LDN Pearls for Beginners by Ginny 10.16.2011

Low Dose Naltrexone (LDN) Pearls
This guide is for people who are thinking of giving LDN a try, and are wondering what to expect. This guide contains a collection of pearls, learned over time, as well as links to resources which have helped others like you. While there is some good research to guide us in making educated decisions about LDN, there have not been large scale trails to provide recommendations. There is wide variation in the way people respond to LDN, and a variety of conditions that LDN is used to treat. LDN is often called “people powered medicine”, because doctors are not learning about LDN from pharmaceutical representations, but from ordinary people, who are finding benefit and spreading the work.

Information here is not to take the place of medical advice from your medical doctor.
Ginny Dudek (ginny.dudek@yahoo.com)

Online Resources: Hit Ctrl and right click mouse to follow hyperlinks in this document.

  • Skips Pharmacy
Skip is a pharmacist who has been an outspoken advocate for LDN for more than 20 years. He and his staff are very helpful in providing guidance and support to LDNers. They have a very reasonable price and can ship to every state except North Carolina.
21000 Boca Rio Rd Suite A-29 Boca Raton, Florida 33433 
561-218-0111 800-553-7429 Fax: 561-218-8873

  • Low Dose Naltrexone - Common Questions & Answers –The Pharmacy Shop

  • Link to published article on LDN for Disease Prevention:

How does LDN work? 
The video on http://www.ldnscience.org/  is the best teaching tool to explain the action of LDN.

In order to understand how LDN works, it is crucial to briefly introduce the workings of the ‘natural opioid’ (endorphin) system.

Endorphins are opiate-like molecules produced naturally in the body. The term ‘endorphin’ comes from ‘endogenous morphine’, meaning that it is created within the body, and differentiating it from opioids that are administered from external sources.

Endorphins are produced in most cells in the body, and are important regulators of cell growth and therefore the immune system. Disorders of the immune system can occur with unusually low levels of these endorphins.  The particular endorphin that has been found to influence cell growth as well as immunity is called Opioid Growth Factor (OGF) or Met-Enkephalin.

For an endorphin such as OGF to exert its beneficial effects, it must interact with the body’s cells. It does this by binding to a receptor on the surface of the cells. The receptor to which OGF binds is the ‘Opioid Growth Factor Receptor’ (OGFr) – previously known as the Zeta (ζ) receptor.

Thus, for the endorphin system to be fully functional, two elements are required: opioid production and cell interaction.

Naltrexone is an externally administered drug that binds to opioid receptors.  In doing so, it displaces the endorphins which were previously bound to the receptors. Specifically, by binding to the OGF receptor, it displaces the body’s naturally produced OGF.

As a consequence of this displacement, the affected cells become deficient in OGF and three things happen:

  1. Receptor production is increased, in order to try to capture more OGF.
  2. Receptor sensitivity is increased, also to try to capture more OGF.
  3. Production of OGF is increased, in order to compensate for the perceived shortage of OGF.

Since LDN blocks the OGF receptors only for a few hours before it is naturally excreted, what results is a rebound effect; in which both the production and utilization of OGF is greatly increased. Once the LDN has been metabolized, the elevated endorphins produced as a result of the rebound effect can now interact with the more-sensitive and more-plentiful receptors and assist in regulating cell growth and immunity.

The duration of the rebound effect varies from individual to individual, but generally persists for about one day.

The benefits of the rebound effect can only be utilized by taking a low dose of regular naltrexone. Taking a high dose of naltrexone or using a timed-release formulation will result in continuous blockade of OGF receptors, and the rebound effect will not serve any useful purpose.

In scientific terminology, the use of regular-dose naltrexone results in ‘continuous opioid receptor blockade’ whilst the use of LDN results in ‘intermittent opioid receptor blockade’. In order to benefit from the rebound effect and achieve the therapeutic benefit of LDN, it is essential to avoid timed-release versions of naltrexone.

Individuals vary in their metabolic speed and this will result in inter-patient variation in the speed at which LDN is eliminated from the body, as well as the length of the rebound effect. Whilst a single daily dose of between 3mg and 5mg will be suitable for most patients, individual modification of dose or frequency is sometimes needed.

What is the best dose of LDN?

There is a lot of variation in what dose seems to work best for different people. Factors include how quickly you metabolize LDN, and what condition you are treating. You know your body better than anyone else, so ultimately the decision is up to you and your doctor. Starting with an elixir preparation (1ml=1mg) may be helpful. This makes it easy to adjust doses as needed.

People take low dose naltrexone in dosages anywhere from 0.5mg to 12mg daily. The most common recommendation is to start at 1.5mg, increase to 3mg in 2 weeks if you do not have side effects. Increase again in 2 weeks to 4.5mg, if you do not have side effects. If you are bothered by side effects, increasing more slowly can make a difference.

Guidelines for finding your right dose were established by Dr, Gilhooly in the LDN Research Trust newsletter on Page 3.  However, this letter does not address starting dosages.

Dr. Gilhooly recommends increasing LDN by 0.5 mg at a time. Some people have side effects such as muscle twitching, nausea and headache, and if side effects are bothersome it's best to wait until they pass. The goal is to get to the maximum dose you can tolerate to get the most benefit from the rebound effect. If you increase your dose by 0.5mg and you feel more fatigue and /or blue, that is a sign that you're blocking too long. At that point, you should drop back 0.5mg to find your ideal dose

Some people benefit from twice a day dosing, and in theory it appears that twice a day dosing reduces inflammation in the body.  People treating cancer and MS should not take LDN twice a day, since it could block endorphin production too long, and in theory, you would not have the benefit from the increase in OGFr.

What should I avoid if I take LDN?
  • Restricting gluten, soy and casein while on LDN may be beneficial, because these foods compete for the opioid receptors that LDN works on.
  • There is a lot of confusion and conflicting information about medications to avoid while taking LDN. These decisions are best discussed with your prescribing physician.

Can LDN be combined with other medications, drugs, vitamins or food supplements?
  • LDN should not be taken at the same time with opiate-type drugs as it will stop them from working for a number of hours. With regards to other medications/drugs/vitamins in the clinical trials conducted to date, no problems have been seen when LDN was combined with other medications being taken by the studies’ participants. Therefore at this moment, there is no known reason to avoid taking LDN with any medication/drug/vitamin/supplement other than opiate-type drugs usually used for treating pain.

How soon after taking LDN can I use opiate painkillers?
  • LDN is metabolized within a few hours. As long as they are kept apart by a few hours, LDN should not interfere with the pain-relieving effects of opiates. In fact, you may find that the pain medication works better after several hours have passed since taking LDN as the naltrexone increases sensitivity of the cell\'s receptors to the opiates.

What conditions does LDN work on?
Because of its action LDN works on a variety of conditions.

  1. 1.     Allergies:
The recent Stanford University study into LDN in Fibromyalgia showed that LDN binds to the toll-like 4 receptors which suppress inflammatory activity. This binding is the probable mode of action in hayfever, where LDN binds to these receptors and reduces the production of inflammation. This suggests that LDN may have a potential action in other atopic conditions such as asthma and eczema.

  1. 2.     Cancer:
No clinical trials have been done using LDN as a cancer treatment, however there is basic science research that shows LDN is effective for ovarian cancer, and there is a lot of anecdotal evidence that LDN works for a variety of cancers. People taking LDN for cancer want the benefits of OGF factor, and it is recommended by experts in the field that they never take LDN more than once a day.

  1. 3.     Chrons Disease:
Research [<<www.ldnscience.org>>] has shown that LDN helps to heal the gut in Chrons disease by increasing healthy bacteria as the gut heals itself. Many with IBS find their symptoms subside. The other thing that LDN dose so well is to reduce inflammation and to modulate the immune system.

  1. 4.     Chronic fatigue:
In theory, the reasons that LDN would work for chronic fatigue is that with CFS we all have a host of co-infections. The immune modulating benefit, plus the healing of the gut will go a long way. There have not been any completed studies on CFS, but the Stanford study of fibro showed that people with fibromyalgia and chronic fatigue had the greatest improvement in quality of life.

  1. 5.     Fibromyalgia:

  1. 6.     Infertility/ PMS/ Endometriosis/ Polycystic Ovary Disease / Menopause:
http://www.youtube.com/watch?v=IdDq9NcF7Tk&NR=1 with Phil Boyle MD, at the second LDN conference

  1. 7.     Multiple Sclerosis:
LDN has been used for MS for more than two decades.  Benefit was show in studies published at <<www.ldnscience.org>>

What are the common side effects from LDN?

While Low Dose Naltrexone appears to be well-tolerated, commonly reported side effects of LDN include: headache,  vivid dreams, insomnia, anxiety & nervousness,  sleepiness & fatigue,  nausea,  diarrhea, abdominal pain/cramping, decreased appetite and  muscle twitching. The side effects diminish as the body adjusts to the increased endorphin production. In the Stanford study, side effects were reported as rare, mild and transient.

Full dose naltrexone (50mg or more per day) has additional side effects, including a warning about liver function abnormalities. This has not been seen with LDN.

What is a Herxheimer reaction?
Some but not all people have a herxheimer (herx) reaction, when their immune system begins to recognize foreign viruses, bacteria and yeast. If you have a strong herx reaction you may feel like you have the flu, and your body’s production of cytokines is a sigh that your immune system is working as it should. You may find that lowering your dose will make your symptoms more manageable.  You may have to address underlying co-infections, in addition to LDN treatment.

Journal Articles:
Public release date: 2-Sep-2011  Contact: Dr. Ian Zagon     isz1@psu.edu      717-531-6409
Society for Experimental Biology and Medicine
Low-dose naltrexone (LDN): Tricking the body to heal itself

Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered the mechanism by which a low dose of the opioid antagonist naltrexone (LDN), an agent used clinically (off-label) to treat cancer and autoimmune diseases, exerts a profound inhibitory effect on cell proliferation. It has been postulated that opioid receptor blockade by LDN provokes a compensatory elevation in endogenous opioids and opioid receptors that can function after LDN is no longer available. Using a novel tissue culture model of LDN action, the mechanism of LDN has been found to target the opioid growth factor (OGF, [Met5]-enkephalin) and OGF receptor (OGFr) axis. This discovery, reported in the September 2011 issue of Experimental Biology and Medicine, provides new insights into the molecular pathway utilized by an increasingly important clinically prescribed agent that serves as a basic biological regulator of cell proliferative events related to pathobiological states such as cancer and autoimmune diseases.

Although the antitumor effects of opioid antagonists were first noted by Drs. Zagon and McLaughlin in 1981 (Life Sci. 28:1095-1102, 1981), the first full reports about opioid antagonists modulating growth processes occurred in 1983 (Science 221:671-673; ibid, 221:1179-1180). This led to the hypothesis that endogenous opioid systems play a role in cancer, development, and cellular renewal (Life Sci. 35:409-416, 1984; ibid, 35:2057-2064, 1984). These papers revealed that a short-term opioid receptor blockade with naltrexone (NTX), a general opioid receptor antagonist devoid of intrinsic activity, results in an elevation in endogenous opioids and opioid receptors in response to the opioid receptor blockade. Interference of opioid peptide-opioid receptor interactions for a short time each day (4-6 hr) with LDN provided a subsequent window of time (18-20 hr) for the increased levels of endogenous opioids and opioid receptors to interface and elicit a robust functional response: inhibition of cell proliferation. The question that now can be addressed is which endogenous opioid(s) and opioid receptor(s) are responsible for LDN's effects on cell proliferative processes.

The present study was structured to focus on the relationship of endogenous opioid pathways and the repercussions of intermittent opioid receptor blockade with regard to cell proliferation. A unique tissue culture model of LDN using a short-term exposure to NTX was developed, thereby avoiding the confounding variables introduced by systemic influences and allowing a dissection of the biological events involved. Screening of a wide variety of opioids (some selective for specific opioid receptors) revealed that only exogenous OGF had a profound effect on depressing cell proliferation. Removal of endogenous OGF by antibody neutralization in cultures given a short-term opioid receptor blockade by NTX eliminated the repressive effects of this peptide on cell proliferation, indicating that the repercussions of short-term NTX exposure in vitro was dependent on OGF. Short-term NTX blockade continued to exert a negative effect on cell proliferation even when the classical opioid receptors, μ, δ, and κ, were knocked down by siRNA technology. However, short-term NTX treatment did not repress cell proliferation when cells were subjected to siRNA to the non-classical opioid receptor, OGFr. These results indicate that the effects of short-term NTX in vitro are dependent on the OGF-OGFr axis. Previous studies have shown that the OGF-OGFr axis regulates cell proliferation by altering the G1/S phase of the cell cycle through the cyclin-dependent inhibitory kinases p16 and p21. Knockdown experiments with siRNA show that a short interval of exposure to NTX in tissue culture required p16 and/or p21 in order to have a functional outcome on cellular processes.

The research team was comprised of Dr. Ian S. Zagon, Distinguished University Professor, and Dr. Patricia J. McLaughlin, Professor, along with Dr. Renee N. Donahue, in the Department of Neural & Behavioral Sciences. Drs. Zagon and McLaughlin not only discovered the phenomenon of LDN, and subsequently the OGF-OGFr axis, but have been at the forefront of translating their findings of LDN - and OGF - from the bench to the bedside. LDN has proven successful in Phase I and II clinical trials in the treatment of Crohn's disease, and OGF has been reported to be safe and efficacious for the treatment of advanced pancreatic cancer. Co-author Dr. McLaughlin states: "Now that we know LDN uses the OGF-OGFr axis as the pathway to control the cell cycle, this expands our arsenal of biological-based treatment modalities to bring about a change in disease states reliant on cell proliferation that not only includes LDN, but exogenous OGF and the imidazoquinoline, imiquimod. This information also provides the basis for a rational approach to the design of diagnostic tools and measures of therapeutic efficacy." Dr. Donahue, who has devoted a concentrated effort on improving the health of women through research explains: "This study joins a series of other investigations (Amer. J. Physiol. 296:R1716-1725, 2009; ibid, 297:R1154-R1161, 2009; Gynecol. Oncol. 122:382-388, 2011; J. Cancer Therapy 2:110-124, 2011; Exp. Biol. Med., in press, 2011) demonstrating that both LDN and OGF offer powerful treatments to combat a devastating cancer that strikes over 20,000 women in the U.S. each year and stands as the 5th leading cause of cancer-related deaths in females. Thus, one should not lose sight that the OGF-OGFr axis is a new frontier in understanding the pathogenesis and treatment of a cancer that has been, up to now, recalcitrant to conventional therapies." Dr. Zagon adds that "The exciting results that the mechanism of LDN uses the OGF-OGFr axis, brings together two very important opioid-based treatment modalities under one umbrella. This common denominator in a physiological pathway does much in now directing our attention to how the OGF-OGFr system works, and explains why an opioid agonist (i.e., OGF) and antagonist (NTX in the form of LDN) have the same effects.

Moreover, LDN is an oral medication, generic, inexpensive, and non-toxic, and has been documented to alter the course of both neoplasias and autoimmune diseases such as Crohn's and multiple sclerosis, making this drug especially attractive as a therapeutic agent. The fact that OGF has been found to be a potent anti-inflammatory agent (Immunobiology 216:173-183, 2011; ibid, 216:579-590, 2011) also opens the door to the potential treatment of diseases of the immune system (HIV/ADS) infections, hypersensitivity, and neurodegeneration, which involve cell proliferation, thereby widening the benefit from therapeutic manipulation of the OGF-OGFr axis by LDN."

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said "These researchers from the Milton S. Hershey Medical Center have made the important discovery of the mechanism by which a low dose of the opioid antagonist naltrexone (LDN) can suppress cell proliferative-related disorders such as cancer and autoimmune diseases. This is an exciting new direction for future therapy".

Experimental Biology and Medicine is a journal dedicated to the publication of multidisciplinary and interdisciplinary research in the biomedical sciences. The journal was first established in 1903.

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