The ZRT Laboratory Blog

Alzheimer’s: A Biological Model of Prevention – Finally! (Part 3)

Fri, 11 Jan 2019 10:00:00 -0800

The Silent Flame

Theories abound on the origins of most major diseases, and many share one factor in common: inflammation. The biological consequences of inflammation are at the root of virtually every human malady from the common cold to cancer, allergies to arthritis, and headaches to heart disease. Yet inflammation is a natural, self-protective response of the body with the best of intentions. Inflammatory chemicals rush to the scene of injury or infection, and safeguards rein in the potent reaction before its benefits are outweighed by potential harm. When these defenses are compromised, immune responses lead to chronic inflammation, the root of major diseases.

Inflammation and the Brain

Just as the cells that make up our organs and tissues can be damaged by incessant inflammation, so too the cells that construct our brain experience its impact. Accelerated activity in the brain renders neurons even more vulnerable to inflammatory injury. Networks of neurons shape the nature and stability of our thoughts, moods, and behaviors; physical injury to these neurons has far greater implications for our health and well-being. In addition to neurological disorders such as Parkinson’s and Multiple Sclerosis and mental health conditions including depression and schizophrenia, Alzheimer’s Disease is one of several brain abnormalities highly associated with inflammation.

As we remarked in the last article in this series, the hallmark features of Alzheimer’s Disease—often called plaques and tangles—are accumulations of malformed protein fragments resulting from aberrant metabolic processes in the brain. Overactive enzymes, inefficient cellular waste removal, and biochemical imbalances caused by nutritional insufficiency and stress represent several research-supported mechanisms that underly the progressive neurodegeneration characterizing Alzheimer’s. In each of these models, inflammatory responses to injury play a major role in initiating and exacerbating the damage that kills neurons and severs the communication required for us to think, remember, and act. Thus, inflammatory status serves as a primary risk factor and measurable biomarker of short and long-term brain health.

A Major Modifiable Risk Factor - Homocysteine

Predictably, high homocysteine is one of the most striking predictors of dementia and Alzheimer’s Disease, and one that is easily measured with a blood test.

Inflammatory status is routinely measured by medical practitioners to assess overall health and risk for chronic disease. Homocysteine levels in the blood are often assessed as sensitive measures of inflammation for screening of cardiovascular disease, as elevations are highly associated with heart attack and stroke. An intermediate amino acid derived from methionine, homocysteine holds a pivotal spot in the methylation cycle, a critical biological process that drives protein synthesis. Importantly, efficient operation of this cycle relies heavily upon Folate, Vitamin B-12, and Vitamin B-6. Elevated homocysteine is a beneficial indicator of deficiencies in these dietary essentials. The most severe symptoms of insufficient Folate, B-12, and B-6 are neurological in nature, and can produce debilitating motor and cognitive issues with potentially permanent consequences. Predictably, high homocysteine is one of the most striking predictors of dementia and Alzheimer’s Disease, and one that is easily measured with a blood test.

Though not initially designed to survey neurological outcomes, the multi-generational Framingham heart study, ongoing since 1946, published population data that revealed highly significant long-term correlations between blood levels of homocysteine, cognitive decline, and eventual Alzheimer’s Disease. Participants with homocysteine levels above normal doubled their chance of being diagnosed, with risk increasing by 40% at each incremental level. Remarkably, these associations were found several years before an official diagnosis and held independent of any other cardiovascular risk factors. A plethora of incontrovertible evidence has added to the Framingham report, leading researchers to formulate the “homocysteine hypothesis” as a leading theory to explain Alzheimer’s Disease. The statement endorsed by an international committee of experts reads “We conclude that elevated plasma total homocysteine is a modifiable risk factor for the development of cognitive decline, dementia, and Alzheimer’s disease in older persons.”

The theoretical basis behind the “homocysteine hypothesis” of Alzheimer’s suggests a similarity in the mechanisms tying homocysteine with cardiovascular disease: excessive inflammation as a result of oxidative stress. As chronically high homocysteine triggers an incessant immune response, brain cells are overstimulated to exhaustion and inundated with toxic levels of inflammatory chemicals causing injury and death. The consortium behind the “homocysteine hypothesis” also added greater beta-amyloid production and phosphorylation of tau, processes that encourage the growth and buildup of plaques and tangles. Synthesis of observational and laboratory data from men and women in middle age substantiates the striking relationship between this simple blood marker and progressive memory loss, cognitive decline, dementia, and Alzheimer’s Disease.

Bs for the Brain

With the recognition of such a strong predictor of neuroinflammation and risk for Alzheimer’s Disease, early detection and arrest of brain deterioration appears straightforward. Although high homocysteine was deemed a “modifiable risk factor”, ample intake of Folate, Vitamin B-12, and B-6 from food is often not a reliable gauge. The concept of biochemical individuality, a central tenet of integrative psychiatry, comes strongly into play. Inherent genetic variations in enzymes involved in the methylation cycle are particularly influential in determining B-vitamin needs, which can differ significantly from USDA recommendations and between individuals.

Without adequate Folate and B-12 to sustain protein methylation in the brain, repair and regeneration of neurons is impaired.

One of the most familiar and common classes of gene variants occurs in Methylene Tetrahydrofolate Reductase (MTHFR), a critical enzyme driving the metabolism of Folate which also requires Vitamin B-12 to function properly. MTHFR defects limit the activation of Folate to a form that can cross the blood-brain barrier. Furthermore, disruptions in the methylation process allow homocysteine levels to build up, triggering its detrimental effects on delicate neurons. Without adequate Folate and B-12 to sustain protein methylation in the brain, repair and regeneration of neurons is impaired. Vitamin B-6 is required to neutralize homocysteine by converting it to the amino acid cysteine, an important factor in protein synthesis and detoxification. Individuals with defects in the Cystathionine-β-synthase (CBS) enzyme do not adequately use Vitamin B-6, leading to poor recycling of homocysteine.

Fortunately, at-risk individuals with and without genetic influences driving B-vitamin status can manipulate homocysteine with specific supplemental forms of Folate, Vitamin B-12, and Vitamin B-6 and adequately protect the brain from neurodegenerative disease. Patients with MTHFR variants respond remarkably well to L-methylfolate, the activated form of Folate that is highly bioavailable to the body and brain, or to 5-methyltetrahydrofolate, which bypasses the MTHFR impediment. Low B-12 responds most quickly and effectively to intravenous or sublingual delivery as either hydroxycobalamin or methylcobalamin. For individuals with a CBS gene mutation, Vitamin B-6 supplements in the bioactive form Pyridoxal-5-Phosphate (P5P or PLP) can kickstart the conversion of homocysteine and prevent its buildup.

Even healthy individuals who supplement with B-vitamins show improved measures of cognition that typically decline with age as well as superior integrity and maintenance of grey matter volume. In addition to showing a direct relationship to homocysteine levels, multiple research studies supply data showing an inverse relationship between B-vitamin status and cognitive decline, dementia, and Alzheimer’s Disease. Consistently, individuals with greater intakes of Folate, Vitamin B-12, and Vitamin B-6 have less brain atrophy and better neurological function over time. Beyond the methylation cycle, B-vitamins are key factors for the synthesis of red blood cells and maintenance of neurological processes throughout the body. Adequate B-vitamin intake from well-rounded diets and high-quality supplements is recommended for optimal health regardless of age or health status.

New Hope is Here

The most effective and unfailing treatment strategies are founded upon knowledge and understanding of the key biological processes involved and what is missing, out of balance, or not functioning correctly. At the same time, the answers to these questions should be reliably measured, precisely targeted, and easily monitored. Homocysteine levels therefore represent a clear marker for early detection, prevention, and treatment of Alzheimer’s Disease, and B-vitamins offer a straightforward, safe, and effective solution for eliminating this substantial risk factor. With readily accessible genetic testing methods, we can even address the “unmodifiable” risk associated with poor B-vitamin metabolism in some patients, providing Folate and Vitamins B-6 and B-12 in ready-to-go forms that enable normal turnover of homocysteine. By providing ample supplies of easily recognizable, naturally present nutrients, cells can withstand the pressures of normal wear-and-tear and are more robustly equipped to combat oxidative stress and inflammation.

We don’t have to look far to sense the pessimism and loss of hope within the medical community as headlines stack up announcing another failed pharmaceutical drug trial in the search for an Alzheimer’s cure. Time ticks on as new diagnoses are charted by the seconds. With despair threatening Alzheimer’s patients and their loved ones, there is an urgent need for fresh news. The big business of conventional medicine ignores any non-lucrative treatment, yet billions are funneled into clinical trials doomed to fail. But wasted money is far from the greatest loss to society from Alzheimer’s; we are losing our parents, grandparents, and mentors far too early. And the cost of elderly care for Alzheimer’s patients is staggering.

After years of studying and practicing integrative psychiatry and following evolving research efforts, my perspective remains grounded in biological models of disease that arise from nutritional and genetic imbalances. Scientific evidence continues to deliver unmistakable confirmation that our diets, environments, and lifestyles have profound roles in determining our physical and mental health, and unseen consequences begin years before disease symptoms begin. This article series gives only a brief glimpse into the biochemical underpinnings of Alzheimer’s disease, but even a cursory glance supplies abundant pathways for prevention and treatment. We have the responsibility to use what we know, and we are privileged with unprecedented tools at our disposal. The future of successful Alzheimer’s treatment is now. As the truth about early detection and measurable risk unfolds and expands, we can reverse the prevailing cynicism and doubt and establish a new paradigm of triumph over this ruthless foe.

James M. Greenblatt, M.D.

Dr. James M. Greenblatt is chief medical officer and vice president of medical services at Walden. He provides medical management, leadership and oversight of Walden’s eating disorder and psychiatric programs in Massachusetts and Connecticut. Dr. Greenblatt is board-certified in child and adult psychiatry.

He received his medical degree and completed his adult psychiatry residency at George Washington University in Washington, D.C. He completed a fellowship in child and adolescent psychiatry at Johns Hopkins Medical School. In addition, Dr. Greenblatt is a clinical faculty member in the psychiatry department at Tufts Medical School as well as the Geisel School of Medicine at Dartmouth College in New Hampshire.

He lectures extensively throughout the United States and Canada on integrative therapies for mental health. Dr. Greenblatt is the author of six books including one textbook and books on depression, eating disorders and ADHD. His latest book is on Integrative Therapies for Alzheimer’s disease, exploring the research on nutritional lithium. Dr. Greenblatt is the founder of Psychiatry Redefined, a healthcare education training program for integrative psychiatry.

He can be reached at: Walden Behavioral Care, 9 Hope Avenue, Suite 500, Waltham, Massachusetts, 02453; (781) 647-2901. For more information on Dr. Greenblatt please visit www.jamesgreenblattmd.com.

Related Resources

References

Alzheimer’s Association. (2018). What is Alzheimer’s – Risk Factors. Alzheimer’s Association website. https://www.alz.org/alzheimers-dementia/what-is-alzheimers/risk-factors. Accessed October 6, 2018.

Cummings, J. L., Morstorf, T., & Zhong, K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer's research & therapy, 6(4), 37.

Durga, J., van Boxtel, M. P., Schouten, E. G., Kok, F. J., Jolles, J., Katan, M. B., & Verhoef, P. (2007). Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. The Lancet, 369(9557), 208-216.

Forlenza, O.V., et al. (2011). Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomized controlled trial. British Journal of Psychiatry 198:351-365.

Greenblatt JM. (2018). Integrative Medicine for Alzheimer’s.

Greenblatt, JD. (2018). New Hope for Alzheimer’s Disease: Nutritional Lithium as the Foundation for Prevention Part 1. Townsend Letter. October 2018.

Hamilton, A., Zamponi, G.W., Ferguson, S.G. (2015). Glutamate receptors function as scaffolds for the regulation of beta-amyloid and cellular prion protein signaling complexes. Molecular Brain, 8, 18.

Hooper, C., Killick, R., Loveston, S. (2008). The GSK3 hypothesis of Alzheimer’s disease. Journal of Neurochemistry, 104(6), 1433.

Kessing, L. V., Gerds, T. A., Knudsen, N. N., Jørgensen, L. F., Kristiansen, S. M., Voutchkova, D., ... & Ersbøll, A. K. (2017). Association of lithium in drinking water with the incidence of dementia. JAMA psychiatry, 74(10), 1005-1010.

Leszek, J., E Barreto, G., Gasiorowski, K., Koutsouraki, E., & Aliev, G. (2016). Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 15(3), 329-336.

Matsunaga, S., Kishi, T., Annas, P., Basun, H., Hampel, H., Iwata, N. Lithium as a treatment for Alzheimer’s disease: A systematic review and meta-analysis. Journal of Alzheimer’s Disease,48(2), 403-410.

Mauer, S., Vergne, D., & Ghaemi, S. N. (2014). Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Australian & New Zealand Journal of Psychiatry, 48(9), 809-818.

Moore, A.H., O’Banion, M. (2002). Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease. Advanced Drug Delivery Reviews, 54 (12), 1627-1656.

Moore, G. J., Bebchuk, J. M., Wilds, I. B., Chen, G., & Menji, H. K. (2000). Lithium-induced increase in human brain grey matter. The Lancet, 356(9237), 1241-1242.

Nunes, M.A., Viel, T.A, Buck, H.S. (2013). Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Current Alzheimer Research, 10(1), 104-107.

Purse, M. (2018). Lithium: The First Mood Stabilizer. Very Well Mind website. https://www.verywellmind.com/lithium-the-first-mood-stabilizer-p3-380277. Accessed October 7, 2018.

Sarkar, S., Ravikumar, B., Floto, R. A., & Rubinsztein, D. C. (2009). Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell death and differentiation, 16(1), 46.

Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D’Agostino, R.B., Wolf, P.A. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. The New England Journal of Medicine, 346(7), 476.

Zylberstein, D.E., Lissner, L., Bjorkelund, C., Mehlig, K, Thelle, D.S., Gustafson, D, Skoog, I. (2011). Midlife homocysteine and late-life dementia in women. A prospective population study. Neurobiology of Aging, 32(3), 380-386.

Alzheimer’s: A Biological Model of Prevention – Finally! (Part 2)

Thu, 20 Dec 2018 12:14:00 -0800

The Alzheimer’s Association states that “the greatest known risk factor for Alzheimer’s is increasing age”, leading many to presume that a diagnosis is inescapable. Sadly, it is not only the uninformed expressing this cynicism; even highly-educated medical professionals have slumped in defeat. Of the leading causes of death in America, Alzheimer’s Disease stands alone as the only malady largely unaffected by pharmaceutical interventions and continues to confound researchers vigorously seeking a cure. Despite decades of earnest effort, medical science seems no closer to clear answers for treating, much less preventing this cruel disease. At the current trajectory, chances are climbing that you or someone you know will face Alzheimer’s Disease.

Why We Need an Integrative Approach to Early Diagnosis and Prevention

In our previous article, we detailed the ongoing waste and failures associated with pharmaceutical research into Alzheimer’s Disease treatments. Billions of dollars, dashed hopes, dear relationships, and precious lives are the unintentional casualties of bureaucracy, ignorance, and greed in Big Pharma. While intentions may be sincere, stubborn adherence to narrow, reductionist theories and methods have resulted in diagnoses at late stages of the disease and treatment applied when brain tissue loss is profound, and most damage is irreversible. We pointed to evidence that brain damage related to Alzheimer’s begins decades before obvious symptoms manifest, and we explained why the focus must shift to early prevention by recognizing modifiable risk factors and defining objective diagnostic markers that can be detected early in the disease process. Science supports an integrative perspective to neurological disease wherein nutritional components play critical roles in the whole human organism, including the brain.

Is Nutrition the Key?

At this point, most physicians recognize the integral relationship between nutrition and overall health. Even without knowing or understanding the specifics, medical practitioners generally agree that well-rounded, nutritious diets and active lifestyle behaviors foster the best environment for disease prevention and longevity. Unfortunately, generic “healthy diet” mantras have done little to demonstrate the powerful and convincing effect that minute components of the human diet have on normal physical and mental function. As a matter of fact, even the drinking water we take for granted contributes to our health beyond hydration. Trace minerals carried in groundwater and that permeate the soil in which our food is grown are absolutely essential to many of the body’s biological processes, and it turns out that our exposure to these elements can vary widely by location, water source, and what we eat.

The Mighty Micro Mineral - Lithium

Lithium is recognized as one of the primordial elements at the foundation of our universe and the planet we call home. Most associate the diminutive metal with the batteries in our phones, electronic gadgets, and most recently, our cars. In fact, battery production demands approximately 75% of the lithium collected from the Earth around the world. Yet while modern society has benefited greatly from the discovery of lithium in terms of technology, this remarkable mineral holds even greater potential for serving humanity. Relatively unrecognized in medicine until the 1940s, early mental health pioneers realized that lithium possesses an amazing influence on brain function, initially revealed by its powerful effects to stabilize moods in psychiatric patients. In fact, 7-Up soda pop began as a lithiated elixir promoted for its ability to lift the spirits, and lithium hot springs became popular tourist attractions in the mid-20^th century. Doctors enthusiastically prescribed lithium for bipolar disorder, then called manic depression, which had the unfortunate consequence of obscuring lithium’s benefits with a negative stigma associated with mental illness and concerns over its toxicity at high doses.

The link between lithium and mental health and mood has been powerfully demonstrated through observational data collected over the last 50 years. Rates of suicide, violence, and dementia have all been studied in relation to drinking water concentrations of lithium, consistently reporting that an opposing relationship exists between lithium intake and aberrant behavior. In a 2014 systematic review, Mauer, et al., revealed significant correlations between these factors in 9 out of 11 epidemiological studies comprising millions of individuals from across America and Europe. Importantly, these data also establish that the high doses used for psychiatric patients are unnecessary to deliver lithium’s mood stabilizing benefits.

While observational health data are often dismissed by medical researchers, gold-standard randomized and controlled trials (RCTs) have unanimously confirmed lithium’s role in neurological health. Remarkably, lithium’s multi-factorial biological effects were not well-defined until recent decades, but with blazing advances in scientific medicine, research has illuminated the numerous pathways through which lithium protects and regenerates neurons. Not only has lithium demonstrated its ability to prevent further destruction of brain tissue caused by Alzheimer’s pathology, it is capable of restoring grey matter volume by stimulating the growth of new brain cells and enhancing their connectivity. Long-term RCTs in high-risk patients indicate not only cognitive improvements at least as effective as FDA-approved pharmaceuticals, but measurable decreases in the accumulation of tau protein, one of the familiar markers of Alzheimer’s Disease status.

Brain-derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3) are two notable signaling molecules whose poor status has been linked to Alzheimer’s Disease.

Lithium: The Vigilant Vanguard of the Brain

Lithium is involved along the entire life cycle of neurons. When adequate amounts are present, lithium counteracts multiple opportunities for nerve degeneration and brain tissue loss. Like other body cells, the birth, differentiation, and maturation of neurons require specific growth factors to instruct them in what to do and how to do it. Brain-derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3) are two notable signaling molecules whose poor status has been linked to Alzheimer’s Disease. They direct and maintain cognition and memory by enhancing the strength and integrity of neural connections. Moreover, as brain cells incur injury caused by the detrimental effects of internal and external stress, growth factors support resilience and repair. Lithium is an integral component in the synthesis of both BDNF and NT-3, and it amplifies the sensitivity of neural receptors to recognize and receive the signals triggered by these molecules.

A second important action of lithium in thwarting the development and progression of Alzheimer’s Disease involves the powerful enzyme Glycogen Synthase Kinase 3 (GSK-3). Normal activity of GSK-3 includes appropriate coordination of the protein synthesis involved in neural growth and development. In Alzheimer’s Disease, the formation of plaques and tangles occurs as the overactivity of GSK-3 increases the rate that beta-amyloid and tau protein fragments accumulate, creating physical barriers to the signals that are key to neural function and survival. Eventually, excessive buildup in certain areas of the brain interfere with the process of memory formation.

The role of GSK-3 in Alzheimer’s Disease is so well-established that it is a primary target for pharmaceutical researchers. Incidentally, lithium is one of the most potent GSK-3 inhibitors, effectively moderating its activity and facilitating cellular processes that eliminate waste products such as beta-amyloid and tau fragments. Furthermore, in addition to promoting cellular waste removal by regulating GSK-3, lithium also influences the genetic expression of chemicals that control cell death. By balancing the concentration of these molecules, lithium optimizes neural life cycles and prevents impediments to communication in support of healthy brain tissue.

Where Do Neurotransmitters Come In?

The brain is a carefully-controlled environment involving precise amounts and ratios of numerous chemicals that largely govern our mood, behavior, and response to stressors by activating and inactivating neural signals. Imbalances resulting from nutritional inadequacy, excess or deficiencies in hormones and neurotransmitters, inflammation, and disease can disrupt normal stimulation of the cellular responses with a multitude of downstream effects. Glutamate is often considered the most important neurotransmitter for its dominant role in allowing neurons to communicate. Yet while strong neural communication is desirable, too much glutamate exhausts neurons and accelerates the production of damaging free radicals that hasten cell death. As it turns out, Alzheimer’s patients often have high levels of glutamate in brain tissue. Overexcitation by glutamate contributes to an environment of heightened oxidative stress that is toxic to delicate neurons, accelerating the loss of brain tissue needed for high-level cognition and learning.

Once again, lithium proves its worth by protecting neurons from potential assault by excessive glutamate. Lithium prevents the damaging effects of overexcitation by reining in the uptake of glutamate by cells. In fact, lithium directly attaches to glutamate receptors on neurons, successfully blocking its unnecessary uptake. Other consequences of heightened inflammation in the brain also benefit from lithium’s utility. Cell studies indicate that lithium dampens the activity of chemicals that promote the inflammatory response; conversely, lithium actually increases the level of anti-inflammatory substances by influencing the metabolism of fatty acids that are required for their synthesis. New data have also shown that lithium encourages learning and memory formation even at the genetic scale by facilitating the expression of related genes.

Validated studies and clinical practice both corroborate the conclusion that early and consistent use of lithium in low doses, matching levels naturally present in some foods and groundwater, prevents cognitive decline and even improves cognitive performance in Alzheimer’s patients.

Lithium Is Key for Alzheimer’s Prevention

Amazingly, we have only scratched the surface of lithium’s multifunctional involvement in the brain. Fortunately, even a brief look at the scientific rationale and research data provides plenty of evidence to endorse the use of lithium for treating dementia and Alzheimer’s Disease. Validated studies and clinical practice both corroborate the conclusion that early and consistent use of lithium in low doses, matching levels naturally present in some foods and groundwater, prevents cognitive decline and even improves cognitive performance in Alzheimer’s patients. Like many essential dietary nutrients, individual access and intake of lithium varies considerably, suggesting that supplemental sources should be a consideration for anyone concerned about boosting brain health.

Inspired by overwhelming support for this miracle mineral that has existed for decades, I have safely used lithium in my own clinical psychiatric practice for over 30 years in a wide range of doses with no adverse effects. Based on what we have learned of lithium’s impact on the brain at even trace levels in the general population and its direct functionality in targeting markers of Alzheimer’s Disease, I advocate that all clinicians should include lithium as a fundamental component of their Alzheimer’s treatment model. As objective biological markers of disease come to light, early detection of risk reveals a critical window for reinforcing the brain’s own capacity to function and heal with nutrient-based interventions that prevent and arrest deterioration. Alzheimer’s, dementia, and cognitive decline are not inevitable; prevention is possible.

We have just learned about the potential of a lesser-known nutrient for protecting and restoring the brain. In our final installment in this series, we will explore the roles that much more familiar B-vitamins play in the features of Alzheimer’s Disease and why despite their ubiquity in the human diet, some individuals may still not receive adequate amounts. At the same time, Vitamin B-12 and Folate are integral in the body’s control of homocysteine levels, a prominent marker of inflammation and a modifiable risk factor for Alzheimer’s.

James M. Greenblatt, M.D.

He lectures extensively throughout the United States and Canada on integrative therapies for mental health. Dr. Greenblatt is the author of six books including one textbook and books on depression, eating disorders and ADHD. His latest book is on Integrative Medicine for Alzheimer’s, exploring the research on nutritional lithium. Dr. Greenblatt is the founder of Psychiatry Redefined, a healthcare education training program for integrative psychiatry.

He can be reached at: Walden Behavioral Care, 9 Hope Avenue, Suite 500, Waltham, Massachusetts, 02453; (781) 647-2901. For more information on Dr. Greenblatt please visit www.jamesgreenblattmd.com.

Related Resources

References

Greenblatt JM. (2018). Integrative Medicine for Alzheimer’s.

Greenblatt, JD. (2018). New Hope for Alzheimer’s Disease: Nutritional Lithium as the Foundation for Prevention Part 1. Townsend Letter. October 2018.

Hooper, C., Killick, R., Loveston, S. (2008). The GSK3 hypothesis of Alzheimer’s disease. Journal of Neurochemistry, 104(6), 1433.

Moore, A.H., O’Banion, M. (2002). Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease. Advanced Drug Delivery Reviews, 54 (12), 1627-1656.

Moore, G. J., Bebchuk, J. M., Wilds, I. B., Chen, G., & Menji, H. K. (2000). Lithium-induced increase in human brain grey matter. The Lancet, 356(9237), 1241-1242.

Nunes, M.A., Viel, T.A, Buck, H.S. (2013). Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Current Alzheimer Research, 10(1), 104-107.

Purse, M. (2018). Lithium: The First Mood Stabilizer. Very Well Mind website. https://www.verywellmind.com/lithium-the-first-mood-stabilizer-p3-380277. Accessed October 7, 2018.

Alzheimer’s: A Biological Model of Prevention – Finally! (Part 1)

Thu, 06 Dec 2018 12:14:00 -0800

News media are replete with alarming statistics about the current and future incidence of Alzheimer’s Disease. A recent CBS headline announced the latest data from the Centers for Disease Control predicting already troubling rates will “soar” in coming decades, with the number of cases potentially doubling by 2060 to almost 14 million Americans. With its impact going significantly beyond a personal toll to create devastating burdens on the family and the economy, Alzheimer’s Disease has become a disturbing public health phenomenon. What is most frightening is that despite billions of dollars spent annually on Alzheimer’s research, we don’t seem to be any closer to pinpointing a cause or finding a cure.

Drug Development Hits a Wall

In the last few years, many major drug companies have ceased conducting clinical trials for Alzheimer’s Disease. Just this year, dramatic articles have announced that Johnson & Johnson, Eli Lilly/AstraZeneca, and most recently Pfizer have abruptly discontinued trials, halted research funding, and laid off researchers due to embarrassing or even dangerous outcomes. From thousands of failed trials, the Food and Drug Administration has approved a total of 5 drugs, only 3 of which arrived in the last 14 years. Sadly, none of these approved prescriptions has shown long-term effectiveness. As discouraging accounts continue to pour in, fresh perspectives and optimism are critical.

The Value of Early Detection

Experts agree that early detection is the primary goal, yet physicians rarely discuss preventive measures beyond generic diet and exercise mantras. Clinicians remain slow to translate into practice mounting scientific research identifying the risk factors and objective diagnostic markers that are essential for developing more effective prevention and treatment strategies. Many lack full understanding of the disease process and thus fail to explore unconventional options, offering little hope to patients and their families. Furthermore, all currently approved prescription drugs for Alzheimer’s were developed using incomplete models of disease, exemplifying the futile efforts of pharmaceutical research.

Many have described Alzheimer’s Disease as an inevitable effect of aging, but proof is mounting that its roots begin decades before obvious symptoms manifest. Neuroscientific discoveries have given us unprecedented knowledge about the how, when, what, and where of disease in the brain, and technological progress is allowing us to distinguish structural and functional impairments in their earliest stages of development. Consensus is gaining that, discovered earlier, brain damage leading to Alzheimer’s Disease may be both treatable and preventable. Robust research indicates that specific risk factors, genetic errors of metabolism, and biochemical imbalances are identifiable in the initiation of Alzheimer’s Disease that suggest precise, achievable treatment models based on individual variations.

Modifiable Factors Potentially Involved in Alzheimer’s Risk

The neurocognitive symptoms of dementia and Alzheimer’s Disease stem from barriers to communication between neurons primarily attributed to plaques and tangles, essentially scar tissue that obstruct, isolate, and kill brain cells. Loss of connection and death occurs when neurons lack access to sufficient nutrients for energy and protection and incur cumulative insults from inflammatory activity. The significant metabolic turnover in the brain requires a substantial variety of nutrients including B-vitamins, mineral cofactors, and antioxidants that neural cells require for optimal functioning, communication, and defense against inflammation. Like the rest of the body, the brain obtains the majority of these substances from the food we eat, and its integrity is determined by the composition and quality of our diets.

While the brain’s significant energy demands are well known, it seems that most physicians overlook the fact that its nutrient needs are also elevated. Despite a bounty of evidence indicating that nutrition is just as important for the brain as it is for the body, conventional medicine stubbornly refuses to abandon reactionary models that attempt to treat nutritional deficiency symptoms with pharmaceutical drugs. The human diet provides not just fuel for cells, but the vitamins, minerals, antioxidants, and other compounds that keep the brain’s machinery running smoothly. Accurate control and response by neurons require careful concentrations and ratios of these invisible means of communication that produce thought, memory, mood, and movement. Given the brain’s profound role in human health and well-being, it is astonishing that more attention is not given to nourishing and protecting our most vital organ.

Pharmaceutical drugs fail patients because, at best, they provide interference within dysfunctional processes and slow the rate of deterioration; they do nothing to promote recovery or provide hope. Since we now know that neural dysfunction and loss ultimately leading to Alzheimer’s Disease originate decades before significant symptoms bring concern. By the time patients display notable problems with cognition and memory, it is likely that much of the damage to the brain is irreversible. In order to repair and strengthen the brain, we must provide what neurons need to revive and restore connections. By targeting specific cellular nutrient requirements, we target neural degeneration at its roots and facilitate the brain’s innate healing capabilities by correcting interrupted processes and providing the tools it needs to rebuild.

Don’t Wait Until It’s Too Late

The impacts of aging on the brain begin years before we want to think about growing old, but just like saving for retirement, we can’t afford to wait until we run out of money. It is similarly irresponsible for doctors to wait until obvious symptoms of dementia and cognitive decline appear before addressing brain health. With the growing epidemic of Alzheimer’s Disease, new perspectives and novel treatments based on advancing science are the clear path forward for preventing this devastating disease from robbing families and society of the love, wisdom, and productivity that come with age.

The only cure for Alzheimer’s Disease is prevention.

Valid and useful models for prevention are clearly outlined in the scientific literature that do not involve prescribing pharmaceuticals at end-stage dementia. Nutritional interventions have both profound public health implications and the potential to stop escalating rates of Alzheimer’s Disease. In this series of articles, I will begin to explore the science and research describing nutritional Lithium, Vitamin B12, and Folate for both treatment and prevention of Alzheimer’s Disease. Next time we will take a closer look at Lithium, an unassuming mineral that holds astounding implications for preventing and treating Alzheimer’s Disease. Supplied primarily from tap water, this essential nutrient has been shown in randomized clinical trials to be at least as effective as currently-approved drugs for inhibiting cognitive decline and dementia in Alzheimer’s patients.

ZRT Laboratory offers a simple to collect, non-invasive way to asses lithium levels in dried urine. The urine lithium test allows for assessment of dietary intake or lithium supplementation.

Bio: James M. Greenblatt, M.D.

Dr. James M. Greenblatt is the author of Integrative Medicine for Alzheimer’s, exploring the research on nutritional lithium (available January 2019). This book, as well as other information about Dr. Greenblatt, can be found on www.JamesGreenblattMD.com. Dr. Greenblatt is chief medical officer and vice president of medical services at Walden. He provides medical management, leadership and oversight of Walden’s eating disorder and psychiatric programs. Dr. Greenblatt is board-certified in child and adult psychiatry.

He lectures extensively on integrative therapies for mental health. . Dr. Greenblatt is the author of six books including one textbook. Dr. Greenblatt is the founder of Psychiatry Redefined, a healthcare education training program for integrative psychiatry.

Related Resources

References

Welsh A. (2018). Number of Americans with Alzheimer's expected to soar in coming decades. CBS News. https://www.cbsnews.com/news/number-of-americans-with-alzheimers-dementias-expected-to-double-by-2060/?ftag=CNM-00-10aac3a. Accessed 09/22/18.

Alzheimer’s Research Impact. (2018). Fiscal Year 2019 Alzheimer’s Research Funding Fact Sheet. http://act.alz.org/site/DocServer/2015_Appropriations_Fact_Sheet__FY16_.pdf?docID=3641. Accessed 09/22/18.

Shurkin J. (2018). Alzheimer's Drug Trials Keep Failing -- It May Be Because We Don't Understand the Disease. Inside Science. https://www.insidescience.org/news/Alzheimer%27s-Drug-Trials-Keep-Failing. Accessed 09/29/18.

Matsunaga S. (2015). Lithium as a Treatment for Alzheimer's Disease: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 48(2):403-10.

Nutritional Lithium: Orchestrating Our Genes & Optimizing Our Moods

Fri, 08 Sep 2017 09:20:00 -0700

This is part two of Dr. Greenblatt's Nutritional Lithium series. Part one can be found here.

Epigenetics & Psychiatry

The field of epigenetics has far-reaching implications for psychiatry. As acquired epigenetic alterations can be transferred to the next generations, what scientists used to label as an inherited psychiatric disease may in fact be the result of epigenetic changes in a family’s shared environment.

Many psychiatric diseases are consistent with the theory of epigenetic dysregulation because of their fluctuating nature and disease course. Single gene and whole genome epigenetic analyses have shown atypical epigenetic markers in the blood and brain of individuals with psychiatric diseases including abnormalities in DNA methylation, histone modifications and microRNA expression.

Among genes that potentially protect against the development of mood disorders, the brain derived neurotrophic factor (BDNF) gene has been the focus of study for the past several years, as it is associated with neural development and proliferation. BDNF is the most prevalent growth factor in the central nervous system. Because it plays a critical role in the development of plasticity of the brain, methylation of BDNF takes a toll on brain health and resilience. The BDNF gene modulates how much or how little environmental experiences become encoded within the neurons and neural circuits and thereby lead to long-lasting effects. BDNF promotes the growth and formation of new neurons, and it is responsible in part for the remarkable effect of exercise on the brain and for the increase in hippocampus size that is linked with improved memory (D’Addario et al., 2012).

Mood disorders are associated with methylation of BDNF. Adverse experiences like major depression can lower BDNF levels and are linked with hippocampal shrinkage, a phenomenon that helps explain some of the cognitive impairments that are a hallmark of depression. Studies have revealed higher levels of DNA methylation at the BDNF gene promoter in patients with major depressive disorder and bipolar disorder II compared to levels in patients with bipolar I (Dell’Osso et al., 2014).

Lithium’s Influences on Genes

I believe lithium deficiency is the most common mineral deficiency associated with nearly every type of psychiatric disorder. Lithium is a powerful epigenetic factor that can be used to dim the expression of genes that lead to aggression and mental illness while stimulating the expression of health-enhancing genes. Genes that are altered by lithium treatment are involved in many functions such as cell communication, immune response, protein metabolism, nucleic acid regulation/metabolism, and cell growth. A study of rat frontal cortex showed chronic treatment with lithium led to the significant up-regulation of 57 genes and down-regulation of 151 genes. Four of those genes have been specifically associated with bipolar disorder (Fatemi, Reutiman, & Folsom, 2009).

Lithium changes gene expression through two basic channels: DNA methylation, and histone modification. Lithium acts by preventing the process of DNA methylation, which is critically important to improving mental health and preventing mental and emotional disorders. At least three studies have demonstrated that lithium decreases DNA methylation of the BDNF gene promoter. In other words, lithium increases the expression of the BDNF gene.

The increased synthesis of BDNF contributes to robust neural growth and healthy dendritic branching. In one study of hippocampal neurons, lithium increased mRNA expression of BDNF by 67%. At a higher lithium dose there was a 100% increase. Likewise, the protein level of BDNF was increased by 53% with the lower lithium dose and by 89% with the higher lithium dose. By ensuring that the BDNF gene is left in the “on” position, lithium promotes the consistent release of protective neurotrophins that protect and nourish the brain (Dwivedi & Zhang, 2015).

BDNF levels are diminished in the brain and serum of Alzheimer’s patients. Alzheimer’s patients treated for ten weeks with lithium showed a significant increase in their BDNF serum levels. They also saw a significant decrease of cognitive impairment compared with placebo-treated Alzheimer’s patients. Reduction of cognitive impairment was inversely correlated with lithium serum concentration (Leyhe et al., 2009).

BDNF also contributes to degradation of amyloid-β, a component of the amyloid plaques found in the brains of Alzheimer’s patients. In addition, BDNF is capable of inactivating GSK-3β (Leyhe et al., 2009). Abnormal regulation and expression of GSK3β is associated with an increased susceptibility towards Alzheimer’s disease and bipolar disorder. Lithium’s ability to enhance the synthesis of BDNF has far reaching implications for improving a wide range of neuropsychiatric disorders.

Lithium affects multiple pathways in the brain which may explain its remarkable effectiveness for the treatment of bipolar disorder.

Lithium also acts through histone modification. Histone function is particularly important for the encoding of high-level cognitive functions including learning and memory. In fact, diminished memory, as seen in patients with Alzheimer’s disease, has been linked to problems with histone metabolism. In experiments with laboratory animals, lithium has been shown to increase histone acetylation by weakening the binding of the DNA to its spool, making it more available to proteins that enhance memory (Lee et al., 2015). Although studies in humans are needed to further delineate the exact mechanism, lithium may be beneficial in preventing the genetic changes associated with the development of Alzheimer’s disease and other neurodegenerative conditions.

These biological mechanisms are also important in lithium’s efficacy in bipolar disorder. Lithium affects multiple pathways in the brain which may explain its remarkable effectiveness for the treatment of bipolar disorder. BDNF has been consistently reported to be decreased in bipolar patients. One study found that bipolar patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. However, for those on lithium treatment, BDNF levels correlated positively with lithium levels (Tunca, 2014).

Lithium has distinct and often dramatic neurotrophic effects, encouraging the survival and growth of nerve cells. Lithium ions modulate multiple biological cascades involved with nerve cell development. Lithium increases levels of key proteins such as BDNF and NT-3, which are known to be directly involved in nerve cell development. Other studies have found that lithium salts are neuroprotective, working to minimize inflammation, enhance mitochondrial function, and increase antioxidants to provide the optimal environment for neurons to thrive. Imaging studies have provided visual evidence that patients taking lithium salts experience increases in brain tissue volume over time, particularly in the gray matter of the brain, which holds the nerve cell bodies. At the cellular level lithium exerts powerful influences on neuroprotection and brain health.

Lithium promotes epigenetic modifications that affect the expression of more than 50 genes, including signaling proteins, transcription factors, activators, cell adhesion proteins, oncogenes, and tumor suppressors (Farah et al., 2013). As research expands our knowledge of how to regulate gene expression and suppression, targeted use of nutritional lithium will enable us to prevent and treat psychiatric disorders that now incapacitate those who suffer from them. By acting directly on the epigenome, lithium restores neural function and improves brain health in ways that just a few years ago were not dreamed possible.

Adapted from Nutritional Lithium: The Cinderella Story written by James Greenblatt, MD and Kayla Grossman, RN (CreateSpace, 2016, https://www.createspace.com/5433178).

About the Author

James M. Greenblatt, MD, is chief medical officer and vice president of medical services at Walden Behavioral Care. Dr. Greenblatt is board-certified in child and adult psychiatry. Dr. Greenblatt is a clinical faculty member in the psychiatry department at Tufts Medical School as well as the Geisel School of Medicine at Dartmouth College in New Hampshire. Dr. Greenblatt is the author of six books including those on depression, eating disorders and ADHD. He can be reached at: (781) 647-2901. For more information on Dr. Greenblatt please visit www.jamesgreenblattmd.com.

Related Resources

References

[1] D’Addario, C., Dell’Osso, B., Palazzo, M.C., et al. (2012). Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology, 37, 1647-1655.

[2] Dell’Osso, B., D’Addario, C., Palazzo, M.C. et al. (2014). Epigenetic modulation of BDNF gene: differences in DNA methylation between unipolar and bipolar patients. Journal of Affective Disorders, 166, 330-333.

[3] Dwivedi, T., & Zhang, H. (2015). Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins. Frontiers In Neuroscience, 8, article 457, 1-8.

[4] Farah, R., Khamisy-Farah, R., Amit, T., Youdim, M. H., & Arraf, Z. (2013). Lithium’s Gene Expression Profile, Relevance to Neuroprotection A cDNA Microarray Study. Cellular And Molecular Neurobiology, 33(3), 411-420.

[5] Fatemi, S. H., Reutiman, T. J., & Folsom, T. D. (2009). The role of lithium in modulation of brain genes: relevance for aetiology and treatment of bipolar disorder. Biochemical Society Transactions, 37(Pt 5), 1090-1095.

[6] Lee, R. S., Pirooznia, M., Guintivano, J., et al. (2015). Search for common targets of lithium and valproic acid identifies novel epigenetic effects of lithium on the rat leptin receptor gene. Translational Psychiatry, 5e600.

[7] Leyhe, T., Eschweiler, G. W., Stransky, E., Gasser, T., Annas, P., Basun, H., & Laske, C. (2009). Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s disease. Journal Of Alzheimer’s Disease, 16(3), 649-656.

[8] Tunca, Z., Ozerdem, A., Ceylan, D., et al. (2014). Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium. Journal Of Affective Disorders, 166, 193-200.

Lithium's Billion Year Journey: A Cinderella Story for Brain Health

Thu, 24 Aug 2017 09:44:00 -0700

This is part one of Dr. Greenblatt's Nutritional Lithium series. Part two can be found here.

As far as cosmologists can tell, there were only three elements present when the universe was first formed some 13.8 billion years ago: hydrogen, helium, and lithium.

As one of the three original elements, lithium is found throughout our atmosphere. The sun, stars, and meteorites burn brightly with the gleam of this highly reactive element. On earth, lithium remains a major mineral component of granite rock, and also lingers in significant amounts in sea water, mineral springs, and soils.

Lithium has also found its way into our cell phones, electric cars, and holiday fireworks. Every organ and tissue in the human body contains the mineral lithium, with particular importance in health, specifically brain health.

Integrative Psychiatry as an Approach to Promoting Brain Health

As a practitioner of integrative psychiatry, I treat individuals with a complex array of emotional, behavioral, and physical symptoms. One of the core concepts of Integrative Psychiatry is the concept of increasing the body’s nutrient reserves to promote long-term health. Lithium is one of the essential nutrients required to achieve optimal health.

History of Lithium use for Improving Mood

Soft drink entrepreneur Charles Leiper Grigg understood there was something special about lithium. In 1929, he unveiled a drink called Bib-Label Lithiated Lemon-Lime Soda with the slogan: “It takes the ouch out of the grouch.” Hailed for improving mood and curing hangovers, this product was eventually rechristened 7-Up. The “7” supposedly represents the rounded-up atomic weight of the element lithium (6.9), and the “Up” suggests its power to lift spirits. Lithium remained an ingredient of 7-Up until 1950.

Centuries before the advent of this celebrated soft drink, lithium was associated with calming moods. Soranus, a physician from ancient Ephesus, observed the benefits of alkaline springs for soothing the wild spirits of some of his patients. Lithium, it turned out, was abundant in these springs.

Efficacy of Low-dose Lithium as an Alternative to Pharmaceutical Dosing

I consider nutritional lithium the most effective nutritional supplement I have used for neurological and psychiatric disorders in 30 years of practice. My respect and enthusiasm for lithium treatment may seem surprising considering some of the drug’s diverse applications throughout history, its association with severe mental health disorders, and its reputation for side effects. At pharmaceutical doses, lithium is an effective treatment for bipolar disorder, recurrent depression, and suicidal tendencies (Lewitzka et al., 2015). But today many psychiatrists, including myself, hesitate to prescribe lithium because of potential side effects at high doses. Their concerns are not unwarranted. Lithium prescribed at pharmaceutical doses can have disabling, irreversible side effects including kidney and thyroid disease.

I consider nutritional lithium the most effective nutritional supplement I have used for neurological and psychiatric disorders in 30 years of practice.

It was not a huge leap for me in 1990 to start exploring the lowest dose of lithium possible that would alleviate my patients’ symptoms. Rather than basing my judgment on a number from a lab test, I listened to patients’ descriptions of their symptoms. I began to see that patients on lower doses of pharmaceutical lithium or nutritional lithium orotate still experienced significant clinical benefits.

I have found that side effects are non-existent when lithium is used as a nutritional supplement. Nutritional lithium is a safe integrative strategy for the treatment of psychiatric and neurological disorders. In fact, it has the potential to dramatically change your clinical practice. Instead of pulling out my prescription pad, in most cases I now recommend that patients take lithium as a nutritional supplement. Not only does low-dose lithium not have any side effects, there are tremendous benefits related to many aspects of mood, behavior, and emotional health.

The Potential of Nutritional Lithium

Even though lithium is among one of the oldest medications in psychiatry, large scale scientific studies of low-dose lithium are limited. Why? Because there is no profit in researching nutritional supplements. Pharmaceutical companies do not eagerly sponsor studies of inexpensive generic drugs. A prescription for lithium costs pennies, and of course, pharmaceutical companies reap no benefit from a nutritional supplement purchased at a health food store.

More recently however, small observational and interventional studies have positively associated modest concentrations of lithium with mental, emotional, and behavioral benefits. Small randomized, double-blind, placebo-controlled trials have indicated positive emotional and behavioral changes with short-term low dose supplementation with lithium. In one study, 24 participants with histories of aggression and impulsivity took a four-week course of 400 mcg of lithium daily. At the end of the month, their scores on measures of happiness, friendliness, energy, and mood had improved (Schrauzer & deVroey, 1990). In another study, participants receiving low-dose lithium for 12 months experienced statistically significant increases in both memory and attention (Leyhe et al., 2009).

Lithium in Drinking Water

Studies of lithium in the water supply provide enlightening evidence of the benefits of low-dose lithium. Low lithium content in the water supply is correlated with higher rates of mental and emotional disorders. In 1970, one research study analyzed levels of organically derived lithium in the water of 27 Texas counties and compared them to the incidence of admissions and readmissions for psychoses, neuroses, and personality disorders at local and state psychiatric hospitals (Schrauzer & Shrestha, 1990). The authors noted a clear trend: the higher the lithium content in the water supply, the lower the rate of psychiatric illness in that county. This association remained significant even after possible confounding variables were accounted for.

Nutritional lithium is a safe integrative strategy for the treatment of psychiatric and neurological disorders. In fact, it has the potential to dramatically change your clinical practice.

Uncertain whether these striking findings were unique to the geographical region, researchers sought to replicate the study in other areas. Lithium water studies have been conducted in Austria, England, Greece, and Japan (Giotakos et al., 2013; Kabacs et al., 2011; Kapusta et al., 2011; Ohgami et al., 2009). Data collection from all of these studies has confirmed a strong inverse correlation between aggressive crime and suicide, and supplemental levels of lithium in the water supply.

The potential of far-reaching use of low-dose lithium remains an exciting possibility. In 2014, Anna Fels MD proposes in her New York Times editorial:

“What if micro-dose lithium were again part of our standard nutritional fare? What if it were added back to soft drinks or popular vitamin brands or even put in the water supply? The research to date strongly suggests that suicide levels could be reduced, and even perhaps other violent acts. And maybe the dementia rate would decline. We don’t know because the research hasn’t been done.” (Fels, 2014)

From Plain Element to Promising Life-changer – Lithium as Cinderella

The story of lithium is a true Cinderella story. Lithium is a common and simple element, found in the rocks we walk on. Its benefits have not been heralded, as the fanfare associated with lucrative pharmaceuticals eclipses its simplicity. When newer treatments appear on the market, lithium is treated like somebody’s stepchild, often ignored and forgotten.

But also like Cinderella, lithium shows great promise. It has only to be recognized. Its ordinary nature is deceptive because it holds the power to transform lives.

Read part two, Nutritional Lithium: Orchestrating Our Genes & Optimizing Our Moods, here.

Adapted from Nutritional Lithium: The Cinderella Story written by James Greenblatt, MD and Kayla Grossman, RN (CreateSpace, 2016, https://www.createspace.com/5433178).

About the Authors

Kayla Grossman, RN, works as a nurse advocate and freelance writer specializing in integrative health research and practice. She supports several large organizations in the field by contributing to their ongoing educational initiatives and clinical programming.

Related Resources

References

[1] Fels, A. (2014). Should we all take a bit of lithium?. The New York Times. p. 6.

[2] Giotakos, O., Nisianakis, P., Tsouvelas, G., & Giakalou, V.V. (2013). Lithium in the public water supply and suicide mortality in Greece. Biological Trace Elements Research, 156(1-3), 376-9.

[3] Kabacs, N., Memon, A., Obinwa, T., Stochl, J., & Perez, J. (2011). Lithium in drinking water and suicide rates across the East of England. British Journal of Psychiatry, 198(5), 406-7.

[4] Kapusta, N.D., Mossaheb, N., Etzersdorfer, E., et al. (2011). Lithium in drinking water and suicide mortality. British Journal of Psychiatry, 198(5), 346-50.

[5] Lewitzka, U., Severus, E., Bauer, R., Ritter, P., Müller-Oerlinghausen, B., & Bauer, M. (2015). The suicide prevention effect of lithium: more than 20 years of evidence-a narrative review. International Journal Of Bipolar Disorders, 3(1), 32.

[6] Leyhe, T., Eshweiler, G.W., Stansky, E. et al. (2009). Increase of BDNF serum concentration in lithium-treated patients with early Alzheimer’s disease. Journal of Alzheimer’s Disease, 16, 649-656.

[7] Ohgami, H., Tetao, T., Shiotsuki, I., et al. (2009). Lithium levels in drinking water and risk of suicide. British Journal of Psychiatry, 194(5), 464-5.

[8] Schrauzer, G. N., & de Vroey, E. (1994). Effects of nutritional lithium supplementation on mood. A placebo-controlled study with former drug users. Biological Trace Element Research, 40(1), 89-101.

[9] Schrauzer, G.N. & Shrestha, K.P. (1990). Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biological Trace Elements Research, 25(2), 105-13.

[10] Zarse, K., Terao, T., Tian, J. et al. (2011). Low-dose lithium uptake promotes longevity in humans and metazoans. European Journal of Nutrition, 50(5), 387-389.

Finally Focused: Mineral Imbalances & ADHD (Part 2: Magnesium Deficiency)

Thu, 25 May 2017 11:33:00 -0700

In part 1 of this series, we discussed the importance of correcting trace mineral imbalances of copper and zinc to reduce behavioral symptoms and improve medication efficiency in children with ADHD. There is another nutrient that should be considered by all healthcare professionals, parents, and those struggling with ADHD: magnesium. Magnesium is a macromineral required for hundreds of the body's biochemical reactions including protein synthesis, muscle and nerve function, blood glucose control, bone development, DNA synthesis, and glutathione synthesis.

Magnesium and Brain Health

Magnesium is an inorganic substance essential for brain function. The bioavailability of magnesium affects the function and binding of neurotransmitters to their receptors, such as serotonin and dopamine. For example, magnesium can increase neurotransmission by endogenous serotonin receptors (5-HT1A). Magnesium also keeps the excitatory neurotransmitter glutamate within appropriate limits by inhibiting NMDA receptors. Magnesium also supports the calming actions of GABA interacting with its receptor.

The Rise of Modern-Day Magnesium Deficiency

Over the last century, magnesium has been progressively declining in our food supply due to the emergence of highly processed foods, modern fertilizers, and soil depletion. Refining grains removes up to 80% of the magnesium originally present. Consumption of refined sugars, soft drinks, and caffeine also depletes magnesium. It is estimated that approximately 50% of Americans of all ages have an inadequate intake of magnesium (Mosfegh et al., 2009). Symptoms of magnesium deficiency include irritability, difficulty with concentration, insomnia, depression, and anxiety. Because up to 95% of those with ADHD are deficient in magnesium, almost all ADHD children can benefit from magnesium supplementation (Kozielec & Starobrat-Hermelin, 1997).

In a recent study on patients with ADHD aged 6 to 16 years, 72% of the children were found to be deficient in magnesium and there was a significant correlation between hair magnesium, total IQ, and hyperactivity. The magnesium deficient children were randomized to magnesium supplementation 200 mg/day plus standard medical treatment or standard medical therapy alone for 8 weeks. Those taking magnesium experienced a significant improvement in hyperactivity, impulsivity, inattention, opposition, and conceptual level compared to those taking medication alone (El Baza et al., 2016).

Magnesium Supplementation Improves ADHD Symptoms

Magnesium supplements with vitamin B₆, which increases magnesium absorption, have shown promise for reducing ADHD symptoms. One study found that 58% of participants with ADHD had low serum magnesium levels. All of the children were given preparations of magnesium plus vitamin B₆ 100 mg/day for a period of 1 to 6 months. In all of the children, physical aggression, instability, attention at school, muscle rigidity, spasms, and twitching improved.

One of the children treated was a six-year-old referred to as “J.” Initially he suffered from aggressiveness, anxiety, inattention, and lack of self-control. After taking the magnesium plus vitamin B₆supplements for 6 months, he experienced better sleep and concentration—and no methylphenidate was needed (Mousain-Bosc et al., 2004). A later study also replicated similar results, as researchers found that a magnesium-vitamin B₆ regimen for at least 2 months significantly improved hyperactivity, aggressiveness, and attention at school (Mousain-Bosc et al., 2006). The researchers concluded, “As chronic magnesium deficiency was shown to be associated to hyperactivity, irritability, sleep disturbances, and poor attention at school, magnesium supplementation as well as other traditional therapeutic treatments, could be required in children with ADHD”. In a larger study evaluating children with ADHD, 30 days of magnesium-vitamin B₆ supplementation led to improved anxiety, attention, and hyperactivity. Magnesium treatment increased attention, work productivity, task performance, and decreased the proportion of errors. The EEG’s of children treated with magnesium showed positive changes as well, with brain waves significantly normalizing (Nogovitsina & Levitina, 2007).

Children with ADHD should be encouraged to increase their consumption of magnesium-rich foods such as bananas, avocados, beans, and green leafy vegetables.

Children with ADHD should be encouraged to increase their consumption of magnesium-rich foods such as bananas, avocados, beans, and green leafy vegetables. A prospective population-based cohort of over 600 adolescents at the 14- and 17-year follow-ups found that higher dietary intake of magnesium was significantly associated with reduced attention problems, aggressiveness, delinquency (Black et al., 2015). However, since only 30% to 40% of dietary magnesium is absorbed by the body, supplementation is the most reliable way to increase magnesium levels in children and adults with ADHD.

Assessing Magnesium Status

It is often difficult to assess magnesium status because magnesium is predominantly stored inside cells or bone. Serum levels have little correlation with total body magnesium levels or concentrations in specific tissues. Tests are usually inaccurate and often unnecessary because most patients with ADHD can benefit from magnesium supplementation. Clinical symptoms of constipation, anxiety, insomnia and irritability are often better assessments of magnesium deficiencies than laboratory testing.

Forms of Magnesium in Supplements

There are several forms of magnesium supplementation, including magnesium glycinate, magnesium oxide, magnesium citrate, and magnesium gluconate. They are equally effective, with one exception: magnesium oxide, which is poorly absorbed and can cause laxative effects. A common side effect from magnesium supplementation is loose stools, but this symptom is usually self-limiting and self-resolving.

Sufficient magnesium is required to adequately support neurotransmitter systems. Although only 1% of magnesium in the body is found in the blood, this 1% is critical because free-circulating magnesium is involved in over 300 vital metabolic reactions. Studies consistently show ADHD children who suffer from greater nutrient imbalances endure more severe symptoms. Fortunately, with appropriate integrative treatments that restore nutrient deficiencies, children can achieve relief from behavioral symptoms including inattention, hyperactivity, impulsivity, and oppositional behavior.

Mineral Balance and ADHD – Conclusions

Thus, correcting copper/zinc imbalances and addressing magnesium deficiencies can yield significant reductions in ADHD symptomology and improve cognitive performance. The available literature suggests that the use of targeted nutritional therapies can be particularly useful in ADHD treatment and maximize treatment outcomes, by minimizing medication side effects while also enhancing the therapeutic effect of medications at lower doses. By incorporating nutritional strategies into modern-day psychiatry, we can effectively provide relief to the millions of children and adults struggling with ADHD.

About the Author

James M. Greenblatt, MD, is the author of Finally Focused: The Breakthrough Natural Treatment Plan for ADHD that Restores Attention, Minimizes Hyperactivity, and Helps Eliminate Drug Side Effects. He currently serves as the Chief Medical Officer and Vice President of Medical Services at Walden Behavioral Care, and is an Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth Geisel School of Medicine. An acknowledged integrative medicine expert, Dr. Greenblatt has lectured throughout the United States on the scientific evidence for nutritional interventions in psychiatry and mental illness. For more information, visit www.FinallyFocusedBook.com

Related Resources

References

[1] Black et al. (2015). Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutrition, 18(10), 1824-30.

[2] El Baza et al. (2016). Magnesium supplementation in children with attention deficit hyperactivity disorder. Egyptian Journal of Medical Human Genetics, 17(1), 63-70.

[3] Kozielec & Starobrat-Hermelin. (1997). Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 10(2), 143-148.

[4] Moshfegh A, Goldman J, Ahuja J, Rhodes D, LaComb R. (2009). What We Eat in America, NHANES 2005–2006: Usual Nutrient Intakes from Food and Water Compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. U.S. Department of Agriculture, Agricultural Research Service: Washington, DC, USA.

[5] Mousain-Bosc et al. (2004). Magnesium VitB6 intake reduces central nervous system hyperexcitability in children. Journal Of The American College Of Nutrition, 23(5), 545S-548S.

[6] Mousain-Bosc et al. (2006). Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. I. Attention deficit hyperactivity disorders. Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 19(1), 46-52.

[7] Nogovitsina & Levitina. (2007). Neurological aspects of the clinical features, pathophysiology, and corrections of impairments in attention deficit hyperactivity disorder. Neuroscience and Behavioral Physiology, 37(3), 199-202.

Finally Focused: Mineral Imbalances & ADHD (Part 1: Zinc Deficiency & Copper Excess)

Tue, 09 May 2017 10:46:00 -0700

What if there was a safe, effective, inexpensive, and simple way to help treat one of the most common neurodevelopmental disorders of childhood?

Health care professionals often overlook nutrients; yet imbalances in many minerals are frequently seen in medical disorders including ADHD. Fortunately, replenishing nutrients with an integrative treatment plan has proven to be an effective treatment for the symptoms of ADHD.

In this two-part series, we will evaluate mineral deficiencies in zinc and magnesium, excess copper, and their relationship with neuropsychiatric symptoms.

Minerals Essential for Health

Minerals are inorganic substances essential for cell metabolism, neurotransmitter synthesis, growth, and development. Major minerals, such as magnesium, need to be consumed in higher amounts than trace minerals, such as copper and zinc, although both types are crucial for many bodily functions. Our bodies cannot synthesize minerals so they must be obtained through food or supplementation.

Mineral deficiencies are commonly seen in patients suffering from psychiatric disorders. Due to modern agricultural practices such as fertilizers and erosion, our soil is tragically depleted in minerals. In addition, when food is processed, it is stripped of essential minerals. Minerals are also depleted from the body with stress and through sweat from exercise or hot yoga practices.

A Toxic Mineral - Lead

In April 2014, the city of Flint, Michigan changed its water supply from Lake Huron to the Flint River. The corrosive water from the Flint River caused lead from old pipes to leach into the water supply, putting up to 12,000 children at risk of consuming dangerous levels of lead. One year after the water supply switch, 5% of children tested in Flint had elevated blood lead levels, prompting President Obama to declare a state of emergency in January 2016.

Overall, blood lead levels in children have plummeted since the US phased out the use of leaded gas and paint in the 1970s. Still, 24 million homes in the US contain deteriorated lead paint and elevated levels of lead-contaminated dust. The reduction in children’s blood lead levels has not been uniform across all areas of the US. Recently, Reuters found nearly 3,000 areas across the US with lead poisoning rates doubling those in Flint. More than 1,000 of these areas had at least a four times higher rate of elevated blood tests than those seen in Flint. The health effects of neurotoxins such as lead are most severe in children, as it can cause irreversible brain damage. Even at low levels, lead has been associated with lower IQ scores, inability to pay attention, impaired motor function skills, and poor academic performance among children.

Lead Exposure and Brain Health

Since lead poisoning causes cognitive, motor, and behavioral changes, it is not surprising that it also plays a role in the pathophysiology of ADHD. Lead exposure is estimated to account for 290,000 excess cases of ADHD in US children (Braun et al., 2006). A study on almost 5,000 US children aged 4 to 15 years found children with the highest blood lead levels were over four times as likely to have ADHD compared to children with the lowest blood lead levels (Braun et al., 2006). A 2016 study exploring the link between lead exposure and hyperactivity and impulsivity in children found that these children had a mutation of a gene that regulates iron uptake and modulates lead metabolism. The researchers concluded, “The findings of our study are difficult to explain unless lead is, in fact, part of the cause of ADHD, not just an association” (Nigg et al., 2016).

Brain scans from participants of the Cincinnati Lead Study revealed that childhood lead exposure was associated with brain volume loss in adulthood. Individuals with higher blood lead levels as children had less gray matter in certain brain regions. Of the regions affected, a significant loss was observed in the prefrontal cortex, which is responsible for executive function, behavioral regulation, and fine motor control (Cecil et al., 2008).

The CDC has set a blood lead level of 5 µg/dL as the reference value to identify children who require case management. However, numerous studies have shown lead levels <5 μg/dL are still associated with inattentive and hyperactivity symptoms and learning difficulties. The risk of ADHD symptoms increases with elevated blood lead levels, even in low concentrations. In one study, 2,200 children aged 7 to 9 years who did not have ADHD at baseline were followed for two years. About 5% (107 cases) developed suspected ADHD. Children with blood lead levels >2.17 μg/dL had a 55% greater risk of developing ADHD compared with those with blood lead levels <2.17 μg/dL (Choi et al., 2016).

Neurotoxic Effects of Excess Copper in Drinking Water

One of copper’s roles in the body is in the synthesis of dopamine, the neurotransmitter that supports alertness and motivations.

Following the water crisis in Flint, Michigan, environmental toxins present in food and water sources raised serious concerns among public health officials. This prompted several states to begin rigorously testing their own water supply. In November 2016, The Boston Globe reported that of the 300 public schools tested in Massachusetts, 227 schools had elevated levels of either copper or lead, or a combination of both, in their drinking water supply. Copper is an essential mineral that is needed in trace amounts; however, excess copper can cause oxidative cell damage and trigger neurobehavioral symptoms such as hyperactivity and irritability.

Our bodies require a delicate balance of copper levels. One of copper’s roles in the body is in the synthesis of dopamine, the neurotransmitter that supports alertness and motivations. However, too much copper creates an excess of dopamine leading to an excess of the neurotransmitter norepinephrine. High levels of these neurotransmitters lead to symptoms similar to ADHD symptoms: hyperactivity, impulsivity, agitation, irritability, and aggressiveness. Like lead, copper can leach into the water supply when copper pipes corrode.

In children with excess copper, stimulant medications are ineffective and can cause side effects such as agitation, anxiousness, and changes in sleep and appetite. Most ADHD medications work by increasing levels of dopamine, intensifying the effects of excess copper. Excess copper also blocks the production of serotonin, which is responsible for regulating mood. The imbalance of copper and neurotransmitter levels triggers emotional, mental, and behavioral problems such as depression and anxiety.

Some studies have assessed the neurotoxic effects of excess copper and its role in ADHD symptoms. High copper levels are correlated with an ADHD diagnosis and with attention and short-term memory difficulties in children and adolescents (Viktorinova et al., 2016; Kicinski et al., 2015). In a randomized controlled trial with 80 adults with ADHD, those with lower baseline copper levels had better response to treatment with a vitamin-mineral supplement. Among those in the highest copper tertile, only 35% responded to treatment. In comparison, 77% of adults in the middle copper tertile responded to treatment (Rucklidge et al., 2014).

Zinc Deficiency and Brain Health

Excess copper in the presence of a zinc deficiency can be particularly harmful in individuals with ADHD. Zinc is another essential trace mineral that is a vital component of the central nervous system and neurotransmitter synthesis. Zinc is involved with over 300 enzymatic reactions within the body to support normal growth and development. Researchers have linked zinc deficiencies in the pathophysiology of several neuropsychiatric illnesses including ADHD. Multiple studies have demonstrated that children and adults with ADHD have been consistently deficient in zinc.

Zinc is required in the synthesis of several neurotransmitters, including dopamine, norepinephrine, and serotonin and enhances GABA, one of our main inhibitory/relaxation neurotransmitters. Daily zinc intake is required to maintain a constant supply as the human body has no zinc storage system. Environmental toxins, such as Bisphenol A (BPA) and phthalates found in everyday plastic products, bind to zinc and deplete zinc levels in the body.

Multiple studies have confirmed that not only are zinc levels lower in children with ADHD, but the extent of zinc deficiency is inversely correlated with symptom severity in those with ADHD. In a recent study case-control study, 70% of the 20 ADHD cases aged 6 to 16 were zinc deficient. Those with lower hair zinc levels had the worst hyperactivity, inattention, oppositional, and impulsivity scores on the Conners’ parent rating scale (Elbaz et al., 2016). In a larger group of 118 children with ADHD, those with the lowest blood levels of zinc had the most severe conduct problems, anxiety, and hyperactivity as rated by their parents (Oner et al., 2010).

Not only are zinc levels lower in children with ADHD, but the extent of zinc deficiency is inversely correlated with symptom severity in those with ADHD.

Electromyogram (EMG) tests, which reflect brain activity, have objectively shown that low plasma zinc levels negatively affect information processing. 28 medication-free boys with ADHD, aged 7 to 12, were compared to 24 control children. Event-related potential indices from parietal and frontal brain regions showed that ADHD children had worse working memory (lower amplitudes of P3) and slower information processing (longer latency of P3) compared to control children. Individuals with ADHD and zinc levels <80 μg/dL showed worse information processing and inhibition (shorter latencies of N2). Plasma zinc levels were significantly lower in ADHD individuals than in controls, but brain waves began to normalize with increasing plasma zinc levels (Yorbik et al., 2008).

Zinc Supplementation to Improve ADHD and Counteract Excess Copper

Zinc supplements improve symptoms more than placebo and enhance the effectiveness of stimulant medications. When 400 ADHD children aged 6 to 14 were randomized to zinc sulfate 150 mg/day or placebo for 12 weeks, those taking zinc had significantly reduced symptoms of hyperactivity, impulsivity, and impaired socialization (Bilici et al., 2004). Similarly, when over 200 children were randomized to zinc 15 mg/day or to placebo for 10 weeks, those taking zinc saw significant improvement in attention, hyperactivity, oppositional behavior, and conduct disorder (Üçkardeş et al., 2009).

Studies also support zinc supplementation as an effective augmentation strategy, as it can help children achieve a therapeutic effect from their stimulant medications at lower dosages. In one study, children received zinc glycinate 15-30 mg/day or placebo. For two weeks, all children were given amphetamine 5-15 mg/day. Over the course of the next three weeks, the children continued the zinc or placebo while amphetamine was titrated. The children receiving zinc had better scores on neuropsychological tests, especially tests of impulsivity. The optimal weight-adjusted mg/kg/day amphetamine dose with zinc was 37% lower than with placebo. Likewise, the optimal absolute mg/day amphetamine dose with zinc was 43% lower than with placebo (Arnold et al., 2011).

The Hair Tissue Mineral Analysis test can be used to measure zinc and copper levels in the body. If these minerals are out of balance, supplementation is a simple correction. Children aged 12 and older should take 30 mg of zinc picolinate, twice daily, with meals. Children aged 6 to 11 years can take 15 mg, twice daily, with meals. It can take three to four months for zinc supplementation to restore a normal copper-zinc balance. Once zinc-copper ratios have been balanced, medication is less likely to cause side effects.

Correcting a child’s unique nutritional imbalances is integral to effectively treating his or her ADHD symptoms. Minerals are essential substances needed for physical and mental health. Zinc and copper are required to create neurotransmitters and are part of our antioxidant defense system protecting cells from free radical damage. Although minerals are crucial for growth and development, they must be maintained in an appropriate balance. Children with ADHD often present with low zinc, high copper, and/or high lead levels. Since zinc, copper, and lead directly affect the brain, these children suffer from inattention, aggression, hyperactivity, and learning problems. Correcting nutrient imbalances through supplementation is a safe and effective strategy to reverse attentional and behavioral symptoms.

Click here to read "Finally Focused: Mineral Imbalances & ADHD (Part 2)"

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References

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