Matthew Pratt-Hyatt, PHD
Rebecca A Haeusler
Kobe C Yuen
William Shaw, PHD
William Shaw, PhD
Concentrations of the dopamine metabolite homovanillic acid, or HVA, have been reported to be much higher in the urine of children with autism compared to controls. In the same study, severity of autism symptoms was directly related to the concentration of HVA. There was a relation between the urinary HVA concentration and increased agitation, stereotypical behaviors, and reduced spontaneous behavior. Furthermore, vitamin B6, which has been shown to decrease autistic symptoms, decreases urinary HVA concentrations. Excess dopamine has been implicated in the etiology of psychotic behavior and schizophrenia for over 40 years. Drugs that inhibit dopamine binding to dopaminergic receptors have been some of the most widely used pharmaceuticals used as antipsychotic drugs and have been widely used in the treatment of autism. Recent evidence reviewed below indicates that dopamine in high concentrations may be toxic to the brain.
Dopamine is a very reactive molecule compared with other neurotransmitters, and dopamine degradation naturally produces oxidative species (Figure 1). More than 90 percent of dopamine in dopaminergic neurons is stored in abundant terminal vesicles and is protected from degradation. However, a small fraction of dopamine is cytosolic, and it is the major source of dopamine metabolism and presumed toxicity. Cytosolic dopamine (Figure 1) undergoes degradation to form 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) via the monoamine oxidase pathway. Alternatively, dopamine undergoes oxidation in the presence of excess iron or copper (common in autism and schizophrenia) to form dopamine cyclized o-quinone, which is then converted to dopamine cyclized o-semiquinone, depleting NADPH in the process. Dopamine cyclized o-semiquinone then reacts with molecular oxygen to form oxygen superoxide free radical, an extremely toxic oxidizing agent. In the process, dopamine cyclized o-quinone is reformed, resulting in a vicious cycle extremely toxic to tissues producing dopamine, including the brain, peripheral nerves, and the adrenal gland.
It is estimated that each molecule of dopamine cyclized o-quinone produces thousands of molecules of oxygen superoxide free radical in addition to depleting NADPH. The o-quinone also reacts with cysteine residues on glutathione or proteins to form cysteinyl-dopamine conjugates (Figure 1). One of these dopamine conjugates is converted to N-acetylcysteinyl dopamine thioether, which causes apoptosis (programmed cell death) of dopaminergic cells. These biochemical abnormalities cause severe neurodegeneration in pathways that utilize dopamine as a neurotransmitter. Neurodegeneration is due to depletion of brain glutathione and NADPH as well as the overproduction of oxygen superoxide free radicals and neurotoxic N-acetylcysteinyl dopamine thioether. In addition, the depletion of NADPH also results in a diminished ability to convert oxidized glutathione back to its reduced form.
What is the likely cause of elevated dopamine in autism? A significant number of studies have documented increased incidence of stool cultures positive for certain species of Clostridia bacteria in the intestine in children with autism using culture and PCR techniques. All these studies have indicated a disproportionate increase in various Clostridia species in stool samples compared to normal controls. In addition, metabolic testing has identified the metabolites 3-(3-hydroxyphenl)-3-hydroxypropionic acid (HPHPA) and 4-cresol from Clostridia bacteria at significantly higher concentrations in the urine samples of children with autism and in schizophrenia.
Treatment with antibiotics against Clostridia species, such as metronidazole and vancomycin, eliminates these urinary metabolites with reported concomitant improvement in autistic symptoms. In addition, I had noticed a correlation between elevated HPHPA and elevated urine homovanillic acid (HVA). The probable mechanism for this correlation is that certain Clostridia metabolites have the ability to inactivate dopamine beta-hydroxylase, which is needed for the conversion of dopamine to norepinephrine (Figure 2).
Such metabolites are not found at only trace levels. The concentration of the Clostridia metabolite HPHPA in children with autism may sometimes exceed the urinary concentration of the norepinephrine metabolite vanillylmandelic acid (VMA) by a thousand fold on a molar basis and may be the major organic acid in urine in those with severe gastrointestinal Clostridia overgrowth, and even exceed the concentration of all the other organic acids combined. Dopamine beta hydroxylase that converts dopamine to norepinephrine in serum of severely retarded children with autism was much lower than in those who were higher functioning. Decreased urine output of the major norepinephrine metabolite meta-hydroxyphenolglycol (MHPG) was decreased in urine samples of children with autism, consistent with inhibition of dopamine beta hydroxylase.
Many physicians treating children with autism have noted that the severity of autistic symptoms is related to the concentration of the Clostridia marker 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) in urine. These are probably the children with autism with severe and even psychotic behavior treated with Risperdal® and other anti-psychotic drugs, which block the activation of dopamine receptors by excess dopamine. I have identified a number of species of Clostridia species that produce HPHPA including C. sporogenes, C.botulinum, C. caloritolerans, C. mangenoti, C. ghoni, C.bifermentans, C. difficile, and C. sordellii. All species of Clostridia are spore formers and thus may persist for long periods of time in the gastrointestinal tracts even after antibiotic treatment with oral vancomycin and metronidazole.
How do the changes in brain neurotransmitters caused by Clostridia metabolites alter behavior? The increase in phenolic Clostridia metabolites common in autism significantly decreases brain dopamine beta hydroxylase activity. This leads to overproduction of brain dopamine and reduced concentrations of brain norepinephrine, and can cause obsessive, compulsive, stereotypical behaviors associated with brain dopamine excess and reduced exploratory behavior and learning in novel environments that are associated with brain norepinephrine deficiency. Such increases in dopamine in autism have been verified by finding marked increases in the major dopamine metabolite homovanillic acid (HVA) in urine. The increased concentrations of HVA in urine samples of children with autism are directly related to the degree of abnormal behavior. The concentrations of HVA in the urine of some children with autism are markedly abnormal.
In addition to alteration of brain neurotransmitters, the inhibition of the production of norepinephrine and epinephrine by Clostridia metabolites may have a prominent effect on the production of neurotransmitters by the sympathetic nervous system and the adrenal gland. The major neurotransmitter of the sympathetic nervous system that regulates the eyes, sweat glands, blood vessels, heart, lungs, stomach, and intestine is norepinephrine. An inadequate supply of norepinephrine or a substitution of dopamine for norepinephrine might result in profound systemic effects on physiology. The adrenal gland which produces both norepinephrine and epinephrine might also begin to release dopamine instead, causing profound alteration in all physiological functions. In addition to abnormal physiology caused by dopamine substitution for norepinephrine and dopamine, dopamine excess causes free radical damage to the tissues producing it, perhaps leading to permanent damage of the brain, adrenal glands, and sympathetic nervous system if the Clostridia metabolites persist for prolonged periods of time, if glutathione is severely depleted, and if there is apoptotic damage caused by the dopamine metabolite N-acetylcysteinyl dopamine thioether.
Depletion of glutathione can be monitored in The Great Plains Laboratory organic acid test by tracking the metabolite pyroglutamic acid, which is increased in both blood and urine when glutathione is depleted. In addition, The Great Plains Laboratory also tests the other molecules involved in this toxic pathway, the dopamine metabolite homovanillic acid (HVA), the epinephrine and norepinephrine metabolite VMA and the Clostridia metabolites HPHPA and 4-cresol.
In summary, gastrointestinal Clostridia bacteria have the ability to markedly alter behavior in autism and other neuropsychiatric diseases by production of phenolic compounds that dramatically alter the balance of both dopamine and norepinephrine. Excess dopamine not only causes abnormal behavior but also depletes the brain of glutathione and NADPH and causes a vicious cycle producing large quantities of oxygen superoxide that causes severe brain damage. Such alterations appear to be a (the) major factor in the causation of autism and schizophrenia. The organic acid test (see sample organic acid test report below) now has the ability to unravel a major mystery in the causation of autism, schizophrenia, and other neuropsychiatric diseases, namely the reason for dopamine excess in these disorders.
In the past, some physicians would order the organic acid test once a year or less. With the new knowledge of the mechanism of Clostridia toxicity via inhibition of dopamine beta-hydroxylase, it seems that the control of such toxic organisms needs to monitored much more frequently to prevent serious brain, adrenal gland, and sympathetic nervous system damage caused by excess dopamine and oxygen superoxide. Below is a test report of a child with autism tested with The Great Plains Laboratory Organic acid test.
DISCUSSION OF PATIENT RESULTS
In the graph above, the vertical bar is the upper limit of normal and the patient’s value is plotted inside a diamond (red for abnormal, black for normal). The above results were from a boy with severe autism. The HPHPA Clostridia marker was very high (979 mmol/mol creatinine), about 4.5 times the upper limit of normal. However, the metabolite due to Clostridium difficile was in the normal range, indicating that Clostridium difficile was unlikely to be the Clostridium bacteria producing the high HPHPA. In other words, a different Clostridia species was implicated. The major dopamine metabolite homovanillic acid (HVA) was extremely high (87 mmol/mol creatinine), almost 7 times the upper limit of normal. The major metabolite of epinephrine and norepinephrine, VMA was in the normal range. The HVA/VMA ratio was 15, more than five times higher than the upper limit of normal, indicating a severe imbalance in the production of epinephrine/norepinephrine and that of dopamine. The very high dopamine metabolite, HVA, indicates that the brain, adrenal glands, and sympathetic nervous system may be subject to severe oxidative stress due to superoxide free radicals and that brain damage due to severe oxidative stress might result if the Clostridia bacteria are left untreated. Below the same patient’s results are displayed in a form that is related to the metabolic pathways. This graphical result now appears on all organic acid results from The Great Plains Laboratory, Inc.
Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010 Jun;13(3):135-43.
James Greenblatt, MD
Misleading Messages: What is the Truth about Cholesterol?
The cultural dogma is that cholesterol is an evil villain that needs to be eradicated for true health. Given the unflagging efforts of the United States medical establishment over the last few decades to lower cholesterol and corresponding media saturation of food and drug promotions boasting cholesterol-lowering effects, it is understandable that most consumers are not concerned about having cholesterol levels that are too low. Clinical practices appear to uphold the belief that “lower is better”, regardless of significant evidence to the contrary. Opposing reports from aggressive cholesterol-lowering methods suggest that, for many patients, the potential cardiovascular benefits may come with unforeseen risks to mental health and behavior. As a matter of fact, in 2012 the FDA was compelled to require black-box warnings on statins as a result of clinical trial outcomes indicating dangerous effects on cognition and psychological symptoms. Further research suggests that while statin drugs and other cholesterol-lowering agents have improved mortality rates for cardiovascular disease, total mortality has not experienced similar reductions, reflecting a rise in death by suicide or other consequence of mental disorders (Sahebzamani, 2013). A prospective six-year cohort study of approximately 500 older adults provided startling data that individuals with lower serum total cholesterol (less than 6 mmol/L) had a higher risk of dying, independent of health or disease status (Tuikkala, 2010).
Cholesterol is a critical component of human biochemistry; indeed, it is so important that it is regularly synthesized by the liver and other organs throughout the body and is continuously recycled. As a key structural constituent of cell membranes, cholesterol is essential for intracellular transport and communication, including signaling between neurons. Synthesis of several hormones and Vitamin D also depend on cholesterol, providing additional clues to the connection between cholesterol and brain health. In addition to other lipid molecules, cholesterol contributes to the approximately 60% dry weight of the brain composed of fat. The brain relies heavily on lipids during growth and development and for optimal daily function, drawing on dietary and endogenous sources to fuel its extreme demands for energy. The increased demand for cholesterol during adolescent brain development underlies the greater risk for psychopathology in teens and young adults. Concurrent anatomical and neurotransmitter changes beginning in childhood persist until roughly age 21, a critical time when psychiatric disorders often erupt (Gogtay, 2004).
Clinical cholesterol panels measure blood lipid levels comprising triglycerides, low-density lipoprotein (LDL), high-density lipoproteins (HDL), and total cholesterol, which is a function of all three. Normal values stretch from 125 to 200 mg/dl, and healthy levels vary by age, gender, race, health status, and family medical history. Although recent media reports dismissed the contribution of high dietary cholesterol to serum status, the debate is far from over and the National Institutes of Health (NIH) continues to recommend dietary restriction of high-cholesterol foods (NIH, 2018). Despite decades of clinical research and practice, experts still do not agree on “optimal” levels for LDL, HDL, or total cholesterol. Medical treatment targets vary from lowering LDL, lowering total cholesterol, or raising HDL, leaving the public more confused than ever and creating a general fear of cholesterol. And while consumers attempt to alter serum cholesterol through dietary and other lifestyle changes, data continue to accumulate showing the detrimental physical and psychological outcomes of fat avoidance.
Like many health paradigms, a reductionist perspective on cholesterol as related only to cardiovascular health has neglected the extensive utility of these important molecules throughout the body. Lipids including cholesterol play fundamental roles in human metabolism, and “healthy” levels can vary widely between individuals based on a complexity of factors. David Horrobin, an ardent medical researcher who devoted much of his career to the relationship between lipids and mental health, developed a substantial hypothesis for the role of dietary fats in human anthropology. He proposed that rapid advances in human evolution that enabled higher intellect and creativity occurred due to increases in fat storage in humans. Focusing on schizophrenia, Horrobin suggested that the genetic factors influencing the severity of schizophrenia symptoms were the same markers that “made us human” (Horrobin, 1998).
Cholesterol’s Role in Mental Health
A significant connection between low cholesterol and poor psychiatric health has been emphasized through decades of observational and retrospective research studies. Correlations with substance abuse, eating disorders, depression, and suicide strongly imply that cholesterol status influences mood and behavior. Inadequate cholesterol levels may represent a shared etiological factor between these conditions and explain the overlapping continuum of pathology. Low cholesterol reduces the function of serotonin, a neurotransmitter responsible for the regulation of emotion and decision-making. Abnormal brain volumes, neural connectivity, and neurotransmitter function are present in patients with depression and eating disorders (Travis, 2015). In Anorexia-Nervosa patients, low serum cholesterol significantly predicts depression, self-injury, and suicidal ideation (Favaro, 2004). Research also suggests that anti-depressant medications may further lower serum cholesterol, counteracting any beneficial mechanisms (Sahebamani, 2003). Lack of impulse control associated with drug addiction may also be attributed to poor cholesterol status. An assessment of cocaine addicts following hospital discharge revealed that lower cholesterol values predicted relapse at each follow-up, suggesting that recovery requires an adequate supply of dietary lipids (Buydens, 2003).
Aggression can describe both physical and psychological behaviors directed towards the self or others, yet each of its manifestations has been linked to cholesterol status. Violent conduct has been related to low cholesterol levels in patients ranging from adolescents with attention-deficit hyperactivity disorder (ADHD) to war veterans with post-traumatic stress disorder (PTSD) (Vilibic, 2014; Virkkunen, 1984). While different genetic and biological mechanisms may be at play, cholesterol’s influence on hormones and neurotransmitters may provide at least one explanatory link (Hillbrand, 1999). Imbalanced neurotransmitters inhibit the normal stress response, triggering expressions of fear at the root of aggressive actions. A 3-month naturalistic observation of pre- and post-discharge psychiatric patients found significant associations between HDL cholesterol levels and violence, building upon more numerous data related to total cholesterol and highlighting HDL as a potential biomarker for risk of violence. The authors reported strong evidence that insufficient cholesterol reduces the transportation capacity of serotonin in the central nervous system, interfering with the limbic brain’s affective and impulse responses (Eriksen, 2017).
One of the most disturbing demonstrations of self-aggression is suicide. A tragically growing public health issue, deaths by suicide are at their highest levels in three decades, increasing 24% between 1999 and 2014 to become the tenth leading cause of death in the United States (Curtin, 2016). Attempts at self-harm and suicide are also rising in the adolescent population, with data suggesting a 65% increase in girls age 13 to 18 and reports of self-injury ranging from 15 to 30% of middle-, high-school, and college age students (Twenge, 2017). Low cholesterol status again emerges as a common thread in otherwise healthy suicidal patients and those with depression and eating disorders, showing associations with abnormal brain volumes and Vitamin D concentrations (Grudet, 2014). In spite of biomarker data obtained from clinical research, suicide prevention through biological strategies remains elusive.
An Integrative Perspective on Cholesterol
Cholesterol levels should be monitored in all patients evaluated for depression, self-injury, and suicidal ideation. With the number of prescriptions to anti-depressants and cholesterol-lowering drugs continuing to rise in patients young and old, it is imperative for clinicians to be aware of the undeniable influence of cholesterol status in both the etiology and treatment of mental health disorders. Based on decades of clinical experience in my integrative psychiatry practice, genetic heritability and dietary cholesterol intake are highly predictive of mental health risk. A family history of aggression, violence, or substance abuse may indicate a heritable metabolic defect affecting normal synthesis and recycling of serum cholesterol and suggesting a need for greater dietary intake. Furthermore, a personal history of trauma, chronic stress, or eating disorders are flags for potential influences on cholesterol metabolism.
While consumption of high-cholesterol foods continues to be vilified in the battle against cardiovascular disease, inadequate dietary cholesterol is often overlooked. Consensus on what represents low total serum cholesterol varies, but the normal range identified by the NIH suggests that levels above 125 mg/dL are adequate in most men and women (NIH, 2018). While many clinicians recommend total cholesterol remain below 150 mg/dL, my concern is triggered in psychiatric patients with levels below 130 mg/dL, particularly in those with restrictive diets or with symptoms of irritability, lack of impulse control, or reckless behavior. In these patients, gradually increasing total serum cholesterol over a period of three to six months has produced clear improvements in mood along with decreases in aggressive tendencies and any drug cravings.
The treatment protocol I have adopted in my integrative psychiatry practice for safely and effectively optimizing total cholesterol levels typically includes a recommendation to increase consumption of organic eggs, one of the richest sources of dietary cholesterol accompanied by protein, B-vitamins, choline, and other nutrients associated with brain health. I also prescribe the use of digestive enzymes that contain lipase to enhance intestinal lipid digestion and absorption. As a second-tier treatment strategy or for patients who avoid or are allergic to eggs, I recommend a supplemental form of cholesterol at a dose based on the individual’s cholesterol status. New Beginnings Nutritionals’ Sonic Cholesterol delivers 250 mg of pure cholesterol per capsule, equivalent to the amount found in a single egg. In addition to symptom monitoring, monthly cholesterol screening is necessary to adjust recommendations and prescriptions as blood levels improve.
It may be medical heresy to advocate for raising cholesterol, but only because of widespread ignorance and stubborn adherence to outdated information and methodology. The World Health Organization predicts that by 2020, the global rate of suicide will increase to a death every 20 seconds, doubling the rate estimated in 2014. This alarming societal epidemic highlighted by recent high-profile deaths and substantial data supporting the prevalence of low cholesterol among mental health patients provides an opportunity to expose a major, potentially preventable risk factor and a simple, straightforward treatment model that may save thousands of lives. As knowledge of the link between diet and the brain grows, now is the time to reverse cholesterol’s erroneous reputation and recognize this essential nutrient as a critical component for mental health.
- Buydens-Branchey, L., & Branchey, M. (2003). Association between low plasma levels of cholesterol and relapse in cocaine addicts. Psychosomatic medicine, 65(1), 86-91.
- Curtin, S. C., Warner, M., & Hedegaard, H. (2016). Increase in suicide in the United States, 1999-2014.
- Eriksen, B. M. S., Bjørkly, S., Lockertsen, Ø., Færden, A., & Roaldset, J. O. (2017). Low cholesterol level as a risk marker of inpatient and post-discharge violence in acute psychiatry–A prospective study with a focus on gender differences. Psychiatry research, 255, 1-7.
- Favaro, A., Caregaro, L., Di Pascoli, L., Brambilla, F., & Santonastaso, P. (2004). Total serum cholesterol and suicidality in anorexia nervosa. Psychosomatic Medicine, 66(4), 548-552.
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- Grudet, C., Malm, J., Westrin, Å., & Brundin, L. (2014). Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood. Psychoneuroendocrinology, 50, 210-219.
- Hillbrand, M., & Spitz, R. T. (1999). Cholesterol and aggression. Aggression and violent behavior, 4(3), 359-370.
- Horrobin, D. F. (1998). Schizophrenia: the illness that made us human. Medical hypotheses, 50(4), 269-288.
- National Institutes of Health. (2018). Cholesterol Levels: What You Need to Know. Medline Plus Website. https://medlineplus.gov/cholesterollevelswhatyouneedtoknow.html#. Accessed 09 June 2018.
- Sahebzamani, F. M., D'Aoust, R. F., Friedrich, D., Aiyer, A. N., Reis, S. E., & Kip, K. E. (2013). Relationship among low cholesterol levels, depressive symptoms, aggression, hostility, and cynicism. Journal of clinical lipidology, 7(3), 208-216.
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- Tuikkala, P., Hartikainen, S., Korhonen, M. J., Lavikainen, P., Kettunen, R., Sulkava, R., & Enlund, H. (2010). Serum total cholesterol levels and all-cause mortality in a home-dwelling elderly population: a six-year follow-up. Scandinavian journal of primary health care, 28(2), 121-127.
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- Vilibić, M., Jukić, V., Pandžić-Sakoman, M., Bilić, P., & Milošević, M. (2014). Association between total serum cholesterol and depression, aggression, and suicidal ideations in war veterans with posttraumatic stress disorder: a crosssectional study. Croatian medical journal, 55(5), 520-529.
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JAMES GREENBLATT, MD & DESIREE DELANE, MS
The National Institutes for Mental Health provide a succinct definition for schizophrenia as periods of psychosis characterized by disturbances in thought and perception and disconnections from reality; however, diagnosis is much less straightforward. Schizophrenia represents a wide illness spectrum with symptomatic features and severity ranging from odd behavior to paranoia. With a prevalence rate over the past century holding steady at 1% worldwide and immovably poor patient outcomes, schizophrenia delivers profound relational and societal burdens, proving to be a complex clinical challenge and an unyielding epidemiological obstacle.
Gluten as a Trigger for Psychosis
Although the role of food hypersensitivities in disease pathologies is highly controversial in the medical community, many recognize a parallel rise with dietary evolution in modern history. Major shifts from ancestral diets largely absent of wheat or dairy to one with these as foundational components generate reasonable arguments on their implications for human health. Industrialized food systems that streamline the way foods are grown, processed, and stored are often charged with altering their very nature down to its most infinitesimal molecules. Yet, despite their diminutive size, micronutrients from food are essential to the complex processes and interactions that represent optimal health.
Intolerance to gluten represents one of the most prominent food hypersensitivities arising in recent history, delivering profound impacts to both physical and mental health. As the most severe reaction to gluten, Celiac Disease (CD) affects a growing population of men and women in the United States. Unfortunately, an estimated 83% of cases remain undiagnosed or wrongly diagnosed with other conditions. Like other autoimmune diseases, CD is a factor of underlying genetic susceptibility combined with environmental pressures. Sometimes remaining non-symptomatic for years, CD progressively damages the lining of the intestine, eventually presenting with severe gastrointestinal symptoms including gas, bloating, diarrhea, and constipation. One of the most dangerous consequences is that digestion and absorption become impaired, resulting in malnutrition and increasing requirements for several key nutrients. Furthermore, chronic, subtle inflammation keeps the immune system on high alert, promoting an environment of oxidative stress in which free radicals wreak havoc throughout the body. By elevating the body’s overall inflammatory status, CD and other immune-mediated food allergies trigger not only immediately apparent physical symptoms, but also biochemical imbalances that alter brain function. Notably, data showing that CD is often incorrectly and inconsistently diagnosed suggests that mental symptoms are often misinterpreted or overlooked.
A separate byproduct of gluten metabolism poses another, possibly more dramatic and direct, threat to brain function. Gliadorphin, a peptide fragment produced through the breakdown of gluten, directly accesses the brain and attaches to opiate receptors. Neuropeptides including gliadorphin and casomorphin, a structurally similar byproduct of dairy, mimic and interfere with normal neurotransmitter communication, producing significant mental symptoms ranging from fatigue and brain-fog to hallucinations and aggression. Like the opiate drugs morphine and heroin, food-derived opiates hold strongly addictive properties as they promote reward, sedation, and satiety. Sensitive individuals are typically marked by excessive cravings and dependence on food sources of gliadorphin and casomorphin, that manifest in difficulties regulating mood and behavior when levels are depleted. Fortunately, mental health practitioners have begun to recognize the contribution of neuropeptides in many psychiatric conditions.
Gluten, Gliadorphin, & Schizophrenia
Like Celiac disease, experts agree that schizophrenia has both genetic and environmental contributors, and evidence even suggests that overlapping genetic risk factors may underlie a shared susceptibility for schizophrenia and Celiac disease. A 2004 Danish case-control study indicated that individuals with a history of Celiac disease may have a 3x greater risk of developing schizophrenia. Additionally, short-term immune-related exposures during gestation or early life can have long-term consequences for the brain by inducing permanent DNA modifications. Maternal or post-natal illnesses and infections have all been linked to a greater risk for psychosis and schizophrenia. Excessive immune activation during these critical developmental periods can also influence the body’s response to potential food allergens. From the other direction, schizophrenia and psychosis may invoke unique immune mechanisms influencing an individual’s reactivity to gluten.
Remarkably, the relationship between gluten and psychosis appears to go beyond Celiac disease. Elevated levels of gliadorphin have consistently been measured in patients with schizophrenia, autism, attention-deficit-hyperactivity disorder, depression, and other psychiatric conditions. Abnormally low activity of the dipeptidyl peptidase IV (DPP-IV) enzyme, involved in the breakdown of gluten, offers a potential link. A clinical study in roughly 60 patients with schizophrenia or depression suggested that significant alterations in DPP-IV activity characterized patients with schizophrenia. The prevalence of elevated gliadorphin and other opiate peptides in psychosis patients has led some researchers to believe that these psychoactive substances carry unique information to the brain that influence disease development.
Without normal breakdown of gliadorphin by DPP-IV, neurotoxic levels accumulate and produce psychoactive effects. Significant behavioral alterations in animal models given food-based neuropeptides reflect symptoms of psychosis that were reversible by pre-treatment with opiate-blocking drugs. Human patients with elevated urinary gliadorphin also demonstrate clinical behavioral improvements when gluten and other sources of “dietary morphine” are removed from the diet. DPP-IV also modulates the activation and proliferation of CD4+ immune cells, providing an additional mechanistic explanation for the excessive inflammation characteristic of both Celiac disease and schizophrenia. Finally, normal DPP-IV activity depends on adequate zinc and other nutrients, common casualties of poor intestinal function.
A New Approach to Schizophrenia Treatment
Despite evidence-based attempts to address the diverse spectrum of physical and mental impairments associated with schizophrenia, weak progress has been made over the last 100 years. The rapid, clear clinical responses of antipsychotic drugs introduced in the 1950s and 1960s once appeared to offer miraculous promise to those suffering with psychotic illness. At least 70 different medications have been developed targeting similar biochemical pathways and are firmly established as first-line therapies. Modern antipsychotics can be profoundly useful with skillful use in the initial stages of illness, particularly for severe cases. But it is no secret that these medications are rarely, if ever, totally effective, have no influence on negative or cognitive symptom categories, and bring debilitating side effects requiring further drug interventions.
A growing wealth of theory and data links nutrition and mental health, yet mainstream psychiatry remains stubbornly fixated on the status quo. Clinical studies suggest that nutrient requirements in schizophrenia patients exceed generally recommended levels, whether due to poor diet, impaired intestinal function, or genetically induced metabolic differences. A 2018 systematic review by Firth, et al., of 11 studies in early-stage psychosis patients found deficiencies in antioxidants, amino acids, and polyunsaturated fatty acids. This recent evidence lends significant support for assertive nutrient-based approaches to schizophrenia treatment, particularly as preventive strategies in high-risk patients.
Normal mental processes require tightly-controlled amounts of B-vitamins, antioxidants, lipids, and many other dietary nutrients as key enzymatic components for neural growth, communication, and protection. On top of the potentially toxic effects of gluten and its byproducts on some individuals, malabsorptive conditions resulting from food sensitivities or Celiac disease further reduce the bioavailability of these critical nutrients to the brain and exacerbate the biochemical imbalances that drive psychiatric illness. Resulting from this malnourished state, neurotransmitter dysfunction and miscommunication dramatically alter sensory perception and distort a patient’s experience of reality, manifesting in abnormal behavior and social dysfunction.
Nutritional and other integrative therapies provide the body and brain with optimal and familiar tools for self-healing. By addressing the origins of symptoms first, medications can be employed as second-tier strategies that support rather than direct treatment. The treatment paradigm for schizophrenia must be expanded to adopt strategies for early recognition and prevention and incorporate holistic therapies that empower patients to be involved in their recovery. Long-term dietary changes, including removal of gluten, and nutritional supplements facilitate recovery and promote resilience and self-care. The integrative care model for mental health care aims not at just the absence of disease, but for healthy minds, bodies, and futures with hope for independence, happiness, and fulfillment.
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Kurt Woeller, D.O.
Organic acids testing is diagnostic tool that every healthcare practitioner should know about. Whether you are a family practitioner, psychiatrist, a nutritionist, or other type of practitioner, the information provided by organic acids testing can help identify underlying causes of a variety of chronic illnesses, including the symptoms of autism, neuropsychiatric disorders like depression and anxiety, and neurodegenerative disorders like Alzheimer’s disease. Below is a review of some of the most clinically significant markers measured with organic acids testing to mental health and the health of the brain in general.
Many of the case studies reviewed in presentations about organic acids testing involve patients with autism. While autism may not typically be considered a mental health disorder, it is a neurodevelopmental disorder and many autistic individuals suffer with mental symptoms such as anxiety and depression, along with associated behavioral problems. Many patients with autism also have mitochondrial dysfunction and chronic infections (like Candida and clostridia), which are measured with organic acids testing. (1)
Mitochondria are linked to every organ system in the body, including the brain, and there markers for mitochondrial function in organic acids testing. Without adequate mitochondrial function, neurons cannot function appropriately to produce neurochemicals such as dopamine and serotonin. Mitochondria are damaged by various endogenous toxins produced by Candida (a fungus) such as tartaric acid and citramalic acid. Also, certain clostridia bacteria produce propionic acid which damages mitochondria. Candida and clostridia are both measured with organic acids testing. Mitochondria are also damaged by oxalate, which is produced by Candida and some molds, and is also measured with organic acids testing. Certain molds like Aspergillus produce mycotoxins which directly damage mitochondria. Organic acids testing specifically measures candida toxins, bacteria toxins, and mold toxins, along with mitochondria markers. (2, 3)
Clostridia bacteria can produce various compounds like HPHPA, 4-Hydroxyphenylacetic acid and 4-Cresol (all measured with organic acids testing), and are known to inhibit dopamine metabolism. These chemicals inhibit Dopamine-Beta Hydroxylase which causes neuronal dopamine levels to rise. This has been associated with paranoia and schizophrenia. Also, the breakdown products of dopamine are neurotoxic and cause brain receptor damage. Chronic infections and the compounds produced from them such as bacteria lipopolysaccharides (LPS), along with elevated cortisol (seen in hypothalamic-pituitary-adrenal dysfunction), viral infections, and beta-amyloid and niacin deficiency (seen in schizophrenia) can trigger tryptophan metabolism problems. Tryptophan is the amino acid precursor to serotonin. In the presence of these chronic stressors, tryptophan conversion to serotonin is reduced. This can lead to depression and anxiety. Elevated tryptophan metabolites can lead to increased quinolinic acid (QA). (4)
Quinolinic acid is neurotoxic and measured with organic acids testing. It is an NDMA receptor agonist, which is linked to various mental health disorders (anxiety, depression, suicidal ideation) and chronic neurodegenerative diseases (Alzheimer’s, Huntington’s). Quinolinic acid can also block acetylcholine production (linked to memory) and gamma-amino-butyric acid (which can trigger anxiety and panic). (5)
The aforementioned markers in organic acids testing are some of the most clinically significant to mental health and brain function, though there are many other examples. This information is critical for mental health professionals to help deepen their knowledge about sophisticated testing and advanced solutions for patient intervention.
- Shaw, W., et. al. Increased Urinary Excretion of Analogs of Krebs Cycle Metabolites and Arabinose in Two Brothers with Autistic Features. Clin Chem 41:1094-1104, 1995.
- Shaw, W., et. al. Assessment of antifungal drug therapy in autism by measurement of suspected microbial metabolites in urine with GC/MS. Clinical Practice of Alternative Medicine: 15-26.
- Persico AM, et. al. Urinary p-cresol in autism spectrum disorders, Neurotoxicol Teratol. 2013 Mar-Apr;36:82-90, 2012 Sep 10.
- Heyes MP, et. al. A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate. Brain. 1993 Dec;116 (pt 6):1425-50.
- Ganiyu Oboh, et. al. Anticholinesterase and Antioxidative Properties of Aqueous Extract of Cola acuminata Seed In Vitro. Int J Alzheimers Dis. 2014; 2014: 498629.
James Greenblatt, MD
While it is human nature to occasionally ruminate or overanalyze important decisions, these thought patterns normally dissipate quickly freeing us of those fleeting moments of inner turmoil. However, for those suffering from Obsessive Compulsive Disorder (OCD), letting go of repetitive thoughts is not so effortless. Relentless ideas, impulses, or images inundate the brain leaving the individual mentally imprisoned to an existence of recurrent, irrational thought patterns. These senseless obsessions often drive the individual to perform ritualistic behaviors or compulsions, in an effort to temporarily relieve their anxiety. Sufferers stagger through life with a sense of pure powerlessness against their disorder; fully aware that the behavior is abnormal, yet unable to stop.
Psychotropic medications such as selective serotonin reuptake inhibitors (SSRI’s) and Anafranil and cognitive behavioral therapy are the conventional treatment options for Obsessive Compulsive Disorder. Sadly, the likelihood of complete recovery from OCD has not been shown to exceed 20% and relapse is quite common. Inadequate treatment and limited biomedical options contribute to the high relapse rate as conventional medicine does not address underlying nutritional deficiencies or the root cause. Though unlikely to be caused by deficiencies alone, addressing vital nutrient depletions is a critical aspect of treating OCD since certain vitamins, minerals, and amino acids significantly impact serotonin neurotransmission. Specifically, natural therapies including: 5-HTP, niacin (B3), pyridoxal-5-phosphate (B6), folate (5-MTHF), vitamin C, zinc, magnesium, inositol, and taurine are important to serotonin synthesis. Therefore, the combination of aforementioned nutrients taken in therapeutic dosages should be part of integrative treatment approach for Obsessive Compulsive Disorder.
The fourth most common psychiatric illness in the United States, Obsessive Compulsive Disorder or “OCD” onset typically occurs by adolescence usually between the ages of 10-24, with one third of all cases appearing by age 15. In fact, OCD is said to be more common than asthma and diabetes (Schwartz, 1997). Despite its prevalence, it is often under diagnosed and under treated with more than half of those suffering receiving no treatment at all for their condition. Gender does not affect susceptibility, as men and women are equally affected by this detrimental disorder.
To fully grasp the inner workings of OCD, consider Jeffrey Schwartz’s description of “Brain Lock” (Schwartz, 1997) where four key structures of the brain become locked together sending false messages that the individual cannot interpret as false. The brain is made up of two structures called the caudate nucleus and the putamen, which can be compared to a gearshift in a car. According to Schwartz, “The caudate nucleus works like an automatic transmission for the front, or thinking part, of the brain…the putamen is the automatic transmission for the part of the brain that controls body movements… the caudate nucleus allows for the extremely efficient coordination of thought and movement during everyday activities. In a person with OCD, however, the caudate nucleus is not shifting gears properly, and messages from the front part of the brain get stuck there. In other words, the brain’s automatic transmission has a glitch. The brain gets ‘stuck in gear’ and can’t shift to the next thought” (Schwartz, 1997).
It is clear that enhancing serotonin neurotransmission through psychotropic medications helps the brain “shift into gear” so to speak. But what exactly causes this glitch that leads to serotonin deficiency syndrome? A number of factors including genes, diet, stress, neurotoxins, and inflammation are responsible for inadequate serotonin synthesis. Amino acid availability for neurotransmitter synthesis is dependent upon certain digestive enzymes, and their activation is dependent on hydrochloric acid. Without sufficient amino acid availability, neurotransmitter synthesis will suffer. Specifically, availability of the essential amino acid L-tryptophan is required for serotonin production. Because serotonin synthesis depends on the availability of L-tryptophan and essential cofactors including vitamin B3, folate (5-MTHF), vitamin B6, and zinc, serotonin levels will be less than optimal if any of the required building blocks are deficient. The process of serotonin synthesis starts when L-tryptophan is converted into 5-hydroxytryptophan with the help of tryptophan hydroxylase (a vitamin B3 dependent enzyme), which requires 5-MTHF. 5-hydroxytryptophan (5-HTP) then converts to serotonin with the aid of decarboxylase, vitamin B6 dependent enzymes, and zinc.
Supplemental 5-hydoxytryptophan (5-HTP) can be beneficial for individuals as it essentially bypasses the need for L-tryptophan availability. Easily crossing the blood brain barrier, 5-HTP works like a targeted missile directly increasing brain serotonin levels. It does not require a transport molecule for crossing the blood brain barrier, and unlike L-tryptophan, it is shunted from incorporation into proteins and niacin conversion (Birdsall, 1998). What’s more, promising research indicates that the therapeutic effect of 5-HTP compared to fluoxetine (Prozac), is actually equal (Jangid et al., 2013). Antidepressant effects are experienced in as little as two weeks with 5-HTP; effectively treating individuals with varying degrees of depression (Jangid et al., 2013).There has been four research studies looking at 5-HTP supplements specifically for OCD. Clinicians around the globe, for more than twenty years, have had success with amino precursors including 5-HTP for the treatment of OCD. I recommend starting all patients with 50 mg of 5-HTP and titrate slowly every 2 weeks up to a maximum of 200 mg per day. Side effects of 5-HTP include nausea, irritability, and possible anxiety.
In addition to the influence of digestive health on serotonin synthesis, absorption of vital minerals specifically zinc and magnesium, are also impacted by Hydrochloric Acid (HCL) availability. Thus, if HCL and digestive enzyme production is low, mineral deficiencies will likely follow. This is worth noting because optimal levels of zinc and magnesium are imperative to maintaining healthy serotonin levels, while moderating the activity of glutamate receptors. As stated previously, zinc is an important coenzyme required for decarboxylase activation and the conversion of 5-HTP to serotonin. Magnesium also plays an essential role, aiding the conversion process of L-tryptophan to serotonin.
In addition to zinc and magnesium, folate plays a critical role in serotonin neurotransmission. Specifically, the enzyme responsible for converting L-tryptophan to 5-HTP, requires 5-MTHF, also known as “L-Methylfolate.” Without sufficient folate, L-tryptophan will struggle to convert to 5-HTP. Research on depression and folate is extensive; hundreds of studies support the relationship between folate and depression. Thus, it is imperative to consider folate status when treating OCD. Specifically, low folate levels are associated with increased incidence of depression, poor response to antidepressants, and higher relapse rates. Because dietary sources of folate are heat labile and easily oxidized (more than 50% is oxidized during food processing) folate malabsorption and deficiency is quite prevalent in our society. To make matters worse, individuals taking certain medications such as anticonvulsants, oral contraceptives, antacids, antibiotics, and Metaformin are at increased risk of deficiency.
Individuals that possess genetic polymorphisms in the gene coding for the methylenetetrahydrofolate reductase (MTHFR) gene are at high risk for low folate status due to reduced ability to convert folic acid to its active form. Folic acid requires a four step transformation process to be converted to L-methylfolate, where dietary folate requires three steps. MTHFR polymorphisms reduce efficiency of this transformation process; severely impacting conversion of folic acid to L-methylfolate. Since L-methylfolate is the active absorbable form of folate that crosses the blood brain barrier for use, inability to properly convert dietary or supplemental folic acid may cause folate deficiency (Lewis et al., 2006).
Inositol has proven particularly effective for SSRI resistant patients as well. Specifically, OCD patients experiencing lack of response to SSRI’s or clomipramine have been examined. There are research studies demonstrating dosages of 18/gms of inositol per day was effective in OCD treatment. Improvement in symptoms had been reported at 6 weeks of treatment with no reported side effects (Fux et al., 1996). A promising finding, inositol is an effective natural therapy for OCD treatment when taken on its own. It is particularly helpful to individuals who are unresponsive to conventional SSRI treatment. However, at this time use of inositol as an augmentation agent to improve SSRI function has not been proven effective (Fux et al., 1999).
Inositol’s effect on treatment resistant patients is likely due to its role in the neurotransmission process. Operating as a secondary messenger, it enhances the sensitivity of serotonin receptors on the postsynaptic neuron using signal transduction. Upon binding to its receptor, messages from serotonin are then translated into signals that are expressed through behaviors such as positive mood, relaxation, and reduced obsessions. Due to its role in serotonin signaling, patients resistant to SSRI treatment may not necessarily have an issue with serotonin synthesis but rather decreased receptor sensitivity.
Controlled trials of inositol have confirmed therapeutic effects in a wide spectrum of psychiatric illnesses generally treated with SSRI’s including: OCD, Major Depressive Disorder, Panic Disorder, and Bulimia. In particular, children exhibiting OCD symptoms have shown considerable life altering improvements with inositol treatment. For instance, “S.M.” a socially withdrawn, 11 year old child who obsessively feared fire and contamination, transformed into a “completely different child” with inositol treatment. Similarly, “P.J.”, treated with inositol and 5-HTP, showed significant improvement in OCD symptoms. A third clinical case, “C.K.” had suffered immensely with severe adverse side effects to Celexa and Prozac including aggressive thoughts of self-harm. Upon treatment with inositol, no side effects were reported and minimal improvement was even displayed. Even though research studies suggest 18 grams of Inositol per day, I start all patients with OCD on approximately 3 grams of Inositol per day (1/2 Tsp. 3 times per day).this minimizes GI side effects including bloating and nausea. If needed, Inositol dosages can be titrated up slowly with most patients responding below 12 grams per day.
Improving serotonin production and neurotransmission is integral to boosting serotonin levels and combating symptoms of OCD. However, preventing over-activity of neurotransmitters should also be considered. Taurine is an essential amino acid and precursor to GABA, an inhibitory neurotransmitter. A regulatory agent, GABA helps maintain healthy serotonin levels and reuptake. Widely known for its calming effect, taurine’s therapeutic use for anxiety and depression treatment has been explored. In one study, animals fed a high taurine diet for 4 weeks exhibited anti-depressive behavior (Caletti, 2015). Furthermore, a study on mice indicated a reduction in anxiety where taurine was administered 30 minutes before anxiety tests (Kong et al., 2006). Though taurine does not directly target serotonin production, it is still worth noting as its inhibitory effect may reduce racing thoughts associated with anxiety disorders such as OCD.
Based on extensive scientific evidence supporting the relationship of aforementioned nutrients to serotonin production, as well as decades of clinical experience, I developed SeroPlus (https://www.nbnus.net/). SeroPlus is a nutritional supplement to help patients with OCD and depression. The formula provides serotonin building blocks including therapeutic doses of 5-HTP (direct precursor to serotonin), Inositol, and Taurine in addition to vital cofactors magnesium, vitamin C, pyridoxal-5- phosphate (activated B6), and Metafolin® (activated folate). Inositol elevates sensitization of serotonin receptors while taurine maintains healthy sympathetic nervous system tone and moderates serotonin activity and reuptake. The formula also includes niacin and zinc picolinate which enhance availability of 5-HTP by reducing the amount of 5-HTP used for activation and absorption of these nutrients. Synergistically, these ingredients work effectively together to optimize serotonin production and restore healthy serum levels of common deficiencies contributing to abnormalities in serotonin neurotransmission.
As with any psychiatric illness, treating OCD is complex and requires a comprehensive multi-prong approach beyond basic SSRI prescriptions and behavioral therapy. Although directly enhancing serotonin production through natural therapies such as 5-HTP as well as correcting underlying B3, B6, zinc, magnesium, folate, and inositol deficiencies is at the heart of integrative treatment there are a number of alternative factors that may be contributing to the cause. Low levels of B12, DHA, and vitamin D must be addressed.
A prisoner to their own thoughts, OCD sufferers are frustrated and searching for alternative treatment options. The complex etiology of OCD includes genetics, inflammation, and the dysfunction of serotonin synthesis. While SSRI’s may enhance serotonin synthesis, a number of OCD patients do not experience long term results. Thus, identifying key nutrient depletions and replenishing them through dietary modification and supplementation is essential to increasing chances of long term recovery.
James M. Greenblatt, MD, is the author of Finally Focused: The Breakthrough Natural Treatment Plan for ADHD (Harmony Books, 2017). He currently serves as Chief Medical Officer and Vice-President of Medical Services at Walden Behavioral Care, and he is an Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth Geisel School of Medicine. An acknowledged expert in integrative medicine, 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.JamesGreenblattMD.com
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Caletti. (2015). Antidepressant dose of taurine increases mRNA expression of GABAA receptor α2 subunit and BDNF in the hippocampus of diabetic rats. Behav Brain Res. 2015 Apr 15; 283:11-5.
Fux et al. (1996). Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry, Vol 153(9) 1219-1221.
Fux et al. (1999). Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: a double blind cross-over study. International Journal of Neuropsychopharmacology 2, 193-195.
Jangid et al. (2013) Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. Feb;6(1):29-34
Kong. (2006). Effect of taurine on rat behaviors in three anxiety models. Pharmacol Biochem Behav. Feb; 83(2):271-6.
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Schwartz, Jeffrey M. Brain Lock: Free Yourself from Obsessive-Compulsive Behavior . Harper Perennial; 1st edition, 1997.
James Greenblatt, MD
Every day we are exposed to toxins from our environment. We may ingest lead and copper from drinking water, phosphate from processed food and soda, various synthetic chemicals from plastic food containers, and pesticides from fruits and vegetables. Both natural heavy metals and man-made chemicals disrupt hormones and brain development. The brain, especially the developing brain, is very vulnerable to contaminants because of its large size (relative to total body weight) and its high concentration of fats which serve as a reservoir for toxicants to build up. This article will explain the role that heavy metals and environmental toxins play in ADHD.
In January 2016, President Obama declared a state of emergency in Flint, Michigan where thousands of residents were exposed to high levels of lead in their drinking water. The corrosive water from the Flint River caused lead from old water pipes to leach into the water supply, putting up to 12,000 children at risk of consuming dangerous levels of lead. Lead poisoning can cause irreversible brain damage and even death, and growing children are especially susceptible to its poisonous effects. Even low blood lead levels reduce IQ, the ability to pay attention, motor function, and academic achievement.
Blood lead levels in children have plummeted since the US phased out the use of leaded gas and paint in the 1970’s. Still, 24 million homes in the US contain deteriorated lead paint and elevated levels of lead-contaminated dust. Soil contains lead from air that settled during our previous industrial use. Old toys and toys from China may contain lead-based paint as well. Again, children are especially at risk of lead poisoning in these environments because they are likely to put their contaminated toys or hands in their mouth.
Since lead poisoning causes cognitive, motor, and behavioral changes, it is not surprising that it also causes ADHD. Lead exposure is estimated to account for 290,000 excess cases of ADHD in US children (Braun et al., 2006). A study on 270 mother-child pairs in Belgium found that doubling prenatal lead exposure (measured in cord blood) was associated with a more than three times higher risk for hyperactivity in boys and girls at age 7-8 (Sioen et al., 2013). A larger study on almost 5,000 US children aged 4-15 found children with the highest blood lead levels were over four times as likely to have ADHD as children with the lowest blood lead levels (Braun et al., 2006).
MRI scans from participants of the Cincinnati Lead Study had striking results: childhood lead exposure was associated with brain volume loss in adulthood. Individuals with higher blood lead levels as children had less gray matter in some brain areas. The main brain region affected was 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, many studies have shown lead levels <5 μg/dL still pose problems. For instance, researchers assessing 256 children aged 8-10 concluded, “even low blood lead levels (<5 μg/dL) are associated with inattentive and hyperactivity symptoms and learning difficulties in school-aged children” (Kim et al., 2010).
Copper is an essential trace mineral we must consume from our food supply. It is found in oysters and other shellfish, whole grains, beans, nuts, and potatoes. Like lead, copper can leach into the water supply when copper pipes corrode. One of copper’s roles in the body is to help produce dopamine, the neurotransmitter that provides alertness. 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. In children with excess copper, stimulant medications don’t work as well and tend to cause side effects (agitation, anxiousness, change in sleep and appetite). Most ADHD medications work by increasing levels of dopamine, intensifying the effects of excess copper. In addition, excess copper blocks the production of serotonin, a mood-balancing neurotransmitter. This triggers emotional, mental, and behavioral problems, from depression and anxiety to paranoia and psychosis.
The neurotoxic effects of excess copper are well known and a few studies have assessed copper’s role in ADHD symptoms. When researchers compared copper levels in 58 ADHD children to levels in 50 control children, they observed that copper levels were higher in ADHD children. ADHD children also had a higher copper-to-zinc ratio that positively correlated with teacher-rated inattention (Viktorinova et al., 2016). Researchers in Belgium measured the heavy metal exposure of 600 adolescents aged 13-17. They found that an increase in blood copper was associated with a decrease in sustained attention and a decrease in short-term memory. This held true even though this population had normal copper levels (Kicinski et al., 2015). In a randomized controlled trial on 80 adults with ADHD, lower baseline copper levels were associated with better response to treatment with a vitamin-mineral supplement. Among those in the highest copper tertile, only 35% were responders compared to 77% in the middle copper tertile (Rucklidge et al., 2014).
Phosphate is a charged particle (an electrolyte) that contains phosphorus. Phosphorus is the second most abundant mineral in the body (the first is calcium). Phosphorus is a building block for bones and about 85% of total body phosphorus is found in the bones. Deficiencies are rare because phosphorus is naturally abundant in protein-rich foods like meat, poultry, fish, eggs, milk, and milk products as well as in nuts, legumes, cereals, and grains. Although phosphorus is an essential nutrient, too much can be problematic. The phosphate content of processed foods is much higher than that of natural foods, because phosphates are commonly used as additives and preservatives in food production. Our daily intake of phosphate food additives has more than doubled since the 1990’s (Ritz et al., 2012). Phosphorus, especially the form found in processed meats, canned fish, baked goods, and soda is quickly absorbed into the bloodstream so levels can rise rapidly.
Phosphorus reduces the absorption of other vital nutrients, many of which ADHD children are deficient in to begin with. For instance, too much phosphorus can lower calcium levels. High phosphorus coupled with low calcium intake leads to poor bone health. The typical American diet contains two to four times more phosphorus than calcium and soda is often a major contributor to this imbalance. In the body, phosphorus and magnesium bind together, making both minerals unavailable for absorption. This is most apparent when magnesium consumption is low and intake of phosphorus is high. Researchers have found that adding Pepsi to men’s diet for two consecutive days causes their blood phosphate levels to increase and their magnesium excretion to decrease (Weiss et al., 1992).
In the 1990’s, German pharmacist Hertha Hafer discovered that excess dietary phosphate triggered her son’s ADHD symptoms. Within her book, The Hidden Drug, Dietary Phosphate: Cause of Behavior Problems, Learning Difficulties and Juvenile Delinquency, she presents a low phosphate diet as a treatment for ADHD. A low phosphate diet led to dramatic improvements in her son’s behavior, well-being, and school performance, rendering medication unnecessary. Her family’s ADHD problem was resolved and her son had no further problems as long as he avoided high phosphate foods. Hafer finds that children with mild ADHD can improve simply by removing processed meats and phosphate-containing beverages like soda and sports drinks from their diets (Waterhouse, 2008).
Everyday plastic products contain hormone-disrupting chemicals, such as Bisphenol A (BPA) and phthalates, that can migrate into our body and affect the brain and nervous system. These environmental toxins bind to zinc and deplete zinc levels in the body. Phthalates are synthetic chemicals used to make plastics soft and flexible. Phthalates are used in hundreds of consumer products and humans are exposed to them daily though air, water, and food. Di(2-ethylhexyl) phthalate (DEHP) is the name for the most common phthalate. It can be found in products made with plastic such as tablecloths, floor tiles, shower curtains, garden hoses, swimming pool liners, raincoats, shoes, and car upholstery. Based on animal studies, the Environmental Protection Agency (EPA) has classified DEHP as a “probable human carcinogen.” Such studies have shown that DEHP exposure affects development and reproduction.
Multiple studies have linked phthalates with ADHD. Researchers assessed the urine phthalate concentrations and ADHD symptoms in 261 children aged 8-11. ADHD symptoms (inattention and hyperactivity/impulsivity), rated by the children’s teachers, were significantly associated with DEHP metabolites (breakdown products) (Kim et al., 2009).
Prenatal phthalate exposure is associated with problems in childhood behavior and executive functioning. Third-trimester urines from 188 pregnant women were collected and analyzed for phthalate metabolites. Their children were assessed for cognitive and behavioral development between the ages of 4 and 9. Phthalate metabolites were associated with worse aggression, conduct problems, attention problems, depression, externalizing problems, and emotional control (Engel et al., 2010).
Exposure to DEHP in pediatric intensive care units (PICU) is associated with attention deficits in children. In the hospital, DEHP can be found in and can leach from medical devices such as catheters, blood bags, breathing tubes, and feeding tubes. Researchers in Belgium measured levels of DEHP byproducts in the blood of 449 children aged 0-16 while they were staying in a pediatric intensive care unit. Four years later, the children’s neurocognitive development was tested and compared to that of healthy children. The researchers found that all medical devices inserted into the body actively leached DEHP. Predictably, hospitalized children had very high levels of DEHP byproducts throughout their stay in the intensive care unit. A high exposure to DEHP was strongly associated with attention deficit and impaired motor coordination four years after hospital admission. Phthalate exposure from the PICU explained half of the attention deficit in post-PICU patients (Verstraete et al., 2016).
BPA is another problem chemical which is found in food and drink packaging. Exposure to BPA may be related to behavior problems in children. A 2016 nationwide study of 460 children aged 8-15 found children with higher urinary levels of BPA had over five times higher odds of being diagnosed with ADHD (Tewar et al., 2016). In another study, researchers measured BPA concentration in urine samples from women at 27 weeks of pregnancy then assessed the behavior of their children at age 6-10. There was a significant positive association in boys between prenatal BPA concentration and internalizing and externalizing behaviors, withdrawn/depressed behavior, somatic problems, and oppositional/defiant behaviors. Researchers speculated that BPA may have disrupted maternal thyroid or gonadal hormones which are critical to proper brain development (Evan et al., 2014).
In addition to heavy metals and plasticizers, pesticides can cause ADHD symptoms. The American Academy of Pediatrics notes, “Children encounter pesticides daily in air, food, dust, and soil. For many children, diet may be the most influential source. Studies link early-life exposure to organophosphate insecticides with reductions in IQ and abnormal behaviors associated with ADHD and autism” (Roberts & Karr, 2012).
Among pesticides, insecticides may be the most harmful to humans. Insecticides were first developed during World War II as nerve gases. They work by targeting and destroying acetylcholinesterase, an enzyme that controls the neurotransmitter acetylcholine which plays a role in attention, learning, and short-term memory. In one study of 307 children aged 4-9, researchers found that lower acetylcholinesterase activity in boys was linked to a four times greater risk of poor attention and executive function and a six times greater risk of memory and learning problems (Suarez-Lopez et al., 2013). Organophosphates (OPs) are a common type of insecticide that target the nervous system. Forty different types of organophosphates are in use in the United States.
Scientists in California studied 320 mothers and their children. They evaluated urinary levels of metabolites of OPs when the mothers were pregnant. Then when the children were 3- and 5- years old, they were evaluated for ADHD. At both time points, levels of prenatal OP metabolites were positively associated with attention problems and ADHD. Children with mothers who had the highest levels of the OP metabolites were five times more likely to develop ADHD (Marks et al., 2010).
Even organophosphate exposure at low levels common among US children may contribute to ADHD prevalence. Researchers at Harvard University studied more than 1,000 children aged 8-15 from the general population and found that those with detectable urinary levels of an OP metabolite were nearly twice as likely to be diagnosed with ADHD (Bouchard et al., 2010).
- Braun et al (2006). Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environmental Health Perspectives, 114(12), 1904-1909.
- Cecil et al. (2008). Decreased Brain Volume in Adults with Childhood Lead Exposure. PLoS Medicine, 5(5), PLoS Medicine, 2008, Vol.5(5).
- Engel et al. (2010). Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environmental Health Perspectives, 118(4), 565-71.
- Evans et al. (2014). Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. Neurotoxicology, 45, 91-99.
- Kicinski et al. (2015). Neurobehavioral function and low-level metal exposure in adolescents. International Journal of Hygiene and Environmental Health, 218(1), 139-146.
- Kim et al. (2009). Phthalates Exposure and Attention-Deficit/Hyperactivity Disorder in School-Age Children. Biological Psychiatry, 66(10), 958-963.
- Kim et al. (2010). Association between blood lead levels (< 5 μg/dL) and inattention-hyperactivity and neurocognitive profiles in school-aged Korean children. Science of the Total Environment, 408(23), 5737-5743.
- Ritz, et al. (2012). Phosphate additives in food--a health risk. Deutsches Ärzteblatt International, 109(4), 49-55.
- Roberts & Karr. (2012). Pesticide exposure in children. Pediatrics, 130(6), E1765-88.
- Rucklidge et al. (2014). Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement. Progress in Neuropsychopharmacology & Biological Psychiatry, 50, 163-171.
- Sioen et al. (2013). Prenatal exposure to environmental contaminants and behavioural problems at age 7–8years. Environment International, 59, 225-231.
- Suarez-Lopez et al. (2013). Acetylcholinesterase activity and neurodevelopment in boys and girls. Pediatrics, 132(6), E1649-58.
- Tewar et al. (2016). Association of Bisphenol A exposure and Attention-Deficit/Hyperactivity Disorder in a national sample of U.S. children. Environmental Research, 150, 112-118.
- Verstraete et al. (2016). Circulating phthalates during critical illness in children are associated with long-term attention deficit: A study of a development and a validation cohort. Intensive Care Medicine, 42(3), 379-92.
- Viktorinova et al. (2016). Changed Plasma Levels of Zinc and Copper to Zinc Ratio and Their Possible Associations with Parent- and Teacher-Rated Symptoms in Children with Attention-Deficit Hyperactivity Disorder. Biological Trace Element Research, 169(1), 1-7.
- Waterhouse, J.C. (2008). Issue 6. Review of the Book: The Hidden Drug, Dietary Phosphate: Causes of Behaviour Problems, Learning Difficulties and Juvenile Delinquency (2000). SynergyHN. https://synergyhn.wordpress.com/phosphate
- Weiss, G. H., Sluss, P. M., & Linke, C. A. (1992). Changes in urinary magnesium, citrate, and oxalate levels due to cola consumption. Urology, 39(4), 331-333.
James Greenblatt MD, Author of Finally Focused (www.finallyfocusedbook.com), Chief Medical Officer and Vice President of Medical Services at Walden Behavioral Care
It is well known that our food choices play a role in our long-term physical health. It is less recognized that nutrition can have profound effects on our mental health and our behavior. Overall, malnutrition in childhood can affect the brain throughout the lifespan, while specific food components can affect our short-term well-being. Sugar, wheat, and milk are among the most common dietary triggers for ADHD symptoms. Fluctuating blood sugar levels and partially-digested foods can also cause a wide range of symptoms from fatigue to hyperactivity. This article will discuss the dietary influences on behavioral problems in children, review how laboratory testing can be critical in identifying food sensitivities, and how to enhance digestion for maximum absorption of nutrients.
One of the most debated treatments for ADHD is the Feingold Diet, introduced in the early 1970’s by pediatrician and allergist Ben Feingold, MD. He initially suggested that children who are allergic to aspirin (which contains salicylates) may react to artificial food colors and naturally occurring salicylates. The Feingold Diet eliminates artificial food additives like flavorings, preservatives, sweeteners, and colors to reduce hyperactivity. The research over the years on the Feingold Diet has been mixed – some studies show no behavior change and some show increases in hyperactivity when children consume artificial ingredients. A landmark study conducted in the UK on three hundred 3-year-old and 8/9-year-old children in the general population found artiﬁcial colors or a sodium benzoate preservative (or both) in the diet resulted in increased hyperactivity (McCann et al., 2007). This study led the European Union to ask manufacturers to voluntarily remove several artificial food colors from foods and beverages or to add a warning label that the artificial food color “may have an adverse effect on activity and attention in children” (Arnold et al., 2012). Conversely, in the US, the FDA reviewed the study and determined that a causal relationship between consumption of color additives and hyperactivity in children could not be definitively established (Arnold et al., 2012).
Genetics often play a role in how a child’s ADHD symptoms are exacerbated. The children most likely to be affected by food additives have a genetic inability to metabolize the compounds. Genetic tests were conducted on the 300 UK children from the artificial food color study. Children with specific variations in the HNMT gene, which helps break down histamine in the body, had stronger behavioral reactions to artificial food colors than children without this variation (Stevenson et al., 2010). This means that in some children, food additives spur the release of histamine that in turn affect the brain.
The Barbados Nutrition Study was a longitudinal case-control study that began in the late 1960’s and investigated the physical, mental, and behavioral developmental effects of infant malnutrition. The 204 participants of this study experienced a single episode of moderate to severe malnutrition during their first year of life. Data was collected on these children through adulthood and compared to data from healthy children. By the end of puberty, all children completely caught up in their physical growth. However, cognitive and behavioral issues persisted into adulthood.
The consequences of malnutrition in infancy manifested in many ways. IQ scores of the children with a history of malnutrition at age 5-11 were significantly lower than those of the control children. 50% of the malnourished children had scores at or below 90 while only 17% of the control children had scores this low (Galler et al., 1983). According to teacher reports, attentional deficits, including shorter attention span, poorer memory, and more distractibility and restlessness, were found in 60% of the malnourished children compared to only 15% of the controls. They also had worse social skills, general health, sleepiness in the classroom, and emotional stability (Galler et al., 1983). When the children were reassessed on these measures at age 9-15, a history of early malnutrition was still associated with behavioral impairment at school, especially attention deficits (Galler & Ramsey, 1989).
Behavior problems reported by teachers when the participants were aged 5-11 significantly predicted conduct problems at age 11-17 (Galler et al., 2012). Age at 5-11, children malnourished as infants had lower performance on 8 out of 9 academic subject areas. 37 children (36 malnourished, 1 control) were below the expected grade for their age (Galler, Ramsey, & Solimano, 1984). Compared to control children, previously malnourished children at age 5-11 had significantly worse scores on parent-rated measures of good behavior (no antagonism between mother and child, obedience), social skills, mother-child relationship, frustration level, eating habits, sleeping habits, and school avoidance. Compared to their siblings, previously malnourished children had significantly worse scores on social skills, good behavior, helpfulness, mother-child interaction, eating habits, toilet training, and language (Galler, Ramsey, & Solimano, 1985). When the children were reassessed on these measures at age 9-15, the same results were seen, especially for aggression and distractibility (Galler & Ramsey, 1989). Problems with self-regulation, displayed as reduced executive functioning and aggression toward peers, persisted through adolescence (Galler et al., 2011).
Years later when the subjects were aged 37-43, attention problems were assessed using an adult ADHD scale and a computerized test of attention-related problems. There was a higher prevalence of attention deficits in the previously malnourished group relative to controls. 69% of the previously malnourished participants had at least one test score that fell within the clinical range for attention disorders (Galler et al., 2012). Previously malnourished participants also had worse educational attainment and income across the entire 40-year study (Galler et al., 2012).
Multiple connections have been made between sugar, hyperactivity, and the risk for ADHD. In group of almost 400 school-age children, researchers found that children with the greatest “sweet” dietary pattern had almost four times greater odds of having ADHD compared to those who ate sweets (ice cream, refined grains, sweet desserts, sugar, and soft drinks) less often (Azadbakht & Esmaillzadeh, 2012). In a similar study on 1,800 adolescents, having a “Western” dietary pattern (higher intakes of total fat, saturated fat, refined sugars, and sodium) more than doubled the odds of an ADHD diagnosis (Howard et al., 2011). Likewise, a study on 986 children, average age 9 years, found a high intake of sweetened desserts (ice cream, cake, soda) was significantly associated with worse inattention, hyperactivity-impulsivity, aggression, delinquency, and externalizing problems. In contrast, a high-protein diet was associated with better scores on these measures. A high level of sweetened dessert consumption was also associated with lower scores on tests of listening, thinking, reading, writing, spelling, and math (Park et al., 2012).
Certain foods may not only influence behavioral and physical symptoms, but may also modify brain activity. When children aged 6-15 with food-induced ADHD consumed provocative foods, they showed an increase in beta activity in frontotemporal regions during EEG topographic mapping of brain electrical activity (Uhlig et al., 1997). Beta waves are involved in normal waking consciousness and tend to have a stimulating effect; while too much beta can lead to anxiety.
A food sensitivity to a protein found in milk or a protein found in wheat is a prevalent but neglected cause of ADHD. Milk and milk products like cheese and butter contain a protein called casein. Casein is different from lactose which is a milk sugar. Grains like wheat, rye, and barley contain a protein called gluten. During digestion, casein becomes casomorphin and gluten becomes gliadorphin. For most people, these proteins are further broken down into basic amino acids. For some with ADHD, they have inactive dipeptidyl peptidase IV, a zinc-dependent enzyme that breaks down both casein and gluten, leaving these opioid peptides substances to build up.
Children with ADHD who have high levels of casomorphin or gliadorphin often have severe, uncontrolled symptoms. Both casomorphin and gliadorphin are morphine-like compounds which attach to opiate receptors in the brain. These substances can act like an addicting drug in susceptible children and cause fatigue, irritability, and brain fog. A child with high levels of casomorphin may have strong cravings for milk products (ice cream, yogurt) and may become irritable when he or she doesn’t eat these types of foods. The Gluten/Casein Peptide Test is a simple urine test that can measure levels of casomorphin and gliadorphin. If a child has high levels of casomorphin or gliadorphin, they should try to eliminate casein or gluten. Supplementation with DPP-IV enzymes can also be beneficial and often required for clinical improvement.
Malnutrition can negatively affect behavior and cognition, but certain nutrients can have detrimental effects on children as well. Louise Goldberg, pediatric dietitian, put it succinctly: “Food allergies and sensitivities can come at children with a one-two punch - first making them agitated, and next robbing them of nutrients that might rein in their behavior” (Peachman, 2013). We are biochemically unique and have different physiological and psychological responses to different foods. The right food for one child may the wrong food for another. For instance, peanut butter on whole wheat toast may be a nutritionally-balanced, energy-boosting snack for one child, while this snack would be harmful to a child who cannot tolerate neither nuts nor wheat. Medical testing can clarify which nutrients a child is sensitive to. Fortunately, eliminating offending substances can rapidly improve physical and behavioral symptoms.
Arnold, et al. (2012). Artificial food colors and attention-deficit/hyperactivity symptoms: Conclusions to dye for. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 9(3), 599-609.
Azadbakht & Esmaillzadeh. (2012). Dietary patterns and attention deficit hyperactivity disorder among Iranian children. Nutrition, 28(3), 242-249.
Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development I. Degree of impairment in intellectual performance. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 8-15.
Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development II. Classroom behavior. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 16-22.
Galler & Ramsey. (1989). A follow-up study of the influence of early malnutrition on development: Behavior at home and at school. Journal Of The American Academy Of Child And Adolescent Psychiatry, 28(2), 254-261.
Galler, Ramsey, & Solimano. (1984). The influence of early malnutrition on subsequent behavioral development III learning disabilities as a sequel to malnutrition. Pediatric Research, 18(4), 309-313.
Galler, Ramsey, & Solimano. (1985). Influence of early malnutrition on subsequent behavioral development: V. child’s behavior at home. Journal Of The American Academy Of Child Psychiatry, 24(1), 58-64.
Galler et al. (2011). Early malnutrition predicts parent reports of externalizing behaviors at ages 9-17. Nutritional Neuroscience, 14(4), 138-144.
Galler et al. (2012). Infant malnutrition predicts conduct problems in adolescents. Nutritional Neuroscience, 15(4), 186-192.
Galler et al. (2012). Infant malnutrition is associated with persisting attention deficits in middle adulthood. The Journal Of Nutrition, (4), 788.
Galler et al. (2012). Socioeconomic outcomes in adults malnourished in the first year of life: a 40-year study. Pediatrics, (1), 1.
Howard et al. (2011). ADHD Is Associated with a "Western" Dietary Pattern in Adolescents. Journal of Attention Disorders, 15(5), 403-411.
Lacy. (2004). Hyperactivity/ADHD-- new solutions. AuthorHouse.
Langseth & Dowd. (1978). Glucose tolerance and hyperkinesis. Food And Cosmetics Toxicology, 16(2), 129-133.
McCann et al. (2007). Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: A randomised, double-blinded, placebo-controlled trial. The Lancet, 370(9598), 1560-1567.
Niederhofer. (2011). Association of Attention-Deficit/Hyperactivity Disorder and Celiac Disease: A Brief Report. Primary Care Companion For CNS Disorders, 13(3), pii: PCC.10br01104.
Park et al. (2012). Association between dietary behaviors and attention-deficit/hyperactivity disorder and learning disabilities in school-aged children. Psychiatry Research, 198, 468-476.
Stevenson et al. (2010). The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms. The American Journal of Psychiatry, 167(9), 1108-15.
Uhlig et al. (1997). Topographic mapping of brain electrical activity in children with food-induced attention deficit hyperkinetic disorder. European Journal of Pediatrics, 156(7), 557-61.
By: James Greenblatt, MD
Attention deficit/hyperactivity disorder (ADHD) is a multifactorial condition that is influenced by genetic, biological, environmental, and nutritional factors. While there are numerous integrative therapies available including vitamins, minerals, herbs, neurofeedback, exercise, and meditation, individuals are unique and thus require personalized treatments based on their own biological needs identified through laboratory testing. In this article, we will discuss commonly overlooked mineral deficiencies and imbalances in the gastrointestinal flora that can exacerbate behavioral symptoms and impede the therapeutic effect of pharmacological treatment.
In the early 1960s, researchers discovered that zinc was an essential trace mineral necessary for normal growth and development. Zinc is also critical for immune function, and the activity of over 300 enzymes is dependent on zinc bioavailability. Zinc is a vital component of the central nervous system, maintaining neurotransmitter activity. This mineral enhances GABA, one of our main inhibitory/relaxation neurotransmitters. Moreover, zinc is needed as a co-factor to produce melatonin which helps regulate dopamine function.
Multiple studies have confirmed that not only are zinc levels lower in children with ADHD, but the extent of the deficiency is proportionately correlated with the severity of ADHD symptoms including inattention, hyperactivity, impulsivity, and conduct problems:
- Toren et al. (1996) found that almost one-third of 43 ADHD children aged 6-16 were severely deficient in serum zinc.
- Another study involving 48 ADHD children aged 5-10 demonstrated that most of the participants had serum zinc levels in the lowest 30% of the reference range.
- There is a highly significant inverse correlation between zinc level and parent and teacher ratings of inattention among children with ADHD (Arnold et al., 2005). A more recent study echoed the same findings, when researchers analyzed the zinc in the hair of 45 children with ADHD against 44 controls. They found that there was a relationship between hair zinc levels and worse overall ADHD symptoms (Shin et al., 2014).
- In a recent study, 70% of the 20 ADHD cases examined were zinc deficient. Those with lower hair zinc levels reported significantly increased symptoms of inattention, hyperactivity, and impulsivity (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).
In children with ADHD, plasma zinc levels were shown to directly affect information processing via event related potentials which reflect brain activity. In ADHD children compared to controls, the amplitudes of P3 waves in frontal and parietal brain regions were significantly lower (worse working memory) and the latency of P3 in the parietal region was significantly longer (slower information processing). Unsurprisingly, plasma zinc levels were significantly lower in the ADHD children compared to the control children. When a low-zinc ADHD subgroup was compared to a nondeficient ADHD subgroup, the latencies of N2 in frontal and parietal brain regions were significantly shorter (worse information processing and inhibition) (Yorbik et al., 2008).
Supplementation with zinc is more effective at improving ADHD symptoms when compared to placebo, and can also be an effective adjuvant therapy to enhance the therapeutic effect of stimulant medication without increasing the dosage. When 400 ADHD children aged 6-14 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. And these children had normal zinc levels to begin with (Üçkardeş et al., 2009). In a small study of 18 boys with ADHD, higher baseline hair zinc levels predicted better behavioral response to amphetamine (Arnold et al., 1990). In a six-week double blind, placebo controlled trial, researchers assessed the effects of zinc in combination with methylphenidate (Ritalin). 44 children aged 5-11 were randomized to methylphenidate plus zinc sulfate 55 mg/day or methylphenidate plus placebo. At week 6, those taking zinc had significantly better scores on the Parent and Teacher ADHD Rating Scale (Akhondzadeh et al., 200452 children aged 6-14 with ADHD were randomized to zinc glycinate 15 mg/day or placebo for 13 weeks. For the first 8 weeks, they only took zinc then for the last 5 weeks they also took d-amphetamine. The optimal absolute mg/day amphetamine dose with zinc was 43% lower than with placebo (Arnold et al., 2011).
Copper is an essential trace mineral that plays an active role in the synthesis of dopamine and norepinephrine. However, excess copper can manifest as displays of aggression, hyperactivity, insomnia, and anxiety. Elevated copper levels can also cause low zinc levels and reduce the efficacy of medications commonly used to treat ADHD.
Copper may affect ADHD through its role in antioxidant status. Copper/Zinc superoxide dismutase (SOD-1) is a key enzyme in our antioxidant defense system. Both copper and zinc participate in SOD enzymatic activities that protect against free radical damage. In a study on 22 ADHD children and 20 controls, serum Copper/Zinc SOD levels of ADHD children were significantly lower in individuals with high serum copper when compared to controls. It is also hypothesized that excess copper can damage dopamine brain cells by destroying antioxidant defenses, such as lowering Copper/Zinc SOD levels (Russo, 2010).
In a randomized controlled trial on 80 adults with ADHD, lower baseline copper levels were associated with better response to treatment with a vitamin-mineral supplement (Rucklidge et al., 2014). Unfortunately, even copper levels that are considered normal can negatively affect cognition. In a group of 600 adolescents with normal copper levels, blood copper was associated with decreased sustained attention and short-term memory (Kicinski et al., 2015).
Magnesium is part of 300 enzymes that utilize ATP (cellular energy) and is important for nerve transmission. It is involved in the function of the serotonin, noradrenaline, and dopamine receptors. Magnesium has been progressively declining in our food supply due to increased consumption of processed foods. The use of medications, presence of stress, and caffeine and soft drink consumption also deplete magnesium, and it is estimated that 50% of Americans are deficient in magnesium (Mosfegh et al., 2009).
Symptoms of magnesium deficiency include irritability, difficulty with concentration, insomnia, depression, and anxiety. 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 externalizing behaviors (attention problems, aggressiveness, delinquency) (Black et al., 2015). 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 25 patients with ADHD aged 6-16, 72% of children were 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 to standard medical therapy alone for 8 weeks. Those taking magnesium saw a significant improvement in hyperactivity, impulsivity, inattention, opposition, and conceptual level while those taking medication alone did not see these improvements (El Baza et al., 2015).
Supplements of magnesium plus vitamin B6, which increases magnesium absorption, have shown promise for reducing ADHD symptoms. One study on 52 children with ADHD found that 58% had low red blood cell magnesium levels. All the children were given preparations of magnesium plus vitamin B6 100 mg/day for a period of 1 to 6 months. In all patients, physical aggression, instability, attention at school, muscle rigidity, spasms, and twitching were improved. One of the treated children was a six-year old identified as “J”. Initially, J suffered from aggressiveness, anxiety, inattention, and lack of self-control. After taking magnesium supplements, he reported better sleep and concentration and no methylphenidate was needed (Mousain-Bosc et al., 2004). A later study by the same researchers also found that 40 children with ADHD had significantly lower red blood cell magnesium values than control children. Likewise, a magnesium-vitamin B6 regimen for at least 2 months significantly improved hyperactivity, aggressiveness, and school attention. 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” (Mousain-Bosc et al., 2006). In a larger study of 122 children with ADHD aged 6-11, 30 days of magnesium-vitamin B6 supplementation led to improved anxiety, attention, and hyperactivity. On a battery of tests, magnesium treatment increased attention, work productivity, task performance, and decreased the proportion of errors. The EEG of treated children showed positive changes as well, with brain waves significantly normalizing (Nogovitsina & Levitina, 2007).
There has also been a considerable amount of research illustrating the symbiotic, bidirectional relationship between the brain and the gut, and animal studies have demonstrated how certain strains of bacteria, or lack thereof, can alter cognitive and emotional processes. In the presence of dysbiosis, where “bad” bacteria outnumber the “good,” harmful strains of bacteria can proliferate and cause behavioral disturbances.
HPHPA is a harmful byproduct of some strains of the bacterium Clostridium that can disrupt the normal gut environment. Elevated urinary levels are commonly seen in ADHD children, especially those with poor response to stimulants. HPHPA inhibits the conversion of dopamine to norepinephrine. This causes dopamine to accumulate, resulting in decreased attention and focus. A patient should especially be tested for HPHPA if he or she experiences stimulant side effects such as irritability, agitation, or anxiety. ADHD medications work by increasing dopamine. But high HPHPA levels prevent the breakdown of dopamine, exacerbating symptoms. HPHPA must be cleared before medications will be helpful. Probiotics, good bacteria found in fermented food such as yogurt, or antibiotics can be used to lower HPHPA.
Intestinal overgrowth of Candida yeast is seen in some children with ADHD, mostly in those with a diet high in sugar that feed Candida, or in those who have received many rounds of antibiotics for recurrent ear infections. Antibiotics are effective at resolving infections by eradicating all bacteria, including the good bacteria. An early study found that children with the greatest history of ear infections (and presumably the greatest frequency of antibiotic use) had an increased chance for developing hyperactivity later (Hagerman & Falkenstein, 1987). Toxins produced by Candida can enter the bloodstream and then enter the brain where they can cause changes leading to hyperactivity and poor attention span. Fortunately, the presence of HPHPA and other yeast overgrowth can be easily detected with an organic acids test or with a stool sample. Candida can be treated with probiotics, antifungal foods (e.g. garlic, oregano, ginger), and a lower sugar diet. In some cases, a regimen of antibiotics and probiotics can be useful in reestablishing a healthy gut flora.
Nutritional augmentation strategies are frequently used as part of the integrative clinician’s toolbox to treat behavioral disorders in children. It is important for healthcare providers to collaborate and communicate with caregivers of children with behavioral disorders to discern whether other complementary therapies could be incorporated into treatment. By carefully assessing a patient’s whole health history and conducting appropriate laboratory testing, providers can make informed treatment recommendations that is tailored specifically for the individual.
Akhondzadeh, et al (2004). Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial ISRCTN64132371. BMC Psychiatry, 4, 9.
Arnold et al. (1990). Does hair zinc predict amphetamine improvement of ADD/hyperactivity? The International Journal of Neuroscience, 50(1-2), 103-7.
Arnold et al. (2005). Serum zinc correlates with parent- and teacher- rated inattention in children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 15(4), 628-36.
Arnold et al. (2011). Zinc for attention-deficit/hyperactivity disorder: Placebo-controlled double-blind pilot trial alone and combined with amphetamine. Journal of Child and Adolescent Psychopharmacology, 21(1), 1-19.
Bilici et al. (2004). Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 28(1), 181-190.
Black et al. (2015). Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutrition, 18(10), 1824-30.
Elbaz et al. (2016). Magnesium, zinc and copper estimation in children with attention deficit hyperactivity disorder (ADHD). Egyptian Journal of Medical Human Genetics, Egyptian Journal of Medical Human Genetics, in press.
El Baza et al. (2016). Magnesium supplementation in children with attention deficit hyperactivity disorder. Egyptian Journal of Medical Human Genetics, 17(1), 63-70.
Hagerman & Falkenstein. (1987). An Association Between Recurrent Otitis Media in Infancy and Later Hyperactivity. Clinical Pediatrics, 26(5), 253.
Kicinski et al. (2015). Neurobehavioral function and low-level metal exposure in adolescents. International Journal of Hygiene and Environmental Health, 218(1), 139-146.
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.
Moshfegh et al. (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.
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.
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.
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.
Oner et al. (2010). Effects of Zinc and Ferritin Levels on Parent and Teacher Reported Symptom Scores in Attention Deficit Hyperactivity Disorder. Child Psychiatry and Human Development, 41(4), 441-447.
Rucklidge et al. (2014). Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement. Progress in Neuropsychopharmacology & Biological Psychiatry, 50, 163-171.
Russo, A. (2010). Decreased Serum Cu/Zn SOD Associated with High Copper in Children with Attention Deficit Hyperactivity Disorder (ADHD). Journal of Central Nervous System Disease, 2, 9-14.
Shin et al. (2014). The Relationship between Hair Zinc and Lead Levels and Clinical Features of Attention-Deficit Hyperactivity Disorder. Journal of the Korean Academy of Child and Adolescent Psychiatry, 25(1), 28-36.
Toren et al. (1996). Zinc deficiency in attention-deficit hyperactivity disorder. Biological Psychiatry, 40(12), 1308-1310.
Üçkardeş et al. (2009). Effects of zinc supplementation on parent and teacher behaviour rating scores in low socioeconomic level Turkish primary school children. Acta Paediatrica, 98(4), 731-736.
Yorbik et al. (2008). Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 32(3), 662-667.
by William Shaw, PhD, and Matthew Pratt-Hyatt, PhD
Director and Associate Director of The Great Plains Laboratory, Inc.
Published in the January 2017 issue of Townsend Letter
Glyphosate is the world’s most widely produced herbicide and is the primary toxic chemical in Roundup™, as well as in many other herbicides. In addition, it is a broad-spectrum herbicide that is used in more than 700 different products from agriculture and forestry to home use. Glyphosate was introduced in the 1970s to kill weeds by targeting the enzymes that produce the amino acids tyrosine, tryptophan, and phenylalanine. This pathway (called the Shikimate Pathway) is also how bacteria, algae, and fungi produce the same amino acids. This pathway is not present in humans, so manufacturers of glyphosate claim this compound is “non-toxic” to humans. However, evidence shows there are indeed human consequences to the widespread use of this product when we consume plants that have been treated with it and animals who’ve also consumed food treated with it.
Usage of glyphosate amplified after the introduction of genetically modified (GMO) glyphosate-resistant crops that can grow well in the presence of this chemical in soil. In addition, toxicity of the surfactant commonly mixed with glyphosate, polyoxyethyleneamine (POEA), is greater than the toxicity of glyphosate alone.1 In 2014, Enlist Duo™, a herbicide product which contains a 2,4-dichlorophenoxyacetic acid (2,4- D) salt and glyphosate, was approved in Canada and the US for use on genetically modified soybeans and genetically modified maize, both of which were modified to be resistant to both 2,4-D and glyphosate. 2,4-D, which has many known toxic effects of its own is perhaps better known as a component of Agent Orange, an herbicide used by the United States during the Vietnam War to increase aerial visibility from war planes by destroying plant growth and crops.
Glyphosate and Chronic Health Conditions
Recent studies have discovered glyphosate exposure to be a cause of many chronic health problems. One specific scientific paper listed Roundup™ as one of the most toxic herbicides or insecticides tested.2 Exposure to glyphosate has been linked to autism, Alzheimer’s, anxiety, cancer, depression, fatigue, gluten sensitivity, inflammation, and Parkinson’s.3-4 A 54-year-old man who accidentally sprayed himself with glyphosate developed disseminated skin lesions six hours after the accident.6 One month later, he developed a symmetrical parkinsonian syndrome. Figure 1 shows the correlation between glyphosate usage and rates of autism, tracking services received by autistic children under the Individuals with Disabilities Education Act (IDEA). This data was originally collected by Dr. Nancy Swanson, along with similar data for many other chronic disorders.14 The causes for these disorders have been linked to glyphosate’s impact on gut bacteria, metal chelation, and P450 inactivation.5-6 It can enter the body by direct absorption through the skin, by eating foods treated with glyphosate, or by drinking water contaminated with glyphosate. A recent study stated that a coherent body of evidence indicates that glyphosate could be toxic below the regulatory lowest observed adverse effect level for chronic toxic effects, and that it has teratogenic, tumorigenic and hepatorenal effects that can be explained by endocrine disruption and oxidative stress, causing metabolic alterations, depending on dose and exposure time.7
Glyphosate, Cancer, and the Microbiome
The World Health Organization International Agency for Research on Cancer published a summary in March 2015 that classified glyphosate as a probable carcinogen in humans.8 Possible cancers linked to glyphosate exposure include non- Hodgkin lymphoma, renal tubule carcinoma, pancreatic islet-cell adenoma, and skin tumors.. Studies have also indicated that glyphosate disrupts the microbiome in the intestine, causing a decrease in the ratio of beneficial to harmful bacteria.9 Thus, highly pathogenic bacteria such as Salmonella entritidis, Salmonella gallinarum, Salmonella typhimurium, Clostridium perfringens, and Clostridium botulinum are highly resistant to glyphosate, but most beneficial bacteria such as Enterococcus faecalis, Enterococcus faecium, Bacillus badius, Bifidobacterium adolescentis, and Lactobacillus spp. were found to be moderately to highly susceptible. The relationship between the microbiome of the intestine and overall human health is still unclear, but current research indicates that disruption of the microbiome could cause diseases such as metabolic disorder, diabetes, depression, autism, cardiovascular disease, and autoimmune disease.
Glyphosate and Chelation
Another study found that glyphosate accumulated in bones. Considering the strong chelating ability of glyphosate for calcium, accumulation in bones is not surprising. Other results showed that glyphosate is detectable in intestine, liver, muscle, spleen and kidney tissue. 5 The chelating ability of glyphosate also extends to toxic metals.10 The high incidence of kidney disease of unknown etiology (renal tubular nephropathy) has reached epidemic proportions among young male farm workers in sub-regions of the Pacific coasts of the Central American countries of El Salvador, Nicaragua, Costa Rica, India, and Sri Lanka.11 The researchers propose that glyphosate forms stable chelates with a variety of toxic metals that are then ingested in the food and water or, in the case of rice paddy workers, may be absorbed through the skin. These glyphosate-heavy metal chelates reach the kidney where the toxic metals damage the kidney. These authors also propose that these chelates accumulate in hard water and clay soils and persist for years, compared to much shorter periods of persistence for non-chelated glyphosate. Furthermore, these chelates may not be detected by common analytical chemistry methods that only detect free glyphosate, thus dramatically reducing estimates of glyphosate persistence in the environment when metals are high (for example, in clay soil or hard water).
Testing for Glyphosate
Because glyphosate has been linked with many chronic health conditions, testing for glyphosate exposure and particularly the level of exposure is important. The lower limit of quantification (LLOQ) for The Great Plains Laboratory’s Glyphosate Test is 0.38 μg/g of creatinine. The Great Plains Laboratory is the only CLIA certified lab currently performing a test for glyphosate in urine. Our Glyphosate Test can be performed on the same urine sample as for some of our other comprehensive tests, including the Organic Acid Test (OAT) or GPL-TOX (Toxic Non-Metal Chemical Profile). See Figure 2 for an example of our Glyphosate Test report.
As previously mentioned, glyphosate works by inhibiting the synthesis of tryptophan, phenylalanine, and tyrosine in plants. Humans need to obtain these amino acids from food sources. When food sources have scarce amounts of these amino acids due to glyphosate use, humans are at risk for deficiency too. Humans also require bacteria to maintain a healthy immune system. Research indicates that glyphosate decreases the amount of good bacteria in the gut such as bifidobacteria and lactobacilli and allows for the overgrowth of harmful bacteria such as campylobacter and C. difficile.12 Our lab has observed this in patients. We had a female patient who was suffering from depression who did a Glyphosate Test and an Organic Acids Test. Her glyphosate results were 2.99, which was over the 95th percentile and can be seen in Figure 3.
Upon analyzing her OAT we noticed two things. The first was that her 4-cresol was extremely high. This increased 4-cresol can be seen in Figure 4. As stated earlier, glyphosate exposure decreases the good bacteria and allows C. difficile to invade. C. difficile produces a toxin called 4-cresol, which we measure in the OAT. Research has shown that 4-cresol inhibits dopamine beta-hydroxylase.13 Dopamine beta-hydroxylase converts dopamine to norepinephrine. In the OAT we measure both homovanillic acid (dopamine metabolite) and vanillylmandelic acid (norepinephrine metabolite). We have observed patients with a high 4-cresol value have elevated homovanillic acid, which indicates an inability to convert dopamine to norepinephrine. The results from our aforementioned patient were consistent with these other results and can be seen in Figure 5. The recommendations for this patient were to treat her glyphosate exposure and to treat her C. difficile infection.
The results from these tests are indicative of why using the Organic Acids Test and Glyphosate Test together is so valuable and can help you provide more focused treatment for your patients. Treatment of glyphosate toxicity should be centered on determining the route of introduction and avoiding future exposure. Eating organic, non-GMO (genetically modified organism) foods and drinking reverse osmosis water are two of the best ways to avoid glyphosate. A recent study showed that people eating organic food had considerably lower concentrations of glyphosate in the urine.7 Drinking extra water may also be beneficial since glyphosate is water soluble, but that water should be filtered to remove pesticides or, ideally, be treated by reverse osmosis. More than 90% of corn and soy used are now of the GMO type. In addition, non-GMO wheat is commonly treated with glyphosate as a drying procedure. Glyphosate is somewhat volatile and a high percentage of rain samples also contained glyphosate.7
High correlations exist between glyphosate usage and numerous chronic illnesses, including autism14. Other disease incidences with high correlations include hypertension, stroke, diabetes, obesity, lipoprotein metabolism disorder, Alzheimer’s, senile dementia, Parkinson’s, multiple sclerosis, inflammatory bowel disease, intestinal infections, end stage renal disease, acute kidney failure, cancers of the thyroid, liver, bladder, pancreas, kidney, and myeloid leukemia.14 Correlations are not causations, yet they raise concern over the use of a chemical to which all life on earth appears to be exposed. Testing for glyphosate along with specific markers in the Organic Acids Test can both help determine the level of exposure to glyphosate and guide you toward the most optimal treatment plans for your patients.
1. Bradberry SM, Proudfoot AT, Vale JA. Glyphosate poisoning. Toxicol Rev. 2004;23(3):159-67.
2. Mesnage R et al. Major pesticides are more toxic to human cells than their declared active principles. Biomed Res Int. 2014: 179691
3. Samsel A, Seneff S. Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance. Interdiscip Toxicol. 2013;6:159-184.
4. Samsel A, Seneff S. Glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies. Surg Neurol Int. 2015; 6: 45.
5. Krüger M, Schledorn P, Schrödl W, Hoppe HW, Lutz W, Shehata AA. Detection of Glyphosate Residues in Animals and Humans. J Environ Anal Toxicol. 2014. 4:2 http://dx.doi.org/10.4172/2161- 0525.1000210
6. Barbosa ER, Leiros da Costa MD, Bacheschi LA, Scaff M, Leite CC. Parkinsonism after glycine-derivative exposure. Mov Disord. 2001. 16: 565-568.
7. Mesnage R, Defarge N, Spiroux de Vendômois J, Séralini GE. Potential toxic effects of glyphosate and its commercial formulations below regulatory limits. Food Chem Toxicol. 2015 Oct;84:133-53.
8. Guyton KZ, Loomis D, Grosse Y et al. Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Lancet Oncol. 2015 May;16(5):490-1
9. Shehata AA, Schrödl W, Aldin AA, Hafez HM, Krüger M. The effect of glyphosate on potential pathogens and beneficial members of poultry microbiota in vitro. Curr Microbiol. 2013 Apr;66(4):350-8.
10. Jayasumana C, Gunatilake S, Siribaddana S. Simultaneous exposure to multiple heavy metals and glyphosate may contribute to Sri Lankan agricultural nephropathy. BMC Nephrology 2015;16:103. doi 10.1186/s12882-015-0109-2
11. Jayasumana C, Gunatilake S, Senanayake P. Glyphosate, hard water and nephrotoxic metals: Are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka? Int. J. Environ. Res. Public Health 2014;11:2125-2147.
12. Clair E et al. Effects of Roundup® and glyphosate on three food microorganisms: Geotrichum candidum, Lactococcus lactis subsp. cremoris and Lactobacillus delbrueckii subsp. bulgaricus. Curr Microbiol. 2012;64: 486-491.
13. DeWolf WE Jr. Inactivation of dopamine beta-hydroxylase by p-cresol: isolation and characterization of covalently modified active site peptides. Biochemistry. 1988;27: 9093-9101.
14. Swanson NL, Leu A, Abrahamson J, and Wallet B. Genetically engineered crops, glyphosate and the deterioration of health in the United States of America. Journal of Organic Systems. 2014; 9(2):6- 37.
15. Environmental Protection Agency. Pesticides Industry Sales & Usage. 2006 and 2007 Market Estimates. Available at https://www.epa.gov/sites/production/files/2015-10/documents/market_ estimates2007.pdf. Accessed July 15, 2015.
16. Shehata AA et al. The effect of glyphosate on potential pathogens and beneficial members of poultry microbiota in vitro. Curr. Microbiol. 2013;66: 350-358.
17. Larsen K et al. Effects of sublethal exposure to a glyphosate-based herbicide formulation on metabolic activities of different xenobiotic-metabolizing enzymes in rats. Int J Toxicol. 2014;33: 307-318.
William Shaw, PhD, is board certified in the fields of clinical chemistry and toxicology by the American Board of Clinical Chemistry. Before he founded the Great Plains Laboratory Inc., Dr. Shaw worked for the Centers for Disease Control and Prevention (CDC), Children’s Mercy Hospital, University of Missouri at Kansas City School of Medicine, and Smith Kline Laboratories. He is the author of Biological Treatments for Autism and PDD, originally published in 1998, and Autism: Beyond the Basics, published in 2009. He is also a frequent speaker at conferences worldwide.
He is the stepfather of a child with autism and has helped thousands of patients and medical practitioners to successfully improve the lives of people with autism, AD(H)D, Alzheimer’s disease, arthritis, bipolar disorder, chronic fatigue, depression, fibromyalgia, immune deficiencies, multiple sclerosis, OCD, Parkinson’s disease, seizure disorders, tic disorders, Tourette syndrome, and other serious conditions.
Matthew Pratt-Hyatt, PhD, received his PhD in cellular and molecular biology from the University of Michigan. He has trained under Dr. Paul Hollenberg, a prominent researcher on drug metabolism, and Dr. Curtis Klaassen, one of the world’s leading toxicologists. He has over a dozen publications in well-known research journals such as the PNAS and Cell Metabolism. He is currently associate laboratory director at the Great Plains Laboratory Inc. in Lenexa, Kansas, focused on diagnosis and treatment of mitochondrial disorders, neurological diseases, chronic immune diseases, and more. He specializes in developing tools that examine factors at the interface between genetics and toxicology. His work is bringing new insight into how genes and toxicants interact and how that may lead to mental health disorders, chronic health issues, and metabolism disorders.
by James Greenblatt, MD, and Kayla Grossmann, RN
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 flame 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 brain health.
Today, we do not tend to think of lithium as an essential mineral in human physiology and its critical use for expanding technology. Lithium does not evoke visions of stars, peaceful rivers, or strong, healthy bodies. Instead images of lithium are associated with pharmacies, doctor's offices, and back wards of psychiatric hospitals. Lithium is perceived, almost exclusively, as a dangerous drug used to treat severe mental illness with incapacitating side effects.
In a recent review in the New York Times titled "I Don't Believe in God, but I Believe in Lithium," author Jamie Lowe delivered a powerful testimony of her dramatic response to lithium – the drug that alleviated her mania and allowed her to live a normal, happy life. Her article also describes the kidney damage that has forced her to stop lithium and placed her on a waiting list for potential kidney transplant. She provides a unique insight into the life-changing prescriptive benefits of lithium, and the overwhelming fear she has of life without her lithium; a life without her sanity.
I have treated thousands of patients with similar backgrounds as Jamie's. This raised the question, how can a medicine provide such life-changing effects on mental health yet cause permanent damage to kidney and often thyroid function?
Twenty-five years ago, I attempted to answer this question by looking for the lowest dose of lithium that would alleviate symptoms. Rather than basing my prescription dosage on a number from a lab test that dictated a "therapeutic blood level," I listened to my patients. I began to see that patients on a lower dose of lithium – doses closer to the trace amounts found naturally in the environment – still experienced significant clinical results.
Psychiatry has much to learn from the untold story of one of its oldest drugs.
Lithium as Mineral
Lithium was given its official name by a Swedish chemist named Johan August Arfvedson in 1817. He isolated the element while studying petalite – a rich mineral deposit found in soils – on the remote island of Uto. The unique substance was named lithium after the Greek word lithos, meaning literally "from stone."
Just one year after its initial discovery, researchers noticed that there was something special about this new element. Lithium ore, when ground into a fine powder, turned flames a bright crimson color that intensified to a dazzling white when burning strongly. In addition to being highly reactive, the metal was also lightweight, malleable, and a good conductor of heat and electricity. These characteristics made lithium an immediately desirable commodity for industrial and manufacturing purposes. Since this time it has been used for manifold applications: in aircraft parts, fireworks, heat-resistant cookware, focal lenses, and even the fusion material in power plants. Today, the mineral is most commonly used for building the lithium-ion batteries that power our cell phones, tablets, laptops, and eco-friendly vehicles.
Over the past two centuries, scientists have gained a deeper appreciation of this alkali earth metal, which is now known to be relatively common in the earth's upper crust. As the 27th most abundant element, it can be found in rock sediments, salt flats, and mineral springs at varying concentrations throughout the globe. The largest deposits of lithium are salars, or vast saline basins in the deserts of South America. Lithium is also highly concentrated in clay beds and hard rock underground mines dotting Australia, China, and some parts of North America.
Lithium is in fact so ubiquitous in these environments that it can readily be found in food and water supplies. The US Environmental Protection Agency has estimated that the daily lithium intake of an average adult ranges from about 0.65 mg to 3 mg. Grains and vegetables serve as the primary sources of lithium in a standard diet, with animal byproducts such as eggs and milk providing the rest. Lithium has even been officially added to the World Health Organization'slist of nutritionally essential trace elements alongside zinc, iodine, and others.
The most frequent source of lithium in the modern diet, however, is tap water. Depending on geographical location, drinking water contains substantial amounts of naturally occurring lithium. According to environmental surveys, water with high mineral content can translate to 2 mg or so of lithium per day.
There has been little research on the specific consequences of lithium deficiency in humans. However, trials in which animals have been put on low-lithium diets have revealed a gross decrease in reproductive function, lifespan, and lipid metabolism. It is quite possible that lithium deficiency has many other effects on human physiology, but the study of nutritional lithium has been overshadowed by the volatile reputation of high-dose pharmaceutical lithium.
Lithium as Medicine
Official documentation of the medical applications of lithium was first publicized by London doctor Alfred Baring Garrod, who used it to treat patients with gout. After discovering uric acid in the blood of his patients with gout, he wrote about pioneering the use of lithium in his 1859 treatise, The Nature and Treatment of Gout and Rheumatic Gout. Between the 1850s and 1890s, several other physicians experimented with lithium treatment because at the time uric acid was viewed as a critical factor in many diseases.
Both the medical literature and popular advertisements of the time abounded with praise for lithium. The Sears, Roebuck & Company Catalogue of 1908 advertised Schieffelin's Effervescent Lithia Tablets for a variety of uric acid afflictions. By 1907, The Merck Index listed 43 different medicinal preparations containing lithium. Even soft drink entrepreneur Charles Leiper Grigg understood that 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.
An Australian psychiatrist, Dr. John Cade, is credited with first experimenting with high doses of lithium citrate and lithium carbonate as a treatment for manic depressive illness in 1949. He observed first in animals and then in human trials that lithium stabilized mood, restored memory, and improved cognitive function, even in his most challenging subjects. Because of his well-structured study and the dramatic results, some historians of medicine consider that Cade ushered in modern psychopharmacology.
Unfortunately, the timing of Cade's treatment successes was ill fated. The very same year, 1949, adverse reaction reports surfaced in the media about patients who were taking lithium chloride in the US. As physicians encouraged patients with heart disease and hypertension to avoid sodium chloride, lithium chloride was marketed as an alternative to sodium chloride in four different preparations: Salti-salt, Milosal, Foodsal, and Westsal. In the late 1940s and early 1950s, physicians around the country released reports of patients who developed lithium poisoning after they had used large, uncontrolled amounts of Westsal. Several deaths were also reported, leading the FDA to ban the use of lithium salt substitutes. "Stop using this dangerous poisoning at once!" exhorted the FDA. Lithium fell out of favor in the American medical community.
Despite this lithium chloride debacle, trials testing the efficacy of lithium carbonate for mania continued in Australia and France. Eventually the research from other countries became so compelling that by the end of the decade, a "lithium underground" had formed of US physicians prescribing lithium in the absence of official FDA approval. Finally, the FDA sanctioned lithium in 1970 as a new investigational drug for use in treatment of acute mania. By this time many other countries had already approved lithium, including France, the UK, Germany, and Italy. In 1974, lithium was finally approved to prevent recurrent mania.
Since the official FDA approval of pharmaceutical-dose lithium, the mineral has proved to be one of the most versatile and successful drugs in psychiatry. According to treatment guidelines, lithium carbonate is recognized as the first-line therapy in patients with bipolar disorder. Recent meta-analyses underscore the superiority of lithium as a prophylactic for both mania and depression. Lithium's effectiveness in suicide prevention has also been demonstrated. While antidepressants may treat depression, they often exacerbate symptoms of agitation, restlessness, irritability, and anger that can lead to impulsivity and aggression. Lithium, by contrast, has specific effects against suicide that are independent of mood stabilization. Substantial literature also exists to support the use of lithium in a broad spectrum of other neurological conditions including substance abuse, violent and aggressive behavior, ADHD, and cognitive decline.
The pharmacological mechanisms under which lithium operates have yet to be understood in totality, although many well-supported hypotheses exist. It appears that lithium functions in two central ways in the body's neurochemistry: repairing damaged neurons and stimulating neuronal growth. Proposed mechanisms for lithium's effect on balancing mood include the altering of dopamine, glutamate, and GABA levels in the synapses as well as modulation of secondary messenger pathways that effect neurotransmission, including the adenylyl cyclase system, cAMP signaling pathway, and phosphoinositide system. Accumulating evidence has shown that lithium's diverse neuroprotective actions involve direct changes in the expression of multiple genes.
It was once believed that genes were destiny. Scientists and clinicians held fast to the idea that a fixed genetic code was hardwired in humans at conception, and that mutations were a sure predictor of disease. However, it is now known that environmental factors have a profound influence on the ways in which genes are expressed. The study of epigenetics has revealed that lifestyle factors, including physical activity, learning, stress exposure, and pharmacological compounds, can essentially switch genes on or off. The mineral lithium is a powerful epigenetic factor. Key epigenetic mechanisms include histone modifications and changes in DNA methylation. Lithium works in both of these channels and has been shown to influence the expression of over 50 different genes. Working in these epigenetic pathways, lithium supports a wide range of neuroprotective and neurotrophic actions that literally change brain physiology.
I believe that lithium is the most effective medication in psychiatry. Psychiatrists over the years have been hesitant to prescribe lithium because it is toxic at pharmaceutical doses. Concerns about side effects and toxicity are nonexistent when lithium is used as a nutritional, low-dose supplement. The untapped potential of low-dose lithium in psychiatry has implications for dramatically changing clinical practice with a safe, integrative strategy for the treatment of mental illness.
I have treated children as young as 4 years old and adults in their 70s with low-dose lithium. Here are a few examples of the hundreds of patients in whom this treatment has been successful.
A 4-year-old boy, Peter, had severe ADHD. Even at this young age, he was shunned by other children, and his parents were asked to remove him from preschool. It was easy to observe his aggressive behaviors in my office. A trace mineral analysis from a hair sample revealed no detectable lithium. I prescribed 250 mcg of lithium in liquid form. Peter's annoying aggressiveness diminished. He became able to make friends, and eventually he began to participate cooperatively with other children in a new preschool.
Shawn at age 8 was often in trouble for bullying. Although he had been diagnosed with ADHD, stimulants had not been helpful. His trace mineral analysis showed no detectable lithium. On 2 mg of lithium orotate, he showed significant improvement, and he lost interest in bullying other children.
A 20-year-old patient, Amy, was diagnosed with bipolar disorder. She had been doing better on Depakote, although she continued to have anger outbursts and uncontrolled rages. Although she had once been on prescription lithium, she had experienced side effects that prevented ongoing use. I prescribed 10 mg of lithium for her in conjunction with the Depakote. Her condition improved so much that she was able to leave a therapeutic boarding school to return home.
A middle-aged man named Brian made an appointment with me to talk about his problems with anger and irritability. I had no trouble imagining these problems, as I was unavoidably 15 minutes late in calling him to my office. He berated me for most of the session, and I later heard that he had been verbally abusive with my staff. Brian, I learned, had suffered from depression and was currently taking an antidepressant, but his irritability remained. His wife reported that his road rage escalated to such intensity that he would get out of the car and yell at other drivers. I added 10 mg of lithium to Brian's antidepressant treatment. Both he and his wife later reported that his simmering road rage subsided to nothing more than mild frustration.
The case of my patient Patricia was revealing by all of my assessment strategies: clinical history, family history, and trace mineral analysis. A 43-year-old therapist, she had been diagnosed at age 18 with depression and alcohol abuse. I learned from her story that her family of origin was deeply impaired by alcoholism. Patricia had been taking an antidepressant and had worked hard at maintaining her sobriety for 10 years. She came to me for enhanced support, as she complained that she was a "dry drunk," clinging to "white-knuckle sobriety." She felt chronically irritable. Trace mineral analysis revealed some level of lithium in her hair, but it was low.
Six weeks after I prescribed 5 mg of lithium, Patricia came to my office in tears. She was partly joyful that she no longer felt a constant level of irritability, but she also realized with regret what it must have been like for her family to have tolerated her irritability and anger for such a long time.
In an effort to organize and disseminate the information of low-dose lithium, I have started to compile additional case studies and ongoing research efforts on the website www.lowdoselithium.org.
In 1970, one research study analyzed levels of organically derived lithium in the water of 27 Texan counties and compared them to the incidence of admissions and readmissions for psychoses, neuroses, and personality disorders at local state mental hospitals. Data from a 2-year period were collected and analyzed. The authors noticed a marked 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 correcting for possible confounding variables such as population density and distance to the nearest state hospitals.
A follow-up study in the same Texan counties looked at similar variables over a longer 9-year span. Researchers came up with almost identical results: the incidences of suicide, homicide, and rape were significantly higher in counties where drinking water contained little or no lithium, versus those with levels ranging from 70 to 170 mcg/L. Unsure if these striking findings were somehow unique to that geographical region, other researchers have sought to replicate the study template in other areas throughout the globe. Lithium water studies have now been repeated internationally at sites in Austria, England, Greece, and Japan. Overall the collection has revealed a strong inverse correlation between aggressive crime and suicide and supplemental levels of lithium in the water supply.
Another interesting finding came from a study that looked at lithium levels in the hair of criminals. Trace mineral hair analysis is one of the most accurate methods for testing long-term mineral status and is therefore highly advantageous for determining where deficiencies are present. This study found that violent criminals had little to no stores of lithium when tested via hair mineral analysis, bringing forth the idea that perhaps lithium deficiency was contributing to oppositional and aggressive behaviors.
The most fascinating research recently, however, has been on the use of lithium for Alzheimer's disease. Given its being the only cause of death in the top 10 in America that cannot be prevented, cured, or slowed, researchers are spending billions of dollars on Alzheimer's disease. There is a fast-growing community of researchers suggesting that lithium may provide significant benefits in the treatment and prevention of Alzheimer's.
Lithium has been shown to disrupt the key enzyme responsible for the development of amyloid plaques and neurofibrillary tangles associated with Alzheimer's disease. This enzyme is glycogen synthase kinase-3 (GSK-3), a serine/threonine protein kinase that is important in neural growth and development. Notably, specific levels of GSK-3 are required to carry out the synaptic remodeling that drives memory formation.
In Alzheimer's disease, GSK-3 becomes hyperactive in the areas of the brain controlling memory and behavior, including the hippocampus and frontal cortex. This upregulation spurs GSK-3 to phosphorylate, or activate, amyloid-B and tau proteins in the neurons of these regions at an aberrantly high rate. Over time these proteins accumulate to create the signature plaques and neurofibrillary tangles that disrupt the brain tissue and result in symptoms of cognitive decline. Lithium works as a direct GSK-3 inhibitor to prevent this overexpression, halting inappropriate amyloid production and the hyperphosphorylation of tau proteins before they impair brain function.
In addition to protecting the brain from the development of plaques and tangles, lithium has been shown to repair existing damages brought about by Alzheimer's disease pathogenesis. Lithium ions, for example, encourage the synthesis and release of key neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), which in turn stimulate the growth and repair of neurons. Patients on lithium have been found to have significantly higher gray matter volumes in the brain. One study has even directly demonstrated that damaged nerve cells exposed to lithium respond with increases in dendritic number and length.
In a recent trial published in Current Alzheimer's Research, a nutritional dose of just 300 mcg of lithium was administered to Alzheimer's patients for 15 months. When compared with the control, those on low-dose lithium showed significant improvements in cognitive markers after just 3 months of treatment. Furthermore, these protective effects appeared to strengthen as the study proceeded, with many of the lithium-treated individuals showing marked cognitive improvements by the end of the trial. These results suggest that lithium could be a viable treatment for Alzheimer's disease when used at low doses over the long term.
Dr. Nassir Ghaemi, one of the more notable and respected advocates of lithium use in the medical community, recently published a review in 2014 in Australian and New Zealand Journal of Psychiatry summarizing the benefits of low-dose lithium therapy. Ghaemi and his colleagues performed a systematic review of 24 clinical, epidemiological, and biological reports that assessed standard or low-dose lithium for dementia along with other behavioral or medical benefits. Five of the seven epidemiological studies established a correlation with standard-dose lithium therapy and low dementia rates, while four other randomized clinical trials demonstrated that low-dose lithium yielded more benefit for patients with Alzheimer's dementia versus placebo. Based on these findings, Ghaemi stressed that "lithium is, by far, the most proven drug to keep neurons alive, in animals and in humans, consistently and with many replicated studies."
The Future of Lithium
Recognizing that nutrition is key to brain health is a fundamental premise of integrative medicine. Instead of focusing on just one type of intervention, integrative medicine tries to address all factors that may contribute to a mental disorder – bringing together nutritional supplements, medicines, psychotherapy, and lifestyle changes.
Lithium must be recognized as a critical component of nutritional assessments. Lithium is an underused nutritional supplement. The diverse neuroprotective mechanisms are truly remarkable. The scientific literature has shown that lithium modulates GSK-3, enhances the release of neurotrophic factors such as BDNF, and promotes epigenetic changes that resets the trajectory of mental illness. Lithium is powerful, reliable, cost effective, and, at low doses, completely safe.
With low-dose lithium, we have a safe nutritional supplement that is effective in treating a wide range of disabling symptoms of mental illness. Perhaps in the future, patients like Jamie Lowe, the author of the New York Times article, will not be forced to make a decision between mental and physical health. The compelling and growing scientific literature on the benefits of low-dose lithium therapy combined with over 25 years of clinical practice have convinced me that with low-dose lithium, it is entirely possible to have both.
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James M. Greenblatt, MD, currently serves as the chief medical officer and vice president of Medical Services at Walden Behavioral Care in Waltham, Massachusetts. He is assistant clinical professor of psychiatry at Tufts University School of Medicine. An acknowledged integrative medicine expert, Dr. Greenblatt has lectured throughout the US on the scientific evidence for nutritional interventions in psychiatry and mental illness. Dr. Greenblatt is on the scientific advisory board and consultant for Pure Encapsulations. He maintains an integrative psychiatric practice in the Boston area.
Kayla Grossmann, 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.
Find out more about their upcoming book and work on www.lowdoselithium.org.