research sarah m Dennis terry h Diamond MBBS, FAMAC, is Conjoint Lecturer, Department of MSc, PhD, is Senior Research Fellow, Centre for MBBCh, MRCP, FRACP, is Associate Professor Community Medicine, University of New South Wales, Primary Health Care and Equity, School of Public and a general practitioner, Sydney, New South Wales. Health and Community Medicine, University of New
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Low-dose naltrexone for disease prevention and quality of lifeLow-dose naltrexone for disease prevention and quality of life a Department of Humanities and Social Sciences, Embry-Riddle Aeronautical University, Daytona Beach, FL 32114, United Statesb Department of VCAPP, College of Veterinary Medicine, Washington State University, P.O. Box 646520, Pullman, WA 99164-6520, United States The use of low-dose naltrexone (LDN) for the treatment and prophylaxis of various bodily disorders is discussed. Accumulating evidence suggests that LDN can promote health supporting immune-modula- tion which may reduce various oncogenic and inﬂammatory autoimmune processes. Since LDN canupregulate endogenous opioid activity, it may also have a role in promoting stress resilience, exercise,social bonding, and emotional well-being, as well as amelioration of psychiatric problems such a autismand depression. It is proposed that LDN can be used effectively as a buffer for a large variety of bodily andmental ailments through its ability to beneﬁcially modulate both the immune system and the brain neu-rochemistries that regulate positive affect.
health, especially along the dimension of reduced likelihood ofcancers and autoimmune problems. Intermediate levels of LDN Preventive medicine has excelled in reducing the risk factors of (at 0.25 mg/kg given every other day) were initially found to have high cholesterol with various statins, and accruing cardiac damage some beneﬁts in the treatment of a subset of autistic children with baby aspirin blood thinners. There is considerable contro- One of the clinical impressions was an increased social initiative versy about general health sustaining effects of adequate vitamins, and cheerfulness, especially on the non-medication days, as if a re- minerals, herbals and speciﬁc puriﬁed nutritionals, but there is rel- bound effect of positive social chemistries (e.g., opioids) was occur- atively little medical research on discrete biochemical supple- ring. There is now increasing data that would suggest that a ments to facilitate general health and well-being. In this essay temporary blockade of opioid receptors with LDN may lead to an we introduce low-dose naltrexone (LDN) as a potential way to upregulation of mood enhancing endogenous opioids, and hence strengthen brain and bodily resources to facilitate emotional perhaps dopamine activity, which may further promote positive homeostasis and also provide background prophylaxis against frames of mind. As importantly, endogenous opioids have robust and potential treatment of various cancers and autoimmune disor- immune modulatory properties, which may be harnessed through ders – an idea that has already been extensively discussed on the LDN to facilitate body resources to retard and combat oncogenic and autoimmune processes and reduce the impact of allostatic Naltrexone, an orally effective, long-lasting opiate receptor antagonist, was approved by the FDA for treating alcohol and opi- Although the data is only now emerging for beneﬁcial endoge- ate addiction in 1984, but its general patent expired the following nous brain and body opioid rebound effects from LDN supplemen- year. It is a non-selective antagonist, with robust effects on plea- tation, indirect evidence does exist for such effects, including the sure promoting mu opioid receptors (MOR) and delta opioid recep- ability of ultra-low LDN to facilitate the analgesic effects of opioids tors (DOR) , with less antagonism of aversion-mediating kappa , and the ability of LDN to facilitate maintenance of drug absti- opioid receptors (KOR) but substantial effect on the more re- nence in former opiate addicts . In this essay we will focus on cently discovered orphanin FQ or nociceptin [N/OFQ] opioid family the potential ability of LDN to serve as a facilitator of immunocom- The beneﬁts of high dose naltrexone in narcotic addiction are petence that may provide prophylaxis for a variety of disorders, explained by blockade of all pleasure producing effects of opioids, from oncogenesis to neurological disorders, where a compromised and similar mechanisms may explain the ability of naltrexone to immune system hastens bodily decline.
Here we will consider the potential beneﬁts of low-dose nal- trexone (LDN) as a way to strengthen both brain and bodily re-sources to promote psychological well-being as well as bodily When administered in low-doses of 3–4.5 mg daily, naltrexone increases the expression of mu, delta, and epsilon opioid receptorsas well as central and circulating met-enkephalin (ME) and beta- * Corresponding author. Tel.: +1 386 226 6631; fax: +1 386 226 7210.
endorphin (BE), which may improve psychological well-being.
0306-9877/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.mehy.2008.06.048 N. Brown, J. Panksepp / Medical Hypotheses 72 (2009) 333–337 The associated bodily changes result in enhanced immune func- no beneﬁcial effect and actually facilitated tumor growth. In con- tions that may stop inﬂammation and the progression of rheuma- trast, a low-dose [0.1 mg/kg] decreased oncogenesis signiﬁcantly toid, gastrointestinal and neurological autoimmune disorders.
Zagon and McLaughlin concluded that LDN increased opiate These hypothesized disease-modifying effects of enhanced im- receptors and elevated circulating BE and ME after a 4–6 h period mune functions contradict current medical opinion that immune of receptor blockade. This ‘‘rebound phase” may release the in- functions must be globally suppressed to retard the progression creased density of mu and delta opioid receptors for endogenous of autoimmune diseases. Yet evidence is mounting that LDN may opioid stimulation with the increasingly available BE and ME.
have substantial therapeutic effects in such disorders. Further- The general principle operative here may be that the increased more, naltrexone’s enhancement of the immune system is a novel concentrations of BE and ME that gain access to increased density approach to arresting or preventing a variety of cancers. Resistance of MOR and DOR receptors may ‘‘functionally supersensitize” to viral diseases may also be enhanced, with a trial currently in endogenous opioid functions throughout the body with beneﬁcial progress to evaluate efﬁcacy of LDN for treating AIDS.
downstream effects on various body parameters, especially Background evidence: Since naltrexone entered the public do- main in1984, little funding has been available for researchingtreatment for any diseases except alcoholism and opiate addiction, The beta-endorphin pathway in immune regulation both heavily supported by federal grants. Now, however, therehave been widespread anecdotal reports of successful treatments To grasp potential LDN paths of action, let us consider the fol- of various cancers, AIDS and Multiple Sclerosis , and lowing well articulated opioid antagonist’s pathways for treating autoimmune diseases such as lupus, arthritis, and ﬁbromyalgia autoimmune disease. The potential action of BE in ameliorating . If chronic LDN could potentiate and regulate the immune sys- autoimmune disease is sketched below.
tem in health promoting ways, it may serve to combat AIDS and Naltrexone modulation of immune regulation and treatment of some cancers and reduce autoimmunological self-destructive ac- The ﬁrst successful clinical trials were for Crohn’s disease in Recent studies have shown BE concentration in circulating 2006 and in late 2007 for Multiple Sclerosis . Trials for blood cells to be dramatically low in rheumatic diseases such as MS and ﬁbromyalgia are underway at medical centers in California arthritis, lupus and gout, with signiﬁcant inverse correlations be- and Cleveland, along with an AIDS trial in Mali.
tween BE and both rheumatoid factor and erythrocyte sedimenta- The normal 50 mg naltrexone dose that blocks opioid receptors tion rate and hence the likelihood of inﬂammation Levels of 24 h per day is commonly prescribed for alcoholics and heroin ad- BE were as low as 1/8 to 1/4 normal in other autoimmune-related dicts who wish to resist a relapse. This typically amounts to more diseases, including ﬁbromyalgia , Crohn’s disease , multi- than 0.5 mg/kg for most adults. In contrast, the most common LDN ple sclerosis chronic migraine and cluster headaches use is typically 4.5 mg, which generally means most adults get no more than 0.08 mg/kg per day, which can block mu opioid receptors A preliminary pilot trial of 4.5 mg naltrexone for Crohn’s Dis- for only a few hours, perhaps up to 6 h. If taken at bedtime, this ease, completed at Penn State in 2005, yielded promising results.
would mean that an individual might wake up the next morning In 3 months 89% of the patients achieved signiﬁcant reduction in with a homeostatic rebound-induced over-activity of their own symptoms and improvement in quality of life measures, and 67% endogenous opioid systems. It is this type of bodily change in opioid went into remission. These results were maintained after 4 weeks dynamics that we focus on here. Until recently signiﬁcant increases in mu, delta and perhaps epsilon opiate receptor expression have Recent work on collagen-induced arthritis in rats have found BE only been documented in animal models for chronic opiate blockade treatment to reduce clinical arthritis manifestations by shifting the with high dose naltrexone which leads to elevated morphine balance of TH-1 and TH-2 cells toward TH-2. This comes from analgesia However, a recent animal study conﬁrmed that a low- down-regulating the NF-kappa2 pathway, including tumor necro- dose (0.1 mg/kg of naloxone) could elevate mu opioid receptor den- sis factor alpha, Interleukin-1beta, Interleukin-6, inducible nitric sity as well More signiﬁcantly, the recently completed Italian oxide synthase, and mRNA for matrix metalloproteinase-2 and Multiple Sclerosis trial utilizing 5 mg of naltrexone daily found sig- mmp-9 . Dr. Sacerdote and her colleagues in Milan have niﬁcant increases in circulating beta-endorphin, along with wide- reached the same conclusion that BE increases ameliorate autoim- mune diseases by suppressing TH-1 and augmenting TH-2 cells Chronic naltrexone affects both immune and endorphinsystems Low-dose naltrexone may work through methione-enkephalinas well While high dose naltrexone can counteract the reduction of im- mune system activity caused by opiate analgesics , when gi- The scientiﬁc case for LDN’s positive effect on immune param- ven alone, it can facilitate immune system parameters eters is strengthened by studies that have evaluated infused ME Zagon and McLaughlin clearly delineated differences between in the treatment of cancers. Plotnikoff et al. report that ME high and low-dose naltrexone while studying mice with trans- stimulates expression of interleukin-2 receptors and blood levels planted neuroblastoma tumors. The full dose of naltrexone of interleukin-2, along with increases in white blood cells, natural [10 mg/kg] producing constant blockade of opiate receptors had killer cell activity, gamma-interferon, active T-cells and other ele- N. Brown, J. Panksepp / Medical Hypotheses 72 (2009) 333–337 ments of the immune system. These results were obtained both Thus, LDN, through its enhancement of immune functions in vitro and in vivo and with normal volunteers as well as people and speciﬁcally of natural killer cell activity may promote pre- suffering from a variety of cancers, including Kaposi’s sarcoma, vention and treatment of viral diseases and bacterial infections.
lung cancer, melanoma, and hypernephroma. These beneﬁts might Evidence from animal models suggests that naltrexone’s path to supporting immune defenses against viral disease begins by Naltrexone’s potential for cancer prevention and treatment increasing both beta-endorphin and met-enkephalin, which maythen bind to sensitized mu opioid receptors to increase natural kill- Potential beneﬁt for cancer treatment has arisen largely from er cell activity for quelling viral infection Since we only have the work of Penn State investigators Ian Zagon and his colleagues.
clinical evidence from uncontrolled observations in the many dis- Zagon published initial evidence that chronic LDN (0.1 mg/kg in orders mentioned above, well-controlled double-blind clinical mice) reduced neuroblastoma tumor incidence by 66%, retarded studies are warranted, despite the difﬁculty in ﬁnancing studies tumor development by 98% and lengthened survival by 36% over controls . The apparently intermittent receptor blockade viaLDN signiﬁcantly reduced cancer cell development, in contrast to a constant blockade that accelerated tumor growth . Further-more, the speciﬁc mu receptor blocker beta-Funaltrexamine did Low-dose naltrexone’s potential for enhancing the quality of life not signiﬁcantly retard tumor development, yet the nonspeciﬁc through both reward and energy functions arises from the well- demonstrated links between mu opioid receptors and central Both ME and BE may enhance NK cell activity via the mu dopamine neurons in the mesencephalon Solid evidence receptor and also by binding to receptors on cancer cells for safety and tolerability of chronic LDN is present in the recent themselves . Animal studies have shown full dose naltrex- Crohn’s trial and MS trial , as well as decades of FDA ap- one to reduce tumor activity in mammary cancer . In hu- proved daily 50 mg doses for alcoholism. There is no published evi- mans, high dose naltrexone has been involved (along with IL- dence to support the old ‘‘black box” warning about potential liver 2) in arresting 6 of 10 metastasized renal cancers and damage from chronic high doses . This only happened at extre- [along with IL-2 and melatonin] in retarding metastasized can- mely high doses that were used in some of the early toxicology cer growth in terminal cases of kidney, stomach, pancreatic, In sum, we conclude that low-dose naltrexone presents a safe While studying the efﬁcacy of ME for neuroblastoma and and promising approach to prevention and/or treatment of many squamous cell, colon, and pancreatic cancer, Zagon and col- autoimmune diseases and cancer variants, as well as potentially leagues used full dose naltrexone to block ME’s retardation of tu- various viral (e.g., AIDS) and neurological diseases (Multiple Scle- mor growth . This contrasts with their prior studies which rosis) that are exacerbated by compromised immunity. LDN’s po- have shown low-dose treatments to be effective on colon cancer tential for modulating both opioid and immune systems yields a , and neuroblastoma . Though acute high doses of nal- very wide ﬁeld for clinical experimentation as well as novel re- trexone effectively block opioid retardation of the growth of search directions for strengthening the scientiﬁc evidence for some cancer cells, chronic low-doses foster that retardation. Fur- linkages between opioid and immune systems in the regulation thermore, LDN has arrested B-cell lymphoma in one published of various disease processes. There are solid reasons to believe case and, along with alpha-Lipoic Acid, metastasized pan- LDN can also promote positive emotional states through the creatic cancer for 3 years in another . Anecdotal reports of endogenous opioid ampliﬁcation of positive affect and energy LDN causing remission include colorectal, mammary, ovarian, From a psychiatric perspective, the facilitation of endoge- small-cell and non-small-cell lung, and prostate cancers, as well nous opioids should alleviate depression since, to some degree, as Hodgkins and non-Hodgkins lymphoma, multiple myeloma, that multifaceted problem reﬂects reduced ability to experience and neuroblastoma Intravenous ME may turn out to be a pleasure. Evidence also exists for resilience against cardiovascu- better treatment for some cancers, or more effective when com- lar stress and for speciﬁc enhancement of the reward bined with LDN. But the paradoxical effect of low-dose generic system for exercise palatable tastes , laughter naltrexone of increasing both circulating BE and ME and the den- , sex social bonding , and even the placebo ef- sity of their mu and delta receptors bears further study because of its impressive cost-effectiveness.
In a time of imperative health care reform, the prospect of so LDN also holds promise for prostate cancer prevention and early many novel contributions to both disease suppression and qual- treatment, since all of the anecdotal prostate cancer cases in one ity of life by a generic pharmaceutical presents signiﬁcant chal- report that had not undergone hormone treatments went into lenges and opportunities for government, the medical research remission Independently, medical interest has begun to focus on the immune system for a ﬁrst defense against this cancer .
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GERDAU S.A. POLÍTICA DE DIVULGACIÓN DE INFORMACIONES SUMARIO 1 OBJETIVO 4 RESPONSABILIDADES DEL DIRECTOR DE RELACIONES CON 5 PROCEDIMIENTOS DE EJECUCIÓN DE LA POLÍTICA DE DIVULGACIÓN 1. OBJETIVO Gerdau S.A. está comprometida en continuamente perfeccionar la atención a todas las personas que con ellas se relacionan, deseando la valorización de los Valores Mobiliarios