WHITE PAPER September Are we ignoring effective substance abuse treatment solutions? The role of vitamin therapy in drug rehabilitation.

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1 F o u n d a t i o n f o r A d v a n c e m e n t s i n S c i e n c e a n d E d u c a t i o n WHITE PAPER September 2008 Are we ignoring effective substance abuse treatment solutions? The role of vitamin therapy in drug rehabilitation.

2 Summary This White Paper is based on the findings from an extensive search which was undertaken over the past several years to answer the question of whether there was clinical evidence and biologic rationale for recommending the use of micronutrient therapy as part of the management of addicted persons undergoing rehabilitation. This search has led to two papers now in preparation for submission for publication. The search, which covered over 50 years of published literature, is briefly summarized in this White Paper. The authors, while noting the lack of large randomized trials in this area, identified consistent external clinical evidence that vitamin, mineral and amino acid therapy in drug withdrawal and rehabilitation can reduce withdrawal symptoms, increase treatment retention, improve psychological status, contribute to higher abstinence rates and improve quality of life. Additionally there was found to be a wide range of evidence for a strong biologic rationale which would support such outcomes. Published outcome studies of programs that included micronutrient therapy reported greater than 50% long-term sobriety rates. Studies on safety of micronutient therapies indicated that adverse effects from short-term use of high-dose vitamin, mineral and/or amino acid therapy were rare, of minor consequence and occurred at doses or duration of use far greater than those seen in practical use. Malnutrition among alcoholics has been well documented. Above- RDA doses of specific vitamins are a standard clinical component of alcohol withdrawal and treatment regimens. Although malnutrition among abusers of illicit drugs has also been well characterized, micronutrient therapy for illicit drug withdrawal and treatment has not been used as widely. The typical program that included a micronutrient component had a social-educational focus; some were entirely drug-free. Available evidence suggests that such therapies have the potential to mitigate the failure rates often seen in drug rehabilitation; it could be argued that above-rda intake of micronutrients is necessary to fully address the physical consequences of addiction. Accessible, cost effective, safe and demonstrated by published studies to improve treatment effectiveness, micronutrient therapy deserves much more research attention and broader implementation. Introduction The latest national survey estimates that 21.6 million Americans suffer from substance dependence or abuse of drugs, alcohol or both. Yet treatment remains unavailable to 1 in 5 persons who seek help. 1 For those who do obtain substance abuse treatment, only 1 in 4 persons remains abstinent for over a year following treatment completion. Reversion rates are high, and often those entering treatment are doing so for the third time, are using multiple substances, and have other health and social problems. 2 Continuously high failure rates have caused some experts to conclude that addiction is an incurable disease. However, it is also possible that treatment models in current use are inadequate. Ideally, treatment would restore health as well as rehabilitate the individual. This paper explores one component essential to fully managing the adverse physical and mental health effects of substance abuse micronutient therapy. Accessible, cost effective, safe and demonstrated by published studies to improve treatment effectiveness, micronutrient therapy deserves much more research attention and broader implementation. Reconsidering recovery goals True recovery from addiction could be described as abstinence without cravings and engagement in productive activities. Factors that improve retention, treatment completion, and increase time in treatment lead to better outcomes. 3 These include factors that decrease withdrawal symptoms and cravings. 4 Where there are unmet micronutrient requirements, whether determined by individual differences or from an unhealthy lifestyle, the body will crave that which it lacks or similar substitutes. Inclusion of a micronutrient component as part of a comprehensive approach to drug rehabilitation appears to be beneficial. Over 50 years of published literature provides consistent evidence that vitamin, mineral and amino acid therapy in drug withdrawal and rehabilitation can reduce withdrawal symptoms and cravings, increase treatment retention, improve psychological status, contribute to higher abstinence rates and improved quality of life. Each decade since 1970 has included a major national outcome study of substance abuse treatment in the U.S. In 1995, a large study was also published in England. Comparing these outcome studies to treatment results for programs that included a micronutrient component shows that the latter were consistently better than the national averages (Figure 1). Appendix 1 summarizes findings of relevant micronutrient treatment studies. In light of this apparent outcome benefit, it would be shortsighted to continue to rely solely on the use of additional or substitute drugs to abate withdrawal symptoms or manage cravings. 2

3 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% DARP TOPS SROS* NTIES NTORS Smith Guenther - Larson - Beasley year abstinence rates except: *SROS gives 5 year outcome, Guenther gives 6 month outcome, Larson gives 1-4 year outcome Figure 1. Long term abstinence rates measured in large national outcome studies (red) vs. programs with high dose vitamin component (blue). Joseph D. Beasley MD, while Director of Comprehensive Medical Care, Amityville, NY, argued that failure to address the nutritional biochemistry and metabolic realities of the addicted individual was an inadequate standard of practice. 5 This viewpoint is shared by the American Dietetic Association in their position statement that improved nutritional status can make treatment more effective while reducing drug and alcohol craving, thereby preventing relapse. 6 High doses of nutrients are needed to reverse depletion and provide therapeutic value Recommended daily allowances (RDAs) are amounts set by committee to meet the needs of most healthy people. There are circumstances where above-rda intakes may be needed. In addiction therapy the need is based on several concepts: a) To address deficiencies from poor diet, impaired absorption, increased excretion, caused by drug use; b) To repair altered neurotransmitter function caused by drug use; c) To supply increased requirements needed to metabolize and eliminate drugs as a chronic toxic exposure; d) To address unmet individually determined requirements. The lifestyle of addiction includes notorious neglect of diet including a tendency to consume foods high in sugars and low in proteins, vitamins and iron.7;8. Chronic alcohol and other drug consumption impair absorption, metabolism and storage of many micronutrients, particularly water-soluble vitamins and minerals. 7;9-19 Numerous papers describe the profound effects of alcohol and illicit drugs on nutritional status, whether due to displaced nutrients or increased demand by metabolic processes Vitamins, minerals, amino acids, and essential fatty acids are constantly required to maintain body tissues and health, are interdependent, and cannot be properly understood in isolation. Lowering just one of these building blocks can limit the rate of formation of many life molecules and can adversely affect health. For example, drug and alcohol consumption creates demand for niacin used in degrading and eliminating foreign chemicals. Should niacin levels drop the body will convert tryptophan to niacin. This leaves insufficient tryptophan to produce the neurotransmitter serotonin. Low levels of serotonin are associated with depression, suicide and substance abuse Further, depleted niacin as well as depleted vitamin E increase the leakiness of the intestinal wall and alter absorption. 44 Breakdown and removal of foreign chemicals depletes certain nutrients Substance abuse is also a form of chronic chemical exposure that places additional demands on the body s detoxification systems. Vitamins and minerals, particularly the antioxidants including vitamin C and vitamin E and niacin are expended in an effort to detoxify foreign chemicals. 27;46;47 Alcohol and other drugs including cocaine, phenobarbital, anesthetics, and solvents such as inhalants increase the generation of reactive free radicals 45, further increasing oxidative stress. Further, ethanol impairs the conversion of beta-carotene to vitamin A and depletes vitamin A levels in the liver. 48 Drugs such as morphine, oxycodone, methadone, amitryptiline, benzoylecgonine 49, cocaine 50-52, marijuana diazepam 56, LSD 57, PCP 58;59 and their metabolites are among the many foreign chemicals that have been identified in fat analysis and other tissues and add to an individual s total contaminant body burden. During periods of fasting, exercise, and stress fat is burned and stored toxins may be released back into the blood stream. Particularly where there is inadequate micronutrient support for detoxification pathways, this toxin mobilization can result in non-specific symptoms such as fatigue, headaches, pain, poor memory or depression, commonly cited reasons a person seeks relief by using drugs. 60 Drugs alter normal levels of chemicals involved in the sensations of pleasure All drugs of abuse, including alcohol, activate a region of the brain referred to as the reward pathway. How drugs accomplish this varies: They may masquerade as natural neurotransmitters directly causing an effect; they may block chemicals that would normally limit reward pathway activity increasing the effect; they may enhance chemicals that in turn increase release of pleasure neurotransmitters greatly increasing activity; or block chemicals that normally remove these neurotransmitters from their site of activity prolonging their effect. The complexity of the reward pathway is one reason why substitute drugs have failed more often than not to offer a solution. Addictive drugs are thought to exert their effects by influencing dopamine directly or altering other neurotransmitters that modulate dopamine levels such as GABA (gamma-aminobutyric acid a neurotransmitter whose deficiency is linked to anxiety, irritability, insomnia and depression), endogenous opioids, serotonin, 3

4 acetylcholine and noradrenalin. 61;62 The resulting unnaturally high levels of the neurotransmitter dopamine then modulates other neurotransmitters. 63 While the person is feeling pleasure, normal brain chemistry is being disturbed in long-lasting ways. Continued use of the drug ultimately depletes the neurotransmitters, while the cells on the receiving end reduce their numbers of active receptors. Recovery from addiction must include a model which provides for adequate supplies of amino acid neurotransmitter precursors, vitamins and minerals found to be essential to restoration of a healthy reward pathway.64;65 What is normal metabolism anyway? Today s understanding of the human genome helps to explain why certain individually-determined nutrient requirements, if left unmet, could predispose a person to addiction. It may also partially explain the increases in long-term sobriety rates when these nutritional needs are met. There are at least 50 diseases caused by genetic variations that lead to known metabolic inefficiencies that can be remedied by feeding high dose B vitamins, raising levels of the corresponding coenzyme.. 46 Genetic variability of certain genes associated with cancer 66-69, is another example in which disease may be addressed through high-dose supplementation. Some gene variations correlate with increased risk of addictive, impulsive and compulsive behaviors 70;7 1 and craving 72. Researchers have argued that if gene alterations such as these predispose to substance abuse and other antisocial behaviors, then corrective nutrition may be the best prevention.73 A long-established therapy Over half a century of research has provided a strong biologic rationale for nutrient inclusion in substance abuse treatment. Appendix 2 provides a summary of micronutrients that have commonly been used in treatment programs, and brief descriptions of relevant biologic roles and benefits. Safety of high dose nutrient combinations Safety studies indicate that adverse effects from short-term use of high dose vitamin, mineral and/or amino acid combinations, such as are used during withdrawal or rehabilitation, are negligible. (Table 2). With the exception of vitamin A, it is most likely that rarely reported adverse events associated with high doses of a single vitamin were actually caused by other unidentified nutrient imbalances; therefore useful therapies should include well-balanced regimens of key vitamins, minerals and amino acids with relevant biologic roles. Table 2 Number of Deaths From Various Causes in the U.S. in Cardiovascular Disease 927,448 Cancer 539,628 Tobacco 175,483 Poor Diet & Physical Inactivity 170,323 Properly Prescribed & Used Drugs ,426 Alcohol 109,587 Microbial Agents 75,000 Toxic Agents 55,000 Avoidable Medical Misadventure 40,000 Suicide 30,622 Incidents Involving Firearms 29,000 Motor Vehicle Crashes 26,347 Homicide 20,308 Sexual Behaviors 20,000 Illicit Use of Drugs 17,000 Anti-Inflammatory Drugs (including Aspirin) 7,600 Adverse Reaction to Dietary Supplements* 5 *Dietary supplements have averaged less than 5 confirmed deaths per year over the past 25 years in the USA. Most of those relate to a single batch of contaminated tryptophan introduced in the late 1980 s. (Source, CDC/FDA) Successful treatment programs include a nutrient component A number of well-respected treatment programs some of which have been entirely drug free have included high doses of micronutrients with results exceeding the typical long term abstinence rates (Appendix 1). Abstinence and quality of life measures were most enhanced when providing nutrient support in combination with psychosocial/educational treatment models. The largest and most established groups to systematically include nutrient based interventions over the past few decades have been the Narconon drug rehabilitation program, the protocols of Joseph Beasley MD, Joan Matthews Larson, Ph.D., Julia Ross, M.A., and Ken Blum, Ph.D./Howard Trachtenberg, Ph.D. Since 1971, the Narconon drug rehabilitation program has utilized high doses of vitamins and minerals in its withdrawal regimen to assist in reducing depression 76, physical symptoms and cravings 77. In a later step, vitamins, minerals and essential fatty acids are used adjunctive to a sauna regimen 78 aimed at enhancing the mobilization and excretion of stored drugs and other toxins. Withdrawal has been reported to be accomplished with minimal discomfort and 4

5 no adverse events attributable to micronutrient supplements. Based on a social-educational model developed from the works of L. Ron Hubbard, the Narconon program is presently delivered at over 100 centers in 37 countries. Over the past three decades, Narconon has completed treatment of more than 10,000 individuals addicted to heroin, amphetamines, barbiturates, alcohol, cocaine and other drugs. The Health Recovery Center in Minneapolis has been utilizing a nutrient repair protocol developed by Joan Mathews Larson, Ph.D. to resolve cravings and restore alcoholic individuals to good health. In conjunction with counseling services, an individualized supplement program based on laboratory testing has been provided to address underlying biochemical abnormalities, including hypoglycemia. Several thousand individuals have now completed this program. A study published in 1987 reported a success rate of 74 percent or more in alcoholics. 79 The use of amino acid supplementation is another approach to biochemical restoration. In 1988 Julia Ross, M.A., founded Recovery Systems in Mill Valley, CA, an outpatient alcohol and other drug rehabilitation clinic that has been incorporating amino acids and nutrient therapy with conventional counseling and education and has reported an 85 percent recovery rate. 80 treatment outcomes in a variety of treatment settings compared with those utilizing conventional pharmacologic approaches. The available observational, experimental and biologic data supporting the use of high dose vitamin/mineral therapy as a beneficial component of substance abuse treatment, the long history of such use without significant adverse effects, and the low cost, argue for wider use of such therapies, as well as increased research regarding their place in the substance abuse treatment field. In view of the considerable financial burden that untreated addiction places on the healthcare system, and its often-devastating social and personal consequences, this work should be a public health priority. Acknowledgements Kathleen Kerr MD, FASE Senior Research Associate, and Marie Cecchini MS, are the authors of this white paper. Carl Smith, FASE Senior Editor, is acknowledged for his review and editing. The neuronutrient research of Ken Blum, Ph.D., and Howard Trachtenberg, Ph.D. has been applied to alcohol, cocaine and opiate addiction. Preliminary withdrawal and treatment studies of specific amino acid, vitamin and mineral combinations (SAAVE for treatment of alcoholism and Tropamine for opiates and cocaine) showed improved outcomes. 64;81 Conclusions: Nutritional approaches reduce withdrawal symptoms, enhance program retention, and improve long term outcomes Despite the modern prevalence of pharmaceutical approaches to withdrawal, drug therapy has unwanted, adverse effects and is not effective in all types of drug withdrawal; cocaine addiction, for example, lacks an effective drug treatment. 82 However, there is consistent evidence that withdrawal protocols incorporating a range of micronutrients provide safe and beneficial interventions. Basic multivitamins are recommended in the recovery phase of many addiction treatment programs. The literature includes numerous case reports and pilot studies, alongside a group of cohort and controlled studies, suggesting that high dose micronutrient intervention can improve rehabilitation outcomes such as drug reversion, craving and quality of life measures. Longer-term use of micronutrient supplements by recovering addicts is likely to also be important, and may help to prevent reversion. This is a particularly important area to explore to gain information that could lead to cost-effective, improved treatment outcomes. Additional studies are warranted to measure the specific effect size of micronutrient support on 5

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7 APPENDIX 1. RESULTS OF NUTRIENT THERAPY IN SUBSTANCE ABUSE TREATMENT Reference Population studied Substance Nutrient intervention Outcome Comments Smith, year study of 507 males, 239 with organic brain syndrome Scher, year study of 615 of narcotic withdrawal and methadone maintained patients Alcohol Narcotics nicotinic acid (niacin), high ( massive ) doses amount not specified Vitamin C 5000 mg per day or more Vitamin E and Multiple vitamin and Minerals 3-4x/day. Libby, 1977[Libby addicts in medical setting Narcotics Vitamin C 25 gm/day (or more with heavy prior narcotic dose) Multivitamins, minerals & liquid amino acids Multiple symptom improvement reduced drinking reduced recidivism over 50% of organic alcoholics showed improvement 60-70% relief of withdrawal symptoms. Improvement in mood, sleep and constipation in methadone maintained patients given high dose vitamins. No withdrawal symptoms within 4-6 days, rapid improvement in well being. Methodological problems but impressive results especially in more severe group. Authors were from the National Council on Drug Abuse and the Methadone Maintenance Institute, Chicago. Used blinded placebo controls early on but dropped this due to clear benefit in Vitamin C groups. Open clinical trial 100% success reported in alleviation of withdrawal symptoms. Free, addicts during 21 day withdrawal Narcotics Vitamin C 24 gm/day or more, tapering to 8-12 gm/day Multivitamins, calcium, magnesium, liquid protein. Dose varied with symptoms. Vitamin treatment: Alleviation of withdrawal symptoms in 4-6 days and increased energy. Case reports that vitamin C blocked effects if subjects reused narcotics. Medication: Withdrawal symptoms reduced somewhat after 17 days of treatment. Controlled, non randomized, study. Guenther, males VA Medical Center enrolled in 12-step, hospitalbased program Alcohol High dose multivitamins and minerals Restricted dietary sugar Nutrition education Sobriety 6 months post discharge 81.3% nutrition group vs. 37.8% control. Controlled, non randomized, field trial. No medications given. Mathews-Larson, clients in 6 wk withdrawal and outpatient treatment program Alcohol Vitamin C 25 grams/day Individualized nutrient corrections see Table 1 Eliminated dietary sugar Allergy correction At 6 wks: 89% anxiety free, 94% without sleep problems, 95% depression free. 81% were abstinent at month follow-up. Descriptive cohort study with long (42 mo) follow-up. A model of highest standard of care. Blum Replogle, alcoholics and polydrug abusers 63 clients in 30 day residential program based on 12-step model Multiple illicit drugs and Alcohol Alcohol SAAVE (see Table 1) Vitamin C 3 grams/day Niacin 3 grams/day Vitamin B6 590 mg/day Vitamin E 590 IU/day Significant reduction in withdrawal symptoms, significantly lled, randomized study. Double-blind, placebo-contro- improved physical, behavioral and emotional scores. Patients able to more quickly focus on behavioral component of treatment. Vitamin group showed significant reductions in anxiety before 21 days of nutrient compared with controls Controlled, randomized trial. No medication allowed. Brown clients Cocaine or Alcohol Tropamine or SAAVE (see Table 1) Beasley clients in social-educational residential program 73 % of alcoholics and 53% of cocaine abusers abstinent at 10 month follow-up Alcohol See Table percent abstinent after 12 months, most were also free from extensive physical pathology that had been measured at enrollment Evangelou, patients in a medical setting Heroin Vitamin C 20 grams/day Vitamin E 330 mg/day Ambrose patients in detoxification Alcohol Vitamin B1 (thiamine) at varying doses during withdrawal Major withdrawal symptoms in 16 percent of vitamin groups vs 56 percent of diazepam + analgesic group Memory improvement increased with increasing doses of thiamine Controlled, randomized trial Longitudinal trial, some medication to address withdrawal symptoms Blinded, controlled trial. 3 groups, vitamins only, vitamins + medication, medication only. Randomized, double-blind, multi-dose study 7

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Is US health really the best in the world? JAMA 284, (2000). 13

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Managing alcohol, tobacco and other drug problems: A pocket guide for physicians and nurses Toronto, Canada, Centre for Addiction and Mental Health. Kahan, M. and Wilson, L Smith, R.F. A Five-Year Field Trial of Massive Nicotinic Acid Therapy in Alcoholics in Michigan. J Orthomolec Psych 3, (1974). 99. Hubbard L.R. Drug Drying Out.Technical Bulletins. Bridge Publications, Los Angeles, CA (1971) Osmond, H. and Hoffer, A. Massive niacin treatment in schizophrenia. Review of a nineyear study. Lancet 1, (1962) Knopp, R.H. Evaluating niacin in its various forms. Am J Cardiol 86, 51L-56L (2000) Elam, M.B. et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA 284, (2000). 84. Scher, J., Rice, H., Kim, S., DiCamelli, R., and O Connor, H. Massive vitamin C as an adjunct in methadone maintenance and detoxification. J Orthomolec Psych 5, (1976). 85. Free, V. and Sanders, P. The use of ascorbic acid and mineral supplements in the detoxification of narcotic addicts. J Psychedelic Drugs 11, (1979). 86. Guenther, R.M. The role of nutritional therapy in alcoholism treatment. Int Journal of Biosocial Research 4, 5-18 (1983) Grundy, S.M. et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med 162, (2002) Pieper, J.A. Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety. Am J Health Syst Pharm 60, S9-14; quiz S25 (2003) Knip, M. et al. Safety of high-dose nicotinamide: a review. Diabetologia 43, (2000). 87. Replogle, W.H. and Eicke, F.J. Megavitamin Therapy in the Reduction of Anxiety and Depression Among Alcoholics. J Orthomolec Medicine 4, (1989). 88. Evangelou, A. et al. 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15 113. Goodman, A.B. Chromosomal locations and modes of action of genes of the retinoid (vitamin A) system support their involvement in the etiology of schizophrenia. Am J Med Genet 60, (1995) Geubel, A.P., De Galocsy, C., Alves, N., Rahier, J., and Dive, C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 100, (1991) Leo, M.A. and Lieber, C.S. Hypervitaminosis A: a liver lover s lament. Hepatology 8, (1988) Hathcock, J.N. Vitamins and minerals: efficacy and safety. Am J Clin Nutr 66, (1997) Diliberto, E.J. Jr, Daniels, A.J., and Viveros, O.H. Multicompartmental secretion of ascorbate and its dual role in dopamine beta-hydroxylation. Am J Clin Nutr 54, 1163S-1172S (1991) Majewska, M.D. and Bell, J.A. Ascorbic acid protects neurons from injury induced by glutamate and NMDA. Neuroreport 1, (1990) Gudelsky, G.A. Effect of ascorbate and cysteine on the 3,4-methylenedioxymethamphetamine-induced depletion of brain serotonin. J Neural Transm 103, (1996) White, L.K. et al. Ascorbate antagonizes the behavioral effects of amphetamine by a central mechanism. Psychopharmacology (Berl) 94, (1988) Leo, M.A. and Lieber, C.S. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 69, (1999) Ang, H.L., Deltour, L., Zgombic-Knight, M., Wagner, M.A., and Duester, G. Expression patterns of class I and class IV alcohol dehydrogenase genes in developing epithelia suggest a role for alcohol dehydrogenase in local retinoic acid synthesis. Alcohol Clin Exp Res 20, (1996) Rice, M.E. Ascorbate compartmentalization in the CNS. Neurotox Res 1, (1999) Rice, M.E. Ascorbate regulation and its neuroprotective role in the brain. Trends Neurosci 23, (2000) Padayatty, S.J. and Levine, M. New insights into the physiology and pharmacology of vitamin C. 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16 Reference List 153. Vieth, R., Kimball, S., Hu, A., and Walfish, P.G. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J 3, 8 (2004) Shulman, A., Jagoda, J., Laycock, G., and Kelly, H. Calcium channel blocking drugs in the management of drug dependence, withdrawal and craving. A clinical pilot study with nifedipine and verapamil. Aust Fam Physician 27 Suppl 1, S19-24 (1998) Singleton, C.K. and Martin, P.R. Molecular mechanisms of thiamine utilization. Curr Mol Med 1, (2001) Saris, N.E., Mervaala, E., Karppanen, H., Khawaja, J.A., and Lewenstam, A. Magnesium. An update on physiological, clinical and analytical aspects. Clin Chim Acta 294, 1-26 (2000) Griffith, H.W. Complete Guide to Vitamins Minerals and Supplements. Fisher, Tucson, Arizona (1988) Guyton, A.C. 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Pharmacological studies on the regulation of biosynthesis of enkephalins. Shagaff, Jofiassen, Bridger, Weiss, Stoff, and Simpson. Proceedings of the Fourth World Congress on Biological Psychiatry. 86. New York, Elsevier Benkelfat, C., Ellenbogen, M.A., Dean, P., Palmour, R.M., and Young, S.N. Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry 51, (1994) Reinhart, R.A. Magnesium metabolism. A review with special reference to the relationship between intracellular content and serum levels. Arch Intern Med 148, (1988) Dacey, M.J. Hypomagnesemic disorders. Crit Care Clin 17, , viii (2001) Berkelhammer, C. and Bear, R.A. A clinical approach to common electrolyte problems: 4. Hypomagnesemia. Can Med Assoc J 132, (1985) Zieve, L. Influence of magnesium deficiency on the utilization of thiamine. Ann N Y Acad Sci 162, (1969) Pall, H.S., Williams, A.C., Heath, D.A., Sheppard, M., and Wilson, R. 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17 189. Rogers, L.L., Pelton, R.B., and Williams, R.J. Amino acid supplementation and voluntary alcohol consumption by rats. J Biol Chem 220, (1956) Peet, M. and Stokes, C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 65, (2005) Williams, R. Alcoholism The Nutritional Approach. University of Texas Press, Austin, TX (1959) Williams, R.J. Physicians Handbook of Nutritional Science. Charles C. Thomas, Illinois (1978) Pozdeez, V.K. Neurochemical heterogeneity of the pathogenesis of epilepsy. Acta Neurologica 7, (1985) Cami, J. and Farre, M. Drug addiction. N Engl J Med 349, (2003) Logan AC. Omega-3 fatty acids and major depression: a primer for the mental health professional. Lipids Health Dis 3, (2004) McCarty, M.F. Fish oil may be an antidote for the cardiovascular risk of smoking. Med Hypotheses 46, (1996) Moyad, M.A. An introduction to dietary/supplemental omega-3 fatty acids for general health and prevention: part II. Urol Oncol 23, (2005) Sabelli, H.C. et al. Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements. J Clin Psychiatry 47, (1986) Sabelli, H.C. and Javaid, J.I. Phenylethylamine modulation of affect: therapeutic and diagnostic implications. J Neuropsychiatry Clin Neurosci 7, 6-14 (1995) Bourre, J.M. Roles of unsaturated fatty acids (especially omega-3 fatty acids) in the brain at various ages and during ageing. J Nutr Health Aging 8, (2004) Frasure-Smith, N., Lesperance, F., and Julien, P. Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biol Psychiatry 55, (2004) Peet, M. Nutrition and schizophrenia: beyond omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 70, (2004). 17

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