoxic drugs did not generally result in dramatic reductions in cell number or viability.

            Another researcher, Dr.Bernard Bihari has reported he has treated about 450 cancer patients with LDN, and he reports that over 270 patients had significant benefits from LDN. Of those patients, 86 of them had shown objective signs of decreased tumor size of at least 75%. Another 125 patients were stabilizing or on a path toward remission.

Dosing

Starting doses can be anywhere from 0.5 mg to 1.5 mg, and is increased up to 4.5 mg; which is the maximum dose for Low Dose Naltrexone. Specifically for cancer patients, the dose should be a goal daily for at least 7 days before starting an "on/off cycle"

●      An "on/off cycle" consists of 3 days on and 3 days off LDN

●      The 3 days off should fall directly before chemotherapy treatment. Although there are no known contraindications with chemotherapy, it is recommended to avoid use together until further research is completed

It has been seen in some cancer patients, that taking a CBD product on the 3 days off increases the anti-tumor effect of LDN

Side Effects

LDN is well tolerated in most patients and limited further when a patient is started on a start low and go-slow method. This means the patient should be started at a low dose and titrated up slowly. When side effects occur, they are usually mild and include:

●      Sleep disturbances

●      Mild headache

●      Mild agitation

●      Nausea/GI effects - consider switching to liquid sublingual LDN to bypass GI tract

It has been found in patients that experienced side effects, that they can be stopped by decreasing the dose by half for 2-3 days, and then continuing with titration again.

Formulations

●      Oral liquid: 1 mg/1 mL daily

●      Capsules or tablets

●      Sublingual drops

o   Drops are placed under the tongue from a dropper bottle

●      Creams: 0.5 mg/mL

o   Useful for children who you have difficulty administering the other formulations, or those who are allergic to additives in other formulations of LDN

Key Resources

Boundless. Overview of Cancer [Internet]. Lumen: Boundless Anatomy and Physiology. Available from: https://courses.lumenlearning.com/boundless-ap/chapter/overview-of-cancer/

Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Medical Hypotheses. 2009;72(3):333–7.

How Low Dose Naltrexone Works [Internet]. How does Low Dose Naltrexone Work | LDN Research Trust - Low Dose Naltrexone. Available from: https://www.ldnresearchtrust.org/how-naltrexone-works

Low Dose Naltrexone [Internet]. The Low Dose Naltrexone Homepage. Available from: http://www.ldninfo.org/

Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization. Medical Sciences. 2018;6(4):82.

written by Jordan Hughes, PharmD Candidate Ohio Northern University

Coronaviruses are one of the largest groups of viruses that we know about in medicine, and it has an extensive range of natural hosts. Recently, newly evolved Coronaviruses have posed a massive threat to public health causing a worldwide pandemic.  The novel coronavirus that causes COVID-19 sparks an inflammatory immune response that is essential to control and eliminate the infection, however, certain immune responses can cause a decrease of gas exchange in the lungs. This causes a huge problem because oxygenation of the blood is essential for human life and is the basis for maintaining function of all major organs. So, will low dose naltrexone target certain immunological markers to ensure that the body does not injure itself during the fight against coronavirus?

Naltrexone is a pure opioid antagonist with activity and many opioid and non-opioid receptors. It is currently used for alcohol use disorders, opioid addictions and obesity. Naltrexone can be used for several different disorders depending on the dosage that is used, and the effects might differ when the doses are changed. Higher doses of naltrexone can be used for impulse control disorders and several other addictions. However, Low Dose Naltrexone (LDN), has been studied and shown promise in the treatment of many diseases such as Crohn’s disease, multiple sclerosis, and chronic fatigue syndrome. Dr. Bernard Bihari, known to some as the father of Low Dose Naltrexone, completed research that showed LDN was used to boost endorphin levels in patients by 3X. These endorphins levels can improve immune function and might be used to help at-risk patients to fight off the Novel Coronavirus infection.

To understand how medications attack and destroy the virus, we need to understand how the virus gets inside the body, how it infects the host, and how it is transmitted to others. Like many other infectious diseases, Coronavirus enters the body through direct contact with direct mucous membranes such as eyes, mouth, or nose. When the virus gets into the body, it will use the body’s own cells to replicate and spread. When the body recognizes the foreign virus, it will send in many natural defenses. These natural defenses will cause a fever, cough, inflammation, possible mucous production, and other symptoms. The virus can then spread from an infected person to others through droplets from a cough, sneeze, or contact with another person. That is why it is essential to follow social distancing guidelines, wash your hands regularly, disinfect areas high touch areas, stay home if you are sick, and wear a mask when you need to go out in public.

The next issue that we need to tackle is clarifying the process of the virus replication and the triggering of the important immune responses. To understand this process, we need look at the shape of the coronavirus.

The coronavirus uses its membrane to protect itself from attack. The spike coming from the outside of the membrane is used to connect to the body’s cells and insert replicating data into the cells to continue to make more of the virus.

The body will recognize the infection and send a variety of immune responses to attack the invader. The body has several natural defenses that are activated by Coronavirus. Some of the defenses are toll-like receptors, IL-6, transforming growth factor beta, and many other pro-inflammatory defenses in the body. These defenses will attack the virus by using complicated pathways and mechanisms. These mechanisms will trigger fever, irritation and inflammation in the lungs, and cough which are the main symptoms of the COVID-19 disease.

Toll Like Receptors (TLR) have several downstream effects when they become activated by an agonist like coronavirus. The downstream products include tumor necrosis factor alpha, IL-6, and inflammatory factor nitric oxide (NO). When low dose naltrexone blocks these TLRs, it inhibits the production of these inflammatory cytokines and acts as an immunomodulator through the suppression of innate immune cells.

Low Dose Naltrexone (LDN) has been proven to reduce several pro-inflammatory cytokines in the treatment of other diseases, but due to the recent discovery of this novel virus, we are unsure of the effectiveness of LDN on this virus. In one study where LDN was used to decrease fibromyalgia pain, the treatment group found reduced plasma levels of many inflammatory cytokines that are also released during immune response to COVID-19. These people found 18% reduction in overall symptoms, and the study suggests that that LDN plays a key role in the reduction of several key pro-inflammatory cytokines and symptoms.

The proposed mechanism by which LDN would work to effectively inhibit the coronavirus from causing severe illness is complicated and theorized. This means that the lungs would become less inflamed and have a larger amount of useful surface area in which oxygen could be passed from the lungs into the blood. When considering the mechanism of the Coronavirus, and the inhibitory effects of LDN, we are proposing the use of LDN to promote treatment and prophylaxis of this new infectious virus. Dr. Phil Boyle, an Irish physician has also proposed the immune enhancing effects of LDN for COVID-19 prophylaxis at doses of 3 mg to 4.5 mg nightly. He claims that daily LDN acts to normalize one’s immune system and could perhaps downregulate an overactive immune system in a time of infection.

When considering the possible benefits in contrast with the risks of using LDN, we should consider prior research to evaluate the likelihood of LDN causing severe adverse reactions. A meta-analysis was conducted analyzing the adverse effects of LDN compared to placebo. This study analyzed 11,194 patients and concluded that LDN does not increase the risk of serious adverse effects over placebo. These studies confirm the overall safety profile of oral LDN in the treatment of patients with varying doses and disease groups. This shows that the use of LDN in patients who are at-risk of contracting COVID-19 safe and highly advantageous.

A vaccine for the novel coronavirus is underway but could take months to years to finally hit the market. However, LDN is available now. With limited treatment options for the Novel Coronavirus and the severity of the disease, it is imperative to search for therapeutic options to improve immune health and reduce the spread of COVID-19. Low Dose Naltrexone could be used as an immune boosting agent for those who are at high risk of contracting the COVID-19 disease. Those who should be considered for this Low Dose Naltrexone therapy include the elderly, those who are immunocompromised, and those who have structural lung disease.

This articles's author Brad White, R.Ph

Working as a pharmacist in New Philadelphia for the last 20 years has provided me with an opportunity to meet and learn from thousands of patients. There have been a lot of opportunities to help improve the quality of life of patients, and those experiences have been very rewarding both personally and professionally. There are also those occasions when you are standing across from a person who is so desperate for help, for a solution, for anything that can ease their pain or make them feel better. Those are the challenging times that you wish you had the power and the knowledge to provide a remedy for what ails them.

Just last week I traveled to an educational pharmacy conference that shared developing research on a variety of topics in medicine, and one topic has me really excited! It is called Low Dose Naltrexone (LDN).

What Are Common Health Conditions That LDN Therapy Has Shown Benefits?

• Cancer

• Crohn’s Disease

• Fibromyalgia

• Multiple Sclerosis

• Anti-Inflammatory

• AIDS/HIV

• Complex Regional Pain Syndrome

• Posttraumatic Stress

• Psoriasis and Eczema

Over the last several years there has been an explosion in research on LDN to treat a variety of autoimmune diseases. PubMed, a literature repository for the US National Library of Medicine, lists 230 published studies from respected academic organizations like Stanford, Harvard, Penn State, Brown University and the Mayo Clinic. LDN is most commonly used to treat Fibromyalgia, Chronic Fatigue, Multiple Sclerosis, Psoriasis, and Autoimmune Thyroid Diseases. Additional research is being conducted on over 100 other health conditions.

What is LDN and How Does It Work?

Low-dose Naltrexone (LDN) therapy was developed in 1985 by Dr. Bernard Bihari, a Doctor of Internal Medicine, Psychiatry and Neurology. Dr. Bihari found that AIDS patients had 20% of the normal endorphin levels of healthy patients. Dr. Bihari’s key discovery was that 1% of the normal dose of naltrexone caused an unusual effect of a 300% increase in endorphin levels!

Endorphins are chemicals that interact with receptors in your brain that reduce the perception of pain. Endorphins also trigger a positive feeling in the body, often described as euphoric. This feeling can be accompanied by a positive and energizing outlook on life and a sense of well-being resulting in less pain. Low levels of endorphins are associated with the opposite effect: physical and emotional pain and depressed feelings. Naltrexone has several mechanisms of action that have an effect on opioid receptors that are distributed throughout the brain, spinal cord, nervous system, and digestive tract. LDN appears to enhance immune function and improve the inflammatory reaction.

Why Haven’t I Heard About This Before?

Naltrexone was patented in 1967 approved by the FDA in 1984 for heroin addiction using a 50mg dose and in 1995 the FDA approved it for treatment of alcoholism. Dr. Bihari’s creative application of a medication that is not controlled by a pharmaceutical company has provided a platform for hundreds of independent research projects that may benefit millions of patients worldwide.

The mechanism of action increases endorphin release, and it appears these endorphins can modulate the immune response. More research needs to be done but LDN appears to have promising benefits in a variety of health conditions. On the other hand, higher doses like 50mg doses appear to overwhelm the receptors and negate the immune system effects.

How Is LDN Therapy Initiated?

LDN is a prescription therapy that requires you to work with a physician and your pharmacist. Your doctor will generally begin therapy at a low dose and increase gradually over several weeks until your condition has stabilized and you are side effect free. Doses start generally at 0.5mg and slowly titrate up depending on your health condition and side effect tolerance. Because a pharmaceutical company does not make LDN, prescriptions can only be filled by an accredited and licensed compounding pharmacy.

What Are The Side Effects?

The most common side effects of LDN are sleep disturbances, often due to endorphin response, vivid dreams, or insomnia. Side effects generally resolve in four to seven days. Only 10% of the cases reported side effects for more than a week.

LDN has great potential with clinical research to support multiple immuno-modulated disease states. It is non-toxic and has a low side effect profile. It can be dosed both orally and topically and there is evidence to support use.

LDN doesn’t work for everyone and the slow titration in dose schedule is important, your pharmacist can work with you and your physician to help you achieve the optimal outcome. If you are in a position where you have tried multiple therapies and specialists searching for a solution to your health problems, then LDN may be an option you should learn more about. LDN is a cost effective therapy that promises to evolve in the next decade as more research is done to evaluate the benefits.

How Can I Learn More?

The Medicine Center Pharmacy in New Philadelphia is your resource in Northeast Ohio for LDN information. Brad White R.Ph. is a graduate of Purdue University School of Pharmacy and has experience with customized medication solutions and operates the only PCAB Accredited Compounding Pharmacy in East Central Ohio.

Low Dose Naltrexone FAQ | New Philadelphia Ohio

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Medicine Center Compounding Pharmacy in New Philadelphia is PCAB Accredited for preparing Non Sterile Compounded prescriptions. Tuscarawas County, Ohio.