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The precursor protein to most endorphins is POMC (pro-opiomelanocortin). In normal physiological function, the hypothalamus secretes CRH (corcitrophin-releasing hormone) in response to stress on the physiological system. This in turn stimulates the pituitary to make POMC, which, as a large complex molecule, can be enzymatically broken up into neuropeptides such as the endorphins. A negative feedback loop then occurs, which suppresses the release of CRH when the by-products of POMC breakdown reach a certain level. Almost every physiological system in the body contains the necessary enzymes to break down POMC to the component neuropeptides.
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There are two main areas of action for analgesia where natural endogenous neuropeptides, such as beta-endorphins, exert a painkilling effect: first, the peripheral nervous system (PNS) and second, the central nervous system (CNS).
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The nerves that transmit the sensation of pain do so by releasing a neurotransmitter called “Substance P.” In the PNS, opiates bind mainly to the presynaptic terminal and prevent the release of Substance P by a cascade reaction. If Substance P cannot be released into the nerve junction, the pain signal cannot be transmitted.
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subclass of opiate receptors called “mu” receptors is ubiquitous through the PNS and is the main target for opiate analgesics.
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In the CNS, specifically the brain, opiate receptors are very well distributed and are involved in a multitude of different neurochemical actions. Unlike the PNS, opiate receptors centrally act to inhibit pain by modifying the release of the potent neurotransmitter dopamine. Dopamine is commonly known as the body’s natural “happy chemical” and is primarily controlled by the release of another neurotransmitter called GABA (gamma-aminobutyric acid).
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When opiates bind to the mu-opioid receptor, they cause a reduction in the release of GABA, which in turn reduces the inhibitory effect that GABA activation has on the presynaptic nerve release of dopamine.
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In layman’s terms, activating a mu-opioid receptor centrally disrupts the normal controls on baseline release of dopamine, meaning that far more dopamine is released than normal. This has an analgesic effect by suppressing the conduction of pain messages and the response to pain caused by the euphoric effect of excess dopamine. The excess dopamine is largely responsible for the “high” desired by people who abuse opiates, but belongs entirely to a natural system that exists to maintain homeostasis and is activated by naturally occurring endorphins as discussed earlier.
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Endogenous endorphins, such as the beta-endorphins discussed earlier, are agonists; these are mimicked by opiate drugs such as morphine and diamorphine. Naltrexone and naloxone are antagonists: keys that fit the same door, but stop the receptor from being activated by an agonist. It has since been discovered that these receptors are fluid and can become more or less sensitive to agonists and can increase and decrease in active number depending on circumstances.
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This is a natural biological phenomenon caused by physiology always attempting to return to a baseline state (homeostasis). In pharmacology, this effect is referred to in terms such as desensitization and down-regulation. This is a reversible reaction, and naltrexone was used widely in the 1980s and 1990s for assistance with abstinence from opiates, but only once a patient had been gradually titrated down from their regular dose and a level homeostasis had returned.
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Opiate-addicted patients taking naltrexone often describe a “flatness,” technically described as dysphoria, which is reported to lead to significant depression.
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In the case of naltrexone, the dose that seems to have an effect in autoimmune diseases is significantly lower (ten to forty times lower) than the dose used for opiate addiction or alcoholism. This is referred to as low dose naltrexone (LDN). Most commonly, LDN is taken daily in doses of between 0.5 mg and 4.5 mg.
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What was also known was that interrupting homeostasis, by blocking these receptors, could result in tricking the body to produce more endorphins to compensate.
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Over the next twenty-nine years, Dr. Ian Zagon championed the basic research into endorphins and naltrexone (LDN), publishing nearly three hundred papers on the subject. The extent of the research is too overwhelming to present here; however, it has confirmed beyond doubt that the endorphin/opioid receptor system is involved in almost every biological system that regulates immune response.
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The mechanism of action of LDN, as proposed by these studies, can be summarized as follows: 1. Many outward diseases are expressions of a malfunctioning immune system. 2. The immune system is regulated by endorphins, which have a primary action on opiate receptors. 3. Blocking opiate receptors briefly using naltrexone causes an up-regulation in the production of endorphins, which can act in an immunomodulatory way to correct immune system malfunction. 4. Furthermore, cell growth (proliferation) is also mediated by a subtype of endorphins; cell proliferation can be suppressed by endorphins, and this is applicable to some forms of cancer.38
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Scientists have long known that naltrexone binds to more than just the opiate receptors; there is also a significant attachment to a group of receptors called toll-like receptors (TLRs). Toll-like receptors were first demonstrated in 1985 by Christiane Nüsslein-Volhard.39 They are an essential part of the innate immune system, providing a first line of defense against microbial invasion, and are present on cells such as white blood cells (macrophages), dendritic cells, neutrophils, B lymphocytes, mast cells, and monocytes, as well as directly on cells of various human organs, such as the kidney and intestines.
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In general, activation of a TLR leads to the production of pro-inflammatory cytokines (a loose class of small proteins), which then mobilize the innate immune system to, for example, send white blood cells to the affected area to engulf the intruder—or in the case of a virus, instruct the infected cell to die. Interestingly, the activation of many types of TLRs has been demonstrated to also produce a highly potent molecule called NF-kB (pronounced enn-eff-kappa-bee) as part of the signaling mechanism.40 NF-kB is currently undergoing intense research and has been shown to be a potent target for the treatment of autoimmune diseases and cancers.41 NF-kB has even been linked to the expression of cancer oncogenes, which turn off the natural cell-death mechanism, leading to the uncontrolled growth of the cancer.42
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more than one way of being activated. As mentioned previously, naltrexone is a potent antagonist of the TLR receptor pathway.43 This pathway has been shown to be clinically relevant in vivo, by studies showing that naltrexone can inhibit TLR-4 and reverse symptoms of neuropathic pain.44
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Hutchinson and colleagues in 2008 effectively demonstrated that opiate-binding receptors are antagonized by levo-naltrexone, whereas the TLR-4 receptor is antagonized by dextro-naltrexone.45
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Clinicians and scientists postulate that in some autoimmune diseases, such as lupus, rheumatoid arthritis, and multiple sclerosis, natural mammalian cell by-products may inappropriately activate TLR receptors, directly leading to the inappropriate inflammation.46
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Table 1.1. Forms and Dosages of LDN
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To summarize the data so far: • Naltrexone, when produced for human consumption, consists of a 50:50 mixture of levo- and dextro-isomers. • Levo-naltrexone is an antagonist for the opiate/endorphin receptors, and is credited with: – Up-regulation of endorphin release; – Immunomodulation; and – Reductions in cell proliferation via endorphins. • Dextro-naltrexone is an antagonist for at least one, if not more, TLRs, and is reported to: – Antagonize TLR, suppressing cytokine modulated immune system; and – Antagonize TLR-mediated production of NF-kB, reducing inflammation, and potentially down-regulating oncogenes.
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Table 1.2. Potential Side Effects of LDN
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Side effects, as reported by patients, can often be prevented by the patient starting at a low dosage and increasing by 1 mg per week until reaching 4.5 mg.
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Low dose naltrexone is commonly started once daily, at 0.5 to 1.5 mg. This is to allow the clinician to evaluate how the patient will respond.
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incidence of side effects is higher when LDN is taken at night, but clinical response is just as good when taken in the morning.
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Historically, a large amount of anecdotal evidence points toward avoiding corticosteroids while taking LDN. This has been largely refuted by recent clinical experience, where most clinicians will initiate LDN if the patient is on 20 mg or lower daily prednisolone equivalent.
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According to a surge of new research,3 the entire process of MS may be initially activated and then maintained by reactive oxygen species and oxidative stress leading to apoptosis of cells, including oligodendrocytes. Apoptotic material then overwhelms the brain’s phagocytic ability (the ability of the cells to remove damaged cells or pathogens), causing local accumulation of damage to cells including damage to the venules, leading to leaky BBB. So oxidative damage, or oxidative stress, becomes one of the mechanisms of cellular damage and potentially the activating event, leading us to question the cause of the oxidative stress.
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According to Dr. Bruce Richardson, a researcher at the University of Michigan, the initial cellular trigger that sparks the ultimate development of lupus is oxidative damage. This in turn leads to an epigenetic change that inhibits DNA methylation in the T cells. This change to the T cells causes the conversion of T-helper (CD4) cells “into autoreactive, cytotoxic, proinflammatory cells that cause lupus-like autoimmunity in mice and humans.”
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Naltrexone has been shown to decrease DNA methylation and other epigenetic changes induced in autoimmune diseases.9 This makes the treatment of autoimmune diseases with LDN very significant as a proven therapy that potentially reverses some of the epigenetic changes that occur in autoimmune diseases.
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These and other studies indicate that autoimmune diseases are multifactorial diseases in which cells of genetically susceptible individuals are epigenetically modified by a combination of factors including one of two basic categories of triggers: 1. Gastrointestinal changes due to: A. Microbiome (all the millions of bacteria that live in our gut) B. Gluten and other food sensitivities C. Other dietary choices 2. Environmental factors including: A. Pathogens (viruses, bacteria, and other infectious agents) B. Nutritional deficiencies C. Chemical and environmental toxicity D. Endocrine (hormone) imbalance E. Sleep disturbance or deprivation F. Stress
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70%–80% of the immune system resides in the gut! • The gut has more neurotransmitters than the brain, with some neurotransmitters being predominately located in the gut. For instance, 95% of serotonin, a common target of antidepressant therapy, is manufactured and utilized in the gut. • The gut manufactures and uses more than twenty hormones that have both local and distant effects on organs such as the brain.12 At least one bacterium in the human gut has even been discovered to produce androgens (male hormones).13 All this makes the gut an important endocrine (hormonal) organ. • Perhaps most obvious but also commonly overlooked, what we put in our mouths is of primary importance. All of the fuel and resources our bodies will ever get must be processed and absorbed through our guts. If we don’t get the right building blocks, we can’t build healthy cells. If we get toxins or poor nutritional content in our food, our hard cellular building gets torn down.
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By decreasing the damaging inflammatory cytokines produced in the gut and altering the pathological cellular balance of autoimmune diseases, LDN supports the immune system to improve the balance of the microbiome.
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reported in a 1996 article in The Lancet, “Our data suggest that gluten sensitivity is common in patients with neurological disease of unknown cause and may have etiological significance.”
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Research published in 201423 demonstrated that digesting gluten (found in grain) and casein (found in dairy) results in the release of peptides with opioid activity. These peptides cause changes to cystein methylation in the DNA, leading to epigenetic changes as well as having negative effects on glutathione and the overall oxidative burden in the brain. Gluten- and casein-containing diets lead to changes in the epithelial cells of both the gastrointestinal tract (leaky gut syndrome) and the brain (leaky BBB) via these opioid pathways.
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Dr. Alessio Fasano, a practicing gastroenterologist and researcher at Harvard Medical School, has shown that gluten intake leads to leaky gut syndrome in which normally excluded products, such as bacteria, yeast, pathogens, toxins, and partially digested foods, get absorbed through the damaged endothelial lining of the gut, activating the immune response to inflammation and autoreactivity.28 He links these changes to a leaky BBB that develops when people with gluten sensitivity have gluten in their diets.
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LDN has a positive benefit on the opioid pathways involved in the damage to the epithelial lining of both the gastrointestinal tract and the BBB. While removing gluten or dairy from the diet of the autoimmune patient can’t be replaced by treatment with LDN, LDN is an important therapy that helps the gut to heal from these insults.
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When blood sugar is even mildly elevated it leads to glycation. The glycation process happens when sugar binds to proteins in the body. When this happens, it increases free radicals (oxidative stress) and inflammation. Glycated proteins, oxidative stress, and inflammation hyperactivate the immune system, causing changes in the microbiome leading to leaky gut syndrome. This in turn instigates a change in the BBB such that it becomes permeable, allowing immune cells access to the brain (where they should not be) as well as causing damage to the DNA.
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In some people, LDN changes the appetite, making it easier to stick with a diet that is low in carbs, sugar, and saturated fats. Research in mice and humans has shown that low doses of naltrexone have a positive benefit on dietary choices,31 decreasing appetite and improving the ability to make healthier food choices.
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LDN improves the immune system’s response to infection. It has been shown in research to have a positive benefit in many types of infections, including HIV, herpes, hepatitis, and EBV. Patients with chronic infections of many types respond well to LDN with fewer, less frequent, and less severe infections, as well as improved response to therapy. LDN’s positive benefits are likely due to its immunomodulatory effects on T cells, monocytes, and macrophages.
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Alpha lipoic acid is a powerful antioxidant that easily crosses the BBB, increases levels of glutathione, and appears to have neuroprotective capabilities outstripping any medication currently available.
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High-dose biotin, another antioxidant, was shown to have a positive effect on symptoms, disease progression, and improvements in brain function over two years with onset of improvement of symptoms taking between two and eight months.57 Dosages used in this study were 100–300 mg of biotin, levels that are unavailable over the counter, although they could be made at compounding pharmacies.
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Melatonin has been found to have anti-inflammatory and immunomodulating effects in the brain and have positive effects on many of the pathological processes in autoimmune diseases. It has also been shown to stabilize the endothelial cells of the vasculature, thereby improving the BBB distortions in MS.58 Melatonin is worth a try to help improve sleep and may actually aid in the disease process itself. We know from research that it is safe to take dosages up to 20 mg nightly before bed.59 I have my patients start at 1–3 mg before bed and increase until they sleep better, get to 20 mg, or must decrease due to nightmares or morning grogginess.
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One research study to date has shown that administration of CoQ 10, a potent antioxidant, decreased disease progression and improved the pathologic mechanisms of MS in a mouse model.60 I normally recommend ubiquinol (a better absorbed form of CoQ10), 200–400 mg daily.
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Vitamin D has been shown to mitigate autoimmune disorders by suppressing the autoimmune cellular activity and enhancing the TH1 immune pathway,64 the imbalance of the TH1 and TH2 pathways being a significant part of the cellular pathology of lupus.
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Although LDN has no direct effect on nutrient status, by contributing to repair of the gut lining, LDN likely improves nutrient absorption.
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Dr. Sherry A. Rogers is a preeminent physician and researcher as well as a prolific writer of scientific papers and books. One of her specialties is environmental toxicity and detoxification. As she explains in her book Detoxify or Die,
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Mercury has been found to be able to bind glutathione,84 the main antioxidant of the CNS, potentially reducing levels of glutathione available for use in the CNS.
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LDN improves the body’s ability to eliminate and manage toxic exposure in several ways. It improves glutathione levels, thereby aiding detoxification. It decreases oxidative damage caused by toxic exposure, making it easier for the body to clear the toxins. It decreases the autoreactive T cells and inflammatory cytokines that are a hallmark of environmental toxicity. It helps to repair the damage to the epithelial cells of the gut and BBB that is caused by toxins. And last, LDN helps to repair the toxin-induced DNA methylation that leads to epigenetic change.91
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Estrogen dominance (more estrogen than progesterone relative to one another in women and high estrogen levels in men, a term coined by Harvard physician John Lee) has been shown to activate inflammatory cytokines via the estrogen receptors on various immune cells associated with the development of autoimmune diseases.93 Exogenous estrogens, nonhuman estrogen-like compounds found in industrial chemicals, pesticides, and surfactants, have also been shown to adversely affect the immune system and lead to development of autoimmune diseases through endocrine disruption.94
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Part of the protective benefit of estrogen in women with MS may be due to a particular form of estrogen called estriol, sometimes referred to as the pregnancy hormone.
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Thyroid hormone is immune modulating in that people with lower thyroid production have higher rates of cancer, infectious diseases, and autoimmune diseases.
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Research has also elucidated part of the mystery of the gender difference in autoimmune diseases. A normally silent immune gene on the X chromosome is demethylated (this is an epigenetic change), making disease flares worse. Men must have a more robust trigger than women because they have only one X chromosome.
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LDN has a positive effect on the neurotransmitters in the brain. Research has shown LDN to be beneficial in depression, anxiety, and bipolar disorder. And it is known to help balance stress hormones. LDN has a balancing effect on the HPA axis and all the body’s hormones. This is the case because endorphins, the production of which are increased with LDN, have a controlling and directing effect on the immune and endocrine (hormonal) systems. Many patients have had resolution of their hormonal symptoms while taking LDN, and it is often prescribed just for this reason because it works so well.
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Research has shown that when an autoimmune attack is ongoing in the human body, cytokines that disrupt sleep are being produced.116 LDN has a balancing effect on those cytokines that disrupt sleep. While the most common side effect of LDN is difficulty sleeping (about 20% of people who start directly on 4.5 mg experience this), most people sleep better and deeper and wake up feeling more refreshed with less daytime fatigue after tapering up to 4.5 mg, or whatever their stable dosage turns out to be.
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LDN has been shown to reverse the cellular imbalances induced by chronic stress that contribute to disease.
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Specifically for lupus, LDN has been shown to enhance the deficient TH1 cell response128 and balance the TH1/TH2 abnormality of lupus.
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Two of my favorites are Detoxify or Die, by Dr. Sherry A. Rogers (dramatic title, I know, but a very well-referenced scientific book), and The Detox Diet for Dummies, by Dr. Gerald Don Wootan.
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Low dose naltrexone has many positive benefits, both for modifying the disease processes of MS and lupus at the cellular level as well as for decreasing their symptoms. LDN can be used to improve sleep, balance hormones, improve the ability of the body to detoxify, help to stabilize epigenetic changes, improve the health of the gut, and modulate the immune response, changing immune pathways to healthier ones. Talk to your doctor about LDN if you have an autoimmune disease or any disease associated with immune system pathology. You have nothing to lose and much to gain. Show your doctor this book—a conscientious physician wants to learn more to help their patients and will be glad for the scientific knowledge that will allow them to help you and many others. If your doctor is resistant to learning, resentful that you know something they don’t, or tries to hamper your attempts to be healthy, please find another doctor. There are many compassionate physicians out there who are inquisitive, intelligent, and open-minded. There are many doctors who know that learning only begins with medical school, it doesn’t end there. But don’t stop there. Explore
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opioid receptors and increased levels of endorphins can be induced by a rebound effect from administration of the short-acting LDN.24 LDN will temporarily displace endogenous endorphins bound to the opioid growth and endorphin receptor. The up-regulation phenomenon is marked by these cells becoming temporarily deficient in OGF, which results in a rebound in receptor production. Receptor sensitivity is increased to capture more OGF and production of OGF is also increased to compensate for the perceived shortage of this molecule.25 These levels of endogenous opioids inhibit cell proliferation, which then suppresses B and T lymphocyte responses.26 In an animal model of colitis, naltrexone reduces the inflammation by decreasing tissue pro-inflammatory interleukins 6 and 12.27 There are opioid receptors on all inflammatory cells28 and endorphin modulation via the mu-opioid receptor may have direct consequences in reducing inflammation.29
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The results of this study showed that 88% of the naltrexone group (N=18) had at least a 70-point decrease in CD activity index scores compared to 40% of the placebo group (N=16). After twelve weeks, 78% of the naltrexone group had a significant response in the Crohn’s disease endoscopy index severity score (CDEIS) compared to a 28% response in the placebo controls; 40% of the naltrexone group had endoscopic remission with CDEIS scores less than 6, compared to 0% of the placebo group.
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At the 2015 American Gastroenterology Association meeting in Washington, DC, results from 56 subjects treated long term with LDN for CD were presented.39 Two-thirds of the patients in this study experienced either complete or partial remission by the Harvey-Bradshaw index.
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Conclusions This chapter summarizes the literature regarding the use of LDN in two inflammatory bowel disease states: Crohn’s disease and ulcerative colitis. In both situations, LDN has promoted mucosal healing, decreased inflammatory activity, and improved quality of life. Furthermore, LDN has been administered in conjunction with immunomodulators and biologics where its concomitant use was clinically beneficial and without additional side effects for extended periods of time. The interaction of LDN with inflammatory cells and chemokine receptors may help explain its role in mediating response to inflammatory states. One possible mechanism of action for LDN includes the transient occupation of the opioid receptors, which up-regulates the endogenous enkephalin and endorphins that subsequently influence cell function and inflammation, has been proposed. Other mechanisms have also been examined, including the blockade of toll-like receptors on microglial cells to decrease neuroinflammation and pain. Others have shown that naltrexone has preferential binding to certain opioid receptors at the low dose (i.e., to the delta and OGF receptor rather than the mu receptor). Further studies are needed using LDN in IBD since all but two of these studies were double-blinded and the numbers of patients were relatively small. Double-blind studies are required to make any firm conclusions regarding likelihood of responding to therapy, since there is a high-placebo response seen in IBD.48 The potential benefits of using a medication of low toxicity and good clinical efficacy is exciting.
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Figure 4.1. Causes of Immune Dysfunction
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Patients with CFS or FM have a TH1 (T-helper 1) to TH2 (T-helper 2) imbalance. TH1 helps the immune system fight against intracellular pathogens such as viruses, yeast, and some bacteria. TH2 helps the immune system fight extracellular pathogens such as parasites, allergens, and other toxins. CFS and FM result in an individual being “stuck” in a TH2-dominant state. This means that immune-modulatory treatment is key to the successful treatment of chronic infections and CFS or FM.
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Conclusion Our centers have specialized in the treatment of CFS and FM for the past fifteen years. Rarely does a day go by when I don’t see someone who has been devastated by these illnesses. It is heartbreaking that the overwhelming majority of physicians lack the tools, knowledge, and even the interest to effectively treat such patients. The “modern” medical system in this country has created huge roadblocks and disincentives for doctors to effectively treat these complex illnesses, so they must rely on simple FDA-approved medications that don’t address the underlying abnormalities, and are frankly not much better than placebo. In fact, they often prove to be worse than placebo because of the risks of side effects. This complaint has been echoed by the majority of doctors who specialize in the treatment of CFS and FM. This raises the question as to
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Low dose naltrexone (LDN) has been shown to be very effective in the treatment of autoimmune thyroiditis, including Graves’ disease and Hashimoto’s disease. Both conditions are caused by an unbalanced immune system where the immune system attacks the thyroid as if it were an invading organism.
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LDN is shown to modulate the immune system and reduce the abnormal production of antibodies causing these disorders.
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Most, if not all, patients who suffer from depression, obesity, diabetes, insulin resistance, premenstrual syndrome (PMS), chronic dieting, stress, chronic fatigue syndrome, and fibromyalgia have immune dysfunction that results in low tissue levels of thyroid hormone.
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Unfortunately, standard thyroid function tests do not detect these more common causes of tissue hypothyroidism.
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This chapter demonstrates that extreme caution should be used in relying on TSH or serum thyroid levels to rule out hypothyroidism in the presence of a wide range of conditions, including physiological and emotional stress, depression, dieting, obesity, leptin insulin resistance, diabetes, chronic fatigue syndrome, fibromyalgia, inflammation, autoimmune diseases, and systemic illnesses, as TSH levels will often be normal despite the presence of significant hypothyroidism.
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Consequentially, LDN can, by improving tissue thyroid levels, be very effective in the treatment of thyroid dysfunction seen with the majority of chronic illnesses.
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Mounting evidence is demonstrating that LDN is an effective treatment for a wide range of autoimmune diseases, including Hashimoto’s disease and Graves’ disease.
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However, the immunomodulatory effects of LDN are showing significant promise in reducing the production of autoantibodies in a wide range of diseases, including Hashimoto’s disease and Graves’ disease, and are emerging as the first line in the treatment of these conditions.
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To accurately assess thyroid function, it must be understood that deiodinase enzymes are essential control points of cellular thyroid activity that determine intracellular activation and deactivation of thyroid hormones.
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local control of cellular thyroid levels is mediated through three different deiodinase enzymes present in different tissues in the body; type I deiodinase (D1) and type II deiodinase (D2) increase cellular thyroid activity by converting inactive thyroxine (T4) to the active triiodothyronine (T3), while type III deiodinase (D3) reduces cellular thyroid activity by converting T4 to the antithyroid reverse T3 (reverse T3).1
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D1 converts inactive T4 to active T3 throughout the body, but D1 is not a significant determinant of pituitary T4 to T3 conversion, which is controlled by D2.
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D1 but not D2 is suppressed and down-regulated (decreasing T4 to T3 conversion) in response to physiological and emotional stress;3 depression;4 dieting;5 weight gain and leptin resistance;6 insulin resistance, obesity, and diabetes;7 inflammation from autoimmune diseases or systemic illnesses;8 chronic fatigue syndrome and fibromyalgia;9 chronic pain;10 and exposure to toxins and plastics.11 In the presence of such conditions there are reduced tissue levels of active thyroid in all tissues except the pituitary.
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D1 activity is also lower in females,13 making women more prone to tissue hypothyroidism, with resultant depression, fatigue, fibromyalgia, chronic fatigue syndrome, and obesity despite having normal TSH levels.
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Figure 5.1. Peripheral thyroid hormone conversion and its impact on TSH and metabolic activity. Image by Kent Holtorf, MD
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Thyroid-stimulating hormone (TSH) is produced in the pituitary and is regulated by intrapituitary T3 levels, which often do not correlate or provide an accurate indicator of T3 levels in the rest of the body.
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As opposed to the rest of the body that is regulated by both D1 and D3, the pituitary contains little D1 and no D3;14 pituitary T3 levels are determined by D2 activity,15 which is a thousand times more efficient at converting T4 to T3 than the D1 enzyme present in the rest of the body16 and is much less sensitive to suppression by toxins and medications.
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In the pituitary, 80%–90% of T4 is converted to T319 while only about 30%–50% of T4 in the peripheral tissue is converted to active T3.20 This is due to the inefficiency of D1 and the presence of D3 in all tissues of the body except the pituitary that competes with D1 and converts T4 to reverse T3.21
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Additionally, D2 has an opposite response from that of D1 to physiological and emotional stress, depression, both dieting and weight gain, PMS, diabetes, leptin resistance, chronic fatigue syndrome, fibromyalgia, inflammation, autoimmune diseases, and systemic illnesses. D2 is stimulated and up-regulated (has increased activity) in response to such conditions, increasing intrapituitary T4 to T3 conversion, while the rest of body suffers from diminished levels of active T3. This causes the TSH to remain normal despite the fact that there is significant cellular hypothyroidism present in the rest of the body.
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Thus, the pituitary levels are under completely different physiological control, and T3 levels will always be significantly higher than anywhere else in the body.22 Consequently, if the TSH is elevated, even mildly, it is clear that many tissues of the body will be deficient in T3, but due to the different physiology, a normal TSH cannot be used as a reliable indicator for normal T3 levels in the rest of the body.
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For instance, as the levels of T4 decline, as in hypothyroidism, the activity of D2 increases and is able to partially compensate for the reduction in serum T4.23 On the other hand, with reduced T4 levels, the activity and efficiency of D1 decreases24 resulting in a reduction in cellular T3 levels, while the TSH remains unchanged due to the ability of the pituitary D2 to compensate for the diminished T4.
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Lim and colleagues measured peripheral (liver) and pituitary levels of T3 in rats in response to induced chronic illness.27 They found that pituitary T3 and TSH levels remained unchanged, while the peripheral tissues were significantly reduced. The authors summarized their findings by stating:
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Larsen and colleagues summarized their finding that the pituitary has a unique composition of deiodinases that is not present in any other tissue in the body, making the pituitary T3 levels, and thus the TSH, a poor indicator for tissue T3 in the rest of the body—stating that the TSH cannot be reliably used as a marker of thyroid status in the rest of the body.29
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Changes in pituitary conversion of T4 to T3 are often opposite of those that occur in the liver and kidney under similar circumstances.
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The pituitary is the only tissue that does not contain D3,31 which converts T4 to reverse T3 and competes with D1 that converts T4 to T3.
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It is up-regulated with chronic physiological stress and illness39 and is an indicator for reduced T4 to T3 conversion and low intracellular T3 levels even if the TSH is normal.
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Figure 5.2. Conditions that cause low cellular T3 (hypothyroidism) not detected by TSH levels. Image by Kent Holtorf, MD
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Pituitary Thyroid Transport and Deiodinase Activity Determines TSH Levels The pituitary is different from every other cell in the body, with its own distinct deiodinases, thyroid transporters, and high-affinity thyroid receptors.44
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Chronic physiological stress results in decreased D1 activity47 and an increase in D3 activity,48 decreasing thyroid activity by converting T4 into reverse T3 instead of T3.49 Conversely, D2 is stimulated, which results in increased T4 to T3 conversion in the pituitary and reduced production of TSH.50
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This stress-induced reduced tissue T3 level and increased reverse T3 results in tissue hypothyroidism and potential weight gain, fatigue, and depression.
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Figure 5.3. Thyroid hormone transport into cellular tissue.
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Chronic emotional or physiological stress can cause significant reduction of transport of T4 into the cells of the body.
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T4 levels can be artificially elevated among physiologically stressed individuals and, thus, serum T4 and TSH levels are poor markers for tissue thyroid levels in this patient population (see figure 5.2).
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Substances produced by physiological stress or calorie reduction (e.g., 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid [CMPF], indoxyl sulfate, bilirubin, and fatty acids) have been shown to reduce the cellular uptake of T4 by up to 42%, while having no effect on T4 or T3 uptake into the pituitary.57
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For instance, Arem and colleagues found that significant physiological stress was associated with dramatically reduced tissue levels of T4 and T3 (up to 79%) without a corresponding increase in TSH.
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The reduced immunity from chronic stress has been thought to be due to excess cortisol production, but the associated reduction in tissue thyroid levels is shown to play a larger role in the decreased immunity seen with stress, and thyroid supplementation is shown to reverse the stress-induced reduction in immunity.60
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treatment with prednisone or other glucocorticoid will suppress D1 and stimulate D3, reducing T4 to T3 conversion and increasing T4 to reverse T3, causing a relative tissue hypothyroidism that is not detected by TSH testing.61
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timed-released T3 is significantly more beneficial than T4 or T4/T3 combination supplementation.
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“Augmentation with supraphysiological doses of T3 should be considered in cases of treatment resistant bipolar depression.”
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it is clear that timed-released T3 supplementation should be considered in all depressed and bipolar patients despite “normal” serum thyroid levels. Additionally, straight T4 should be considered inappropriate and suboptimal therapy for replacement in such patients.
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Chronic pain will significantly suppress D1 and up-regulate D2, resulting in a reduction in tissue T3 without a change in TSH.74 Thus, significant cellular hypothyroidism is not detected by serum TSH and T4 testing.
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narcotics also suppress D1 but not D2, so such treatment is also a cause of low tissue levels of T3 accompanied by a normal TSH, and so again the tissue hypothyroidism remains undetected.
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It has been shown that women or men who perform more than moderate exercise, especially when associated with dieting, have reduced T4 to T3 conversion and increase reverse T3, counteracting many of the positive effects of exercise, including weight loss.78 Consequently, T3 and reverse T3 levels should be evaluated in individuals who exercise and/or diet to better determine cellular thyroid levels, as TSH and T4 would not necessarily reflect tissue levels in such patients.
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They found that obese individuals in the processes of dieting exhibited a 50% reduction of T4 into the cell and a 25% reduction of T3 into the cell.
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Iron deficiency is shown to significantly reduce T4 to T3 conversion, increase reverse T3 levels, and block the thermogenic (metabolism boosting) properties of thyroid hormone.
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The inflammatory cytokines IL-1, Il-6, C-reactive protein, and TNF-α will significantly decrease D1 activity and reduce tissue T3 levels.85 Any person with an inflammatory condition—including physical or emotional stress,86 obesity,87 diabetes,88 depression,89 menopause (surgical or natural),90 heart disease,91 autoimmune diseases (lupus, Hashimoto’s disease, multiple sclerosis, arthritis, etc.),92 injury,93 chronic infection,94 or cancer95—will have a decreased T4 to T3 conversion in the body and a relative tissue hypothyroidism. The inflammatory cytokines will, however, increase the activity of D2 and suppress the TSH despite reduced peripheral T3 levels, again, making a normal TSH an unreliable indicator of normal tissue thyroid levels.
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Having a very low risk and incidence of side effects, a trial of LDN should be considered with any patient having symptoms suggestive of hypothyroidism or any of the common diseases listed above.
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RLS. In all categories of this commonly occurring syndrome, four primary symptoms are present: (1) the compelling urge to move the extremities, usually the legs, often associated with discomfort; (2) occurrence during rest or inactivity; (3) occurrence or worsening typically in the evening; and (4) temporary improvement with movement, including stretching or walking.
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Idiopathic RLS has been shown to be associated with small intestinal bacterial overgrowth (SIBO), and preliminary evidence suggests that treating the underlying gastrointestinal disorder can improve RLS severity.
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RLS is reviewed and its pathophysiology is discussed. Central nervous system (CNS) endorphin deficiency, altered dopamine interactions, and central iron deficiency due to inflammation are discussed as RLS pathophysiology for which LDN may play a role in therapy. Preliminary experience with LDN in RLS patients with and without SIBO will be reviewed.
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The precise etiology and pathophysiology of RLS are unknown. Current evidence revolves around dopaminergic dysfunction and altered control of iron homeostasis with CNS iron depletion.5 Data for RLS-associated genetic links that allow for iron deficiency and other pathophysiological changes is also emerging.6 Several risk polymorphisms (BTBD-9 [BTB (POZ) domain containing 9], MEIS-1 [Meis homeobox 1], protein tyrosine phosphatase, receptor type, D, and others) appear to play an important role and may interact or disturb dopaminergic and iron interactions.7
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Recently the endogenous opiate system has been suspected as having a role by stabilizing dopaminergic substantia nigra degeneration
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In addition to SIBO, three other gastrointestinal disorders have recently been linked to RLS: liver disease, Crohn’s disease, and celiac disease.
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The means by which inflammation and altered immunity could contribute to the cause and/or exacerbation of RLS includes three major theories: (1) inflammation causes CNS iron deficiency through alterations in hepcidin; (2) humoral or cellular immunological mechanisms cause a direct attack on the CNS or PNS; or (3) RLS gene variants interact with inflammatory disorders, immune alterations, and/or chronic infections such as SIBO to potentiate them.
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Summary More work remains to be done before we can recommend LDN to RLS patients. Various questions need to be addressed. With regard to the role in therapy, is LDN the drug best used for maintenance of SIBO treatment or can it be used for primary therapy? Concerns for pathophysiology are addressed by questions that include: Does it exert effect through improving SIBO via motility, does it change central or peripheral nerve pain via toll-like receptors and reduce neuroinflammation, and does it improve endorphin activity and hence improve dopamine nerve function in the setting of iron deficiency?
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Any substance that can increase the amount of endorphins in the body can find an application in psychiatry. The vast majority of the low dose naltrexone (LDN) literature, however, is written about the benefits in treatments of somatic illnesses.
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What Makes LDN a Psychiatric Medication? LDN increases the release of opioid peptides, which is a collective name for endorphins, enkephalins, dynorphins, and other psychoactive substances, produced by our body. This clearly makes it relevant to psychiatry. LDN can help decrease fatigue and other somatic symptoms.
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LDN is frequently reported to cause vivid dreams, which implies that it can change sleep architecture. Modifying sleep architecture by itself can modify many psychiatric conditions.2
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The anti-inflammatory properties of LDN can assist in recovery from depression.
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By providing additional endorphins or by increasing sensitivity of receptors to endorphins, LDN can be effective for relieving these symptoms of endorphin deficiency.
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The mu receptors, activated by beta-endorphins and enkephalins, are linked not only to pain modulation but also to euphoria and sedation experienced by the users of opiates. Activation of these receptors also leads to an increase in GABA, the effect sought by the users of Valium, Xanax, or alcohol.
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Activation of delta receptors can also increase the production of brain-derived neurotrophic factor (BDNF),7 which has become one of the most frequent targets for recent psychiatric research.8 Conditions linked to decreased BDNF include depression, bipolar disorder, obsessive-compulsive disorder, schizophrenia, anorexia nervosa, and bulimia, as well as autism spectrum disorders and dementias, including Alzheimer’s disease. There is also a link between BDNF and addiction. BDNF-level modification with LDN can possibly decrease the risk of addiction.
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Besides LDN, BDNF can also be increased by glutamine, curcumin, exercise, cannabidiol (an orphan drug, Epidiolex, based on cannabidiol, is FDA-approved for a rare form of childhood epilepsy), and tetrahydrocannabinol (THC—Marinol, based on THC, is an FDA-approved medication for AIDS-related anorexia). Intermittent fasting and calorie restriction—the same strategies that can prolong lifespan and decrease the likelihood of dementia—can also increase BDNF.
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“The results of the study suggest that depression need not be considered as a common adverse effect of naltrexone treatment or a treatment contraindication and that engaging with or adhering to naltrexone treatment may be associated with fewer depressive symptoms.”15
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Antidepressant Effects of LDN Related to Opioid-Receptor Activity From what we know about endorphins, it seems logical to assume that they play a role in the alleviation of depression. The research supports this intuitive assumption.
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Enhancing endorphins can assist in treatment of depression. Massage, acupuncture, sex, exercise, and other activities can increase endorphins temporarily. To achieve a more sustained increase, LDN, along with vitamins, supplements, and dietary changes, can be used.
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Dietary changes include a high-protein diet, preferably without sugar, flour, and coffee (the “exorphins”). In addition, vitamin B, vitamin C, omega-3 with vitamin D, vitamin E, zinc, capsaicin, and D-phenylalanine (up to 2,000 mg, three times a day) can be used. Recommendations also include minimizing stress and chronic pain and avoiding a sedentary lifestyle.
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The Anti-inflammatory Pathway of the Antidepressant Effects of LDN
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Many antidepressant medications themselves have anti-inflammatory properties, not only peripherally, but also centrally, in microglia—the same place where LDN works.24 This means that LDN works synergistically with antidepressant medications.
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is possible that the doses of many medications (SSRIs, SNRIs, etc.) could be decreased with the addition of LDN to the treatment regimen.25 For this reason, I frequently recommend LDN not only to my depressed patients with such inflammatory conditions as lupus, Crohn’s disease, and ulcerative colitis, but also to patients with no known inflammatory conditions.
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The role of LDN as a dopamine enhancer is a consequence of the further cascade of events triggered by the direct effects of LDN on opioid receptors. The beta-endorphins, produced in the arcuate nucleus of the brain, stimulate dopamine release in the nucleus accumbens directly and also indirectly by inhibiting GABA production in the ventral tegmental area.
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Adding LDN to the Depression Treatment Regime To summarize the above, LDN—via both opioid and nonopioid receptors, and via direct and indirect actions—modulates inflammatory response and the level of endogenous opioids and dopamine.
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Treating depression with LDN produces great results, and the effect of the treatment is shown to be independent from the improvement in the general medical condition that the depression frequently accompanies.
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Dopamine-Deficient Depression Dopamine is involved in pleasure and reward; in memory and motor control; in activation, arousal, and cognition; and in reward-motivating behavior. Dopamine facilitates attachment and love and altruism; it also helps to integrate thoughts and feelings. Consequently, depressed people with a predominantly low dopamine level complain of a loss of satisfaction; chronic boredom; apathy; no attachment and love; no remorse; and difficulties concentrating, focusing, remembering, and thinking abstractly. They oversleep, have no motivation, procrastinate, and report that pleasures feel dull and that their libido is decreased.
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For patients with a predominantly dopamine-depletion-related depression, we use LDN along with medications that likely increase dopamine levels.
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Providing building blocks for dopamine and trying to protect dopamine from depletion is another important strategy in LDN augmentation. This can be partially achieved by recommending certain foods—such as raw almonds, dark chocolate, bananas, apples, and strawberries; vitamins B6, C, E, and the antioxidants phenylalanine and tyrosine (up to 5,000 mg per day for a short time in severely depressed patients); and adoptogens such as Rhodiola, ginseng, and ashwagandha. Stress reduction and weight loss also help to preserve the supply of building blocks for dopamine.
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Serotonin-Deficient Depression While patients with a relative deficiency of dopamine crave stimulating foods such as caffeine or chocolate, patients with predominantly decreased levels of serotonin tend to crave dairy, bananas, and foods high in carbohydrates. Such depression is often accompanied by a lot of worrying and obsessiveness,
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While dopamine-depleted patients reporting suicidal ideations often describe feeling that they have “nothing to live for,” serotonin-depleted patients with depression, in contrast, report feeling suicidal because “life is full of pain and suffering.” Normalizing serotonin levels can help eliminate these feelings, but will not necessarily make the patient feel happy. This is why LDN, with its dopaminergic effects, is important for them to take along with an antidepressant medication that acts predominantly on serotonin.
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Even if no serotonergic medication is used alongside LDN, we routinely recommend adding tryptophan or 5-HT, preferably with a small amount of carbohydrate and vitamin B3 or B-complex. Magnesium, zinc, SAMe (S-Adenosyl methionine), St. John’s wort, and Rhodiola can also increase the level of serotonin.
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enhance LDN’s anti-inflammatory activity, our patients use St. John’s wort (it is also a COX-1 inhibitor with an effect possibly greater than aspirin), willow bark, or arnica. We also prescribe omega-3 polyunsaturated fatty acids or their pharmaceutical forms such as Lovaza and Animi-3.
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There is an interesting product called Vayarol, which is a medical food made by combining krill oil with phytosterols. In addition to reduction in inflammation, Vayarol lowers triglycerides without elevation in plasma LDL-C levels.34 Another example of a medical food that can be used along with LDN to reduce inflammation is L-methylfolate (for example, 15 mg or more of Deplin35 per day).
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One of the latest research studies, “Low-Dose Naltrexone for Depression Relapse and Recurrence,”36 conducted by David Mischoulon, MD, from Massachusetts General Hospital, was completed in June 2015, but no study results had been posted at the time of this chapter’s writing. The purpose
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A common denominator in such a disparate group of possibilities is the presence of inflammation and oxidative stress, which leads to reduced energy production. Dr. Jill James has been reporting about the presence of impaired methylation since the beginning of this century. She has written that, “Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione.
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Dr. McCandless noted, “When LDN is given between 9 p.m. and midnight, the pituitary is alerted and the body attempts to overcome the opioid block with an endorphin elevation, staying elevated throughout the next 18 hours.” Because of the bitterness of the naltrexone, it is applied as a cream while the child sleeps. Furthermore, she noted, “Although naltrexone is non-toxic and virtually free of side effects, occasionally it can cause sleep problems or hyperactivity during the first week or two of its use. If sleep problems persist, reducing the dose from 4.5mg to 3mg in adults, or in children from 3mg to 1.5–2mg, is often helpful.”
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2014, fifty-three children (forty-six boys and seven girls, ages three to thirteen) with ASD were evaluated, treated with appropriate supplements and necessary medications, and prescribed LDN cream at a concentration of 3 mg per 0.5 cubic centimeter (cc). The increased concentration (vs. Dr. McCandless’s protocol) has become preferable because the cream takes time to rub into the skin. These fifty-three patients were seen for a total of 393 visits (table 8.1).
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This protocol resulted in improvements noted in 45% of a selected population of the total population of high-risk infants and children who seek alternative treatments, because of the child’s unresponsiveness to conventional therapy. This represents a significant improvement
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Clinical practice reflects supporting research that improving gastrointestinal health is important in improving many of the most troubling signs and symptoms of ASD.62 The utility of naltrexone to modulate immune responses may play an important role in effective treatment. Additionally, mast cell release of inflammatory chemicals such as IL-8 and TNF in the central nervous system has been implicated as a type of “brain allergy” in autism.63 The finding that neurotensin, a mast cell-stimulating neuropeptide, is elevated in patients with ASD64 is consistent with these observations.
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However, there are a few major impediments preventing LDN from more common usage, including: 1. This condition is extremely complex. It is complicated by genetic and environmental influences and presents differently at different ages and even affects the sexes differently. Parents require information, resources, education, and support. With a myriad of presentations, response to various treatments will vary as well. Further research into how/why/who responds, and in what manner, is necessary. 2. The “spectrum” of autism needs to be better categorized and refined to take into account the various conditions that present with like symptoms, but are, perhaps, separate disorders. 3. No biomarkers exist to independently evaluate the extent of the problem and response to various treatment modalities. 4. Gastrointestinal health needs to be evaluated and properly addressed in order for improvement to be noticed. 5. After starting, the therapy requires continued tailoring to the patient’s responses and the family situation. Some will have few resources and many other children, and so will tend to rely on conventional, available treatments as time and resources are at a greater premium. Other parents will utilize every available moment to search for answers to this enigmatic condition. Trying out new or unique treatments is within reach, though outcomes are quite variable. 6. Patients don’t usually show immediate improvement; it may take up to eight weeks. 7. Not infrequently, an apparent deterioration in behavior may occur in the early stages of treatment.
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has been shown, mainly through the work of Dr. Zagon, that low doses of naltrexone are capable of suppressing tumor growth.2 A definitive mechanism of action has yet to be established, but the effect could be achieved through direct antagonism of tumor growth or via modifications to the host immune system.
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There is a good scientific reason to take LDN seriously as having a potential role as an anti-cancer agent. First, it is an anti-inflammatory, a class of agents that have been proven to improve cancer outcomes as shown by numerous aspirin and COX-2 inhibitor studies as well as the surprising benefit reported with statins. Second, LDN appears to have a marked immune modulatory response leading to an increase in innate immunity (such as natural killer cell activity) with a possible knock-on effect on CD8 adaptive T cells (the appearance of vitiligo after commencing LDN can only be explained by the induction of CD8 cells against tyrosinase). Third, cancer patients can be suppressed by their disease, its treatments, and the psychological effects of living with a lethal condition. Patients report a remarkable benefit from commencing LDN with regard to their psychological status, feeling much better than on previous treatments, which may be due to its subtle effects on various opiate receptors.
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Question 5: I can’t sleep. Why must I take LDN at bedtime? The simple answer: You want LDN to be in your body and working during the period of time at which your endorphin levels are increasing naturally. This increase is coincidental with the dream cycle. It has been my experience that patients with an autoimmune disease do not generally dream very often. So when dreams come, the patient experiences them as “intense” or “vivid,” and may cause them to wake up. Generally, this problem will resolve itself in a couple of days.
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Question 19: When should I take LDN? We suggest taking it at bedtime.
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Question 20: What dose should I take? Some doctors recommend starting LDN at 3 or 4.5 mg. However, we recommend starting at 1.5 mg for thirty days. This is a very tiny dose, but it can still produce minor side effects. The second month, you should take 3 mg. This is a step up and should produce clinical results. Recently, after reviewing the literature and speaking with patients, we recommend that you stay at 3 mg for sixty days, see how you are doing, and then re-evaluate with your doctor to decide whether you should stay on 3 mg, or move to 4.5 mg.
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