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.
by James Greenblatt, MD
Chief Medical Officer at Walden Behavioral Care in Waltham, MD
Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth College Geisel School of Medicine
Magnesium is a cofactor in more than 325 enzymatic reactions—in DNA and neurotransmitters; in the bones, heart and brain; in every cell of the body. Unfortunately, a deficiency of this crucial mineral is the most common nutritional deficiency I see in my practice as an integrative psychiatrist. Fortunately, supplementation with magnesium is the most impactful integrative treatment I use, particularly in depression and attention deficit hyperactivity disorder (ADHD).
Why is magnesium deficiency so common, and why is restoring the mineral so essential to mental and emotional well-being and behavioral balance? The rest of this article addresses those two questions, and presents aspects of my therapeutic approach.
The population is deficient in magnesium—found abundantly in whole grains, beans and legumes, nuts and seeds, and leafy greens, as well as cocoa and molasses—for several reasons.
Soil depletion. Intensive agricultural practices rob the soil of magnesium and don’t replace it. As a result, many core food crops—such as whole grains—are low in magnesium. A recent paper in Crop Journal put it this way: Magnesium’s “importance as a macronutrient ion has been overlooked in recent decades by botanists and agriculturists, who did not regard Mg deficiency in plants as a severe health problem. However, recent studies have shown, surprisingly, that Mg contents in historical cereal seeds have markedly declined over time, and two thirds of people surveyed in developed countries received less than their minimum daily Mg requirement.” 
Food processing. Magnesium is stripped from foods during food processing. For example, refined grains—without magnesium-rich germ and bran—have only 16% of the magnesium of whole grains. 
Stress. Physical and emotional stress—a constant reality in our 24/7 society—drain the body of magnesium. In fact, studies show inverse relationships between serum cortisol and magnesium—the higher the magnesium, the lower the cortisol. Stress robs the body of magnesium—but the body must have magnesium to respond effectively to stress.
Other factors. Many medications—such as medications for ADHD—deplete magnesium. So does the intake of alcohol, caffeine and soft drinks.
The result: In 1900, the average intake of magnesium was 475 to 500 mg daily. Today, it’s 175 to 225 mg daily. Which means that only one-third of adult Americans get the daily RDA for magnesium—320 mg for women, and 420 mg for men. (And many researchers consider the RDA itself inadequate.) And that magnesium deficit causes deficits in health. Magnesium deficiency has been cited as contributing to atherosclerosis, hypertension, type 2 diabetes, obesity, osteoporosis and certain types of cancer.  But detecting that deficiency in laboratory testing is difficult, because most magnesium in the body is stored in the skeletal and other tissues. Only 1% is in the blood, so plasma levels are not a reliable indicator. That means a “normal” magnesium blood level may exist despite a serious magnesium deficit. An effective therapeutic strategy: Assume a deficit is present, and prescribe the mineral along with other appropriate medical and natural treatments. That’s particularly true if the patient has symptoms such as anxiety, irritability, insomnia and constipation, all of which indicate a magnesium deficiency.
The Mind Mineral
Some of the highest levels of magnesium in the body are found in the central nervous system, with studies dating back to the 1920s showing how crucial magnesium is for a balanced brain…
It’s known, for example, that magnesium interacts with GABA receptors, supporting the calming actions of this neurotransmitter. Magnesium also keeps glutamate—an excitatory neurotransmitter—within healthy limits. Patients with higher magnesium levels also have healthy amounts of serotonin in the cerebrospinal fluid. And the synthesis of dopamine requires magnesium.
In summary, the body needs magnesium to create neurotransmitters (biosynthesis) and for those neurotransmitters to actually transmit. Magnesium also acts at both the pituitary and adrenal levels. In the pituitary gland, it modulates the release of ACTH, a hormone that travels to the adrenal glands, stimulating cortisol release. In the adrenal gland, it maintains a healthy response to ACTH, keeping cortisol release within a normal range. As a result, magnesium is a must for maintaining the homeostasis of the HPA axis. Given all these key mechanisms of action, it’s not surprising that a lack of the mineral can produce psychiatric and other types of problems. The patient may have: Difficulty with memory and concentration. Depression, apathy and fatigue. Emotional lability. Irritability, nervousness and anxiety. Insomnia. Migraine headaches. Constipation. PMS. Dysmenorrhea. Fibromyalgia. Autism. ADHD. Fortunately, studies show that magnesium repletion—restoring normal levels of the mineral—produces positive changes in mood and cognition, healthy eating behavior, healthy stress responses, better quality of sleep, and better efficacy of other modalities, such as medications. Let’s look at two areas in which magnesium supplementation is particularly effective: Depression and ADHD.
A cross-sectional, population-based data set—the National Health and Nutrition Examination Survey—was used to explore the relationship of magnesium intake and depression in nearly 9,000 US adults. Researchers found significant association between very low magnesium intake and depression, especially in younger adults.  And in a recent meta-analysis of 11 studies on magnesium and depression, people with the lowest intake of magnesium were 81% more likely to be depressed than those with the highest intake.  In a clinical study of 23 senior citizens with depression, low blood levels of magnesium and type 2 diabetes, magnesium was compared to the standard antidepressant medication imipramine (Tofranil)—one group received 450 mg of magnesium daily and one group received 50 mg of imipramine. After 12 weeks, depression ratings were equally improved in both groups.  In my practice, I nearly always prescribe magnesium to a patient with diagnosed depression. You can read more about the integrative approach to depression in Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention (CRC Press), which I co-edited, and in Breakthrough Depression Solution: Mastering Your Mood with Nutrition, Diet & Supplementation (Sunrise River Press, 2nd Edition).
Attention Deficit Hyperactivity Disorder
Magnesium deficiency afflicts 90% of all people with ADHD and triggers symptoms like restlessness, poor focus, irritability, sleep problems, and anxiety. These symptoms can lessen or vanish one month after supplementation starts. Magnesium can also prevent or reverse ADHD drug side effects. That’s why all of my ADHD patients get a prescription for magnesium. For adolescents, I typically prescribe 200 mg, twice daily. For children 10 to 12, 100 mg, twice daily. For children 6 to 9, 50 mg, twice daily. Typically, I recommend magnesium glycinate, using a powdered product. I describe my entire approach to magnesium and ADHD (and to the disorder’s overall integrative treatment) in my book Finally Focused: The Breakthrough Natural Treatment Plan for ADHD That Restores Attention, Minimizes Hyperactivity, and Helps Eliminate Drug Side Effects. (Forthcoming from Harmony Books in May 2017)
Dosage and Form
I have found that 125 to 300 mg of magnesium glycinate at meals and a bedtime (four times daily) produces clinically significant benefits in mood. (This form of magnesium is gentle on the digestive tract.) 200 to 300 mg of magnesium glycinate or citrate before bed supports sleep onset and duration through the night. You can also find magnesium in powder or liquid form, which are effective alternatives to capsules, particularly for children with ADHD. Ways to increase the bioavailability of magnesium include: Supplementing with vitamin D3, which increases cellular uptake of the mineral. Vitamin B6 also helps magnesium accumulate in cells. Taking the mineral in divided doses instead of a single daily dose. Taking it with carbohydrates, with improves absorption from the intestine. And taking an organic form, such as glycinate or citrate, which improves absorption by protecting the mineral from antagonists in the digestive tract. Avoid giving magnesium in enteric-coated capsules, which decreases absorption in the intestine.
Magnesium oxide is poorly absorbed and tends to cause loose stools. Magnesium-l-threonate has been shown to readily cross the blood-brain barrier, and animal studies show that it supports learning ability, short and long-term memory and brain function, I don’t typically prescribe it, however, because of its higher cost, and the clinical effectiveness of other forms. The therapeutic response to magnesium typically takes several weeks, as levels gradually increase in the body.
 Guo W., et al. Magnesium deficiency in plants: An urgent problem. The Crop Journal, Volume 4, Issue 2, April 2016, Pages 83-91.
 Volpe, SL. Magnesium in Disease Prevention and Overall Health. Advances in Nutrition, 2013 May; 4(3): 378S-383S.
 Tarleton EK, at al. Magnesium Intake in Depression in Adults. Journal of the American Board of Family Medicine, 2015 Mar-Apr;28(2):249-56.
 Li B, et al. Dietary magnesium and calcium intake and risk of depression in the general population: A meta-analysis. Australian and New Zealand Journal of Psychiatry, 2016 Nov 1. [Epub ahead of print].
 Barragan-Rodriquez L, et al. Efficacy and safety or oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial. Magnesium Research, 2008 Dec;21(4):218-23.
James Greenblatt, MD
Trichotillomania (TTM) is an impulsive disorder that causes people to repeatedly pull out their hair, most often from the scalp. It affects about 1-2% of adults and adolescents, but it is ten times more prevalent in women than in men (APA, 2013). The name is Greek in origin: thrix (hair), tillein (to pull), and mania (madness). The first allusion to TTM may have come from the Greek philosopher Epictetus in 101 AD: “Indeed I think that the men who pluck out their hairs do what they do without knowing what they do…Much from his head he tore his rooted hair. And what does he say himself? 'I am perplexed,' he says, 'and disturbed I am,' and 'my heart out of my bosom is leaping.'" (Epictetus, 1981). The first medical case was described by French dermatologist Francois Henri Hallopeau in 1889, who described a young man who pulled out his hair in tufts (Parakh & Srivastava, 2010).
The American Psychiatric Association first recognized TTM as a mental disorder in 1987. The DSM V classifies TTM as an obsessive-compulsive disorder, a change from the DSM IV where is was classified as an impulsive-control disorder (APA, 2013). The cause is complex and unclear. Those with TTM often suffer from other psychiatric conditions such as major depression, generalized anxiety disorder, OCD, eating disorders, substance abuse, and excoriation (skin-picking) disorder (Parakh & Srivastava, 2010).
The last 20 years have begun to shed some light on the disorder with an increase in clinical and research attention; however, there is yet to be a consensus on the best treatment. Traditional treatments primarily involve cognitive-behavioral therapy including habit reversal therapy. Cognitive-behavioral therapy identifies factors triggering hair pulling behavior and then teaches skills to interrupt the behavior. This includes keeping records of hair pulling, being aware of emotional states or environmental cues causing the behavior, or bandaging fingers to interfere with hair pulling. Habit reversal therapy is currently the most effectively used treatment, although treatment varies on an individual basis and relapse is common. Medications used to treat TTM include selective serotonin reuptake inhibitors (SSRIs), olanzapine, clomipramine, fluoxetine, and paroxetine. SSRIs are currently the most commonly used treatment in children and adults (Bruce et al., 2005).
Unfortunately, the effectiveness of these traditional treatments is mixed. One meta-analysis concluded that there was no evidence to demonstrate that SSRIs are more efficacious than placebo in the treatment of trichotillomania (Bloch et al., 2007). According to a Trichotillomania Impact Project survey, treatments for TTM have only been successful with 15% of adult patients and 17% of pediatric patients (Woods et al., 2006). Due to the lack of effective treatment options for TTM, individuals struggling with TTM are seeking alternative treatments that may be more successful than traditional forms of treatment, such as probiotics, N-acetylcysteine, and inositol.
Probiotics are beneficial bacteria that are introduced into the gastrointestinal tract. Interestingly, gut bacteria are able to synthesize the same neurotransmitters that are found in the brain. These gut neurotransmitters have the same structure and are produced via the same biosynthetic pathway as those in the brain. Gut bacteria are able to communicate with the brain through the vagus nerve, a phenomenon known as the “gut-brain connection.” Researchers have found that probiotics can improve many aspects of psychological health including depression and anxiety by modifying the gut microbiome. Probiotics can also directly modulate the immune system (Lyte, 2011).
Success stories attest to the ability of probiotics to offer relief to individuals suffering from TTM. A year after my article “Gut feelings: the future of psychiatry may be inside your stomach” was published on The Verge, I was contacted via email by a gentleman who shared his incredible story on how he was able to cure himself from trichotillomania by using probiotics after reading the article. Here is his story:
“I am a middle aged Caucasian male, and my first history of chronic hair pulling was when I had a very brief episode when I was in the 7th grade. First off, let me explain what I tried to do in the past, all unsuccessfully, to find a solution. I tried pure willpower. I tried discussing my hair pulling with my family doctor. I went to a psychiatrist, one of the most talented psychiatrists in the field, and he told me that there was nothing that psychiatry could do for me. I just happened to stumble onto an article on the web about a psychiatrist that was successfully treating some of his patients with various Obsessive Compulsive disorder symptoms with Probiotics! I started taking two capsules of 30 billion CFU capsules a day on the day after Thanksgiving, 2013. In the last week of January of 2014 I all of a sudden realized, one day, “Hey, wait a minute, I have not pulled my hair for the past 2 weeks now”. It seems I had stopped hair pulling in mid-January and didn’t even notice it until two weeks had gone by. I was hopeful, but skeptical at that point. Over the past 15 years, I have never, ever, had more than a 1 day period of time that I did not pull out my own hair. I continued taking the probiotics every day. As of the day I am writing this, today, July 17, 2014, I have not pulled even one hair since mid-January. Not only have I been symptom free, but I never had to apply any will power or focus on stopping the hair pulling to help me stop. What happened is that the urges did not need to be fought off, they simply dissipated by themselves and have completely disappeared, all by themselves. I did no counseling sessions, no coaching sessions, no group therapy, no psychiatric medications, no psychological treatments of any kind, nothing except the probiotics.”
You can read his full story on https://howicuredmyhairpulling.wordpress.com
N-acetylcysteine (NAC) also shows promise for reducing compulsive behavior. NAC is an amino acid that is converted in the body to a powerful antioxidant known as glutathione. In a double-blind trial, 50 adults with trichotillomania were randomized to NAC (1,200-2,400 mg/d) or placebo for 12 weeks. Those receiving NAC significantly improved on measures of urges to pull hair, actual amount of pulling, perceived control over the behavior, and distress associated with hair pulling. Of those taking NAC, 56% were “much” or “very much” improved compared with 16% of those taking placebo (Grant et al., 2009).
There is also emerging evidence for inositol as treatment for TTM. Inositol is a sugar produced by the human body from glucose. The sugar is found in many foods, particularly fruits such as cantaloupe and oranges. Inositol is a signaling molecule involved in many important functions such as nerve guidance and the breakdown of fats. In the past, inositol has been used effectively for depression, anxiety, and OCD. Two case studies have been documented of young women with TTM who befitted from 18 grams per day of inositol (Seedat et al., 2001). Inositol is thought to help regulate serotonin levels, which is particularly relevant for disorders including TTM, OCD, depression, and anxiety that may be caused by low levels of serotonin.
Indeed, disruptions in the gastrointestinal tract or gut microbiota can manifest as physiological and psychological symptoms. Fortunately, several animal studies have found that the introduction of probiotics were effective at modulating the gut microbiota. While the complex connection between the gut and brain continue to be examined, the available research suggests that probiotics may be a promising intervention for several illnesses including depression, anxiety, and compulsive disorders.
American Psychiatric Association (APA). (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.
Bloch, M. H., Landeros-Weisenberger, A., Dombrowski, P., Kelmendi, B., Wegner, R., Nudel, J., & ... Coric, V. (2007). Review: Systematic Review: Pharmacological and Behavioral Treatment for Trichotillomania. Biological Psychiatry, 62(Bipolar Disorder and OCD: Circuitry of Impulsive and Compulsive Behaviors), 839-846.
Bruce, T. O., Barwick, L. W., & Wright, H. H. (2005). Diagnosis and management of Trichotillomania in children and adolescents. Pediatric Drugs, (6), 365.
Epictetus, Long, G., & Epictetus. (1891). The discourses of Epictetus ; with the Encheiridion and fragments / reprinted from the translation of George Long. London : G. Bell and Sons, 1891 ([London] : Chiswick Press).
Grant, J., Odlaug, B., & Suck, W. (2009). N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: A double-blind, placebo-controlled study. Archives Of General Psychiatry, 66(7), 756-763.
Lyte, M. (2011). Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics. Bioessays, 33(8), 574-581.
Parakh, P., & Srivastava, M. (2010). The Many Faces of Trichotillomania. International Journal of Trichology, 2(1), 50–52.
Seedat, S., Stein, D. J., & Harvey, B. H. (2001). Inositol in the treatment of trichotillomania and compulsive skin picking. The Journal Of Clinical Psychiatry, 62(1), 60-61.
Woods, D. W., Flessner, C. A., Franklin, M. E., Keuthen, N. J., Goodwin, R. D., Stein, D. J., & Walther, M. R. (2006). The trichotillomania impact project (TIP): Exploring phenomenology, functional impairment, and treatment utilization. Journal Of Clinical Psychiatry, 67(12), 1877-1888.
JAMES GREENBLATT, MD
Guest: Dr. James Greenblatt
Presenter: Neal Howard
Guest Bio: James M. Greenblatt, MD, is a pioneer in the field of integrative medicine and one of the founders of Integrative Medicine for Mental Health (IMMH). He currently serves as the chief medical officer and vice president of medical services at Walden Behavioral Care in Waltham, Massachusetts. Dr. Greenblatt is also an assistant clinical professor in the Department of Psychiatry at Tufts University School of Medicine in Boston.
Segment overview: Dr. James Greenblatt, MD, author of “Breakthrough Depression Solution: Mastering Your Mood with Nutrition, Diet & Supplementation”, talks about the treatment of depression in the future and how it is not a one-size-fits-all prescription.
Originally published to Health Professional Radio
JAMES GREENBLATT, MD
Vitamin D deficiency has been linked to a wide range of major psychiatric illnesses and is an emerging area of interest for researchers. From my experience working with individuals with psychosis and schizophrenia in both inpatient and outpatient settings, I have often found low vitamin D levels in this patient population where the severity of symptoms were inversely correlated to serum vitamin D levels. Most recently, laboratory tests of individuals with schizophrenia, psychosis, elective mutism, and bipolar disorders revealed consistent serum vitamin D levels below 20 ng/ml. As vitamin D levels normalized, symptoms improved. While the mechanism is unclear, recent research suggests that vitamin D’s action on the regulation of inflammatory and immunological processes likely affects the manifestation of clinical symptoms and treatment response in schizophrenic patients (Chiang, Natarajan, & Fan, 2016).
The link between vitamin D deficiency and the development of schizophrenia has been researched among patients of all ages around the globe. One meta-analysis reviewed 19 studies published between 1988 and 2013 and found a strong association between vitamin D deficiency and schizophrenia. Of the 2,804 participants from these studies, over 65% of the participants with schizophrenia were vitamin D deficient. Vitamin D deficient participants were 2.16 times more likely to have schizophrenia than vitamin D sufficient participants (Valipour, Saneei, & Esmaillzadeh, 2014).
The risk of schizophrenia and vitamin D status vary with season of birth, latitude, and skin pigmentation. The UV rays required to make vitamin D are reduced in the months most associated with an increase in the birth of individuals who later develop schizophrenia. One review including a total of 437,710 individuals with schizophrenia found that most individuals were born in January and February. These newborns were thus exposed to lower levels of UV rays in their prenatal and perinatal periods. An increased rate of schizophrenia is also seen at higher latitudes, especially among immigrants. This may again be related to UV availability and subsequent vitamin D status. At higher latitudes, a dark skinned individual will also have a more pronounced reduction in vitamin D than a lighter skinned individual. The lighter skinned individual will have less melanin which allows the skin to absorb UV rays more effectively. It is estimated that individuals with darker skin at higher latitudes are more likely to develop schizophrenia than the general population (Chiang et al., 2016).
Swedish researchers reviewed medical charts at a psychiatric outpatient department to identify possible predictors of vitamin D deficiency. Over 85% of the 117 psychiatric patients had suboptimal vitamin D levels. Those with schizophrenia and autism had the lowest levels. Middle East, Mediterranean, South-East Asian or African ethnic origin were strong predictors of low vitamin D. The patients receiving vitamin D supplements to correct their deficiencies achieved considerable improvement of psychosis and depression symptoms (Humble et al., 2010).
Vitamin D concentrations were measured in 50 schizophrenia patients in Israel aged 19-65. Lower mean vitamin D concentrations were detected among patients with schizophrenia (15 ng/ml) compared to controls (20 ng/ml) after adjusting for the impact of sun exposure and supplements (Itzhaky et al., 2012). Likewise, 92% of 102 adult psychiatric inpatients in New Zealand also had suboptimal vitamin D levels and were more than twice as likely as Europeans to have severely deficient levels below <10 ng/ml (Menkes et al., 2012).
In a prospective birth cohort of 3,182 children in England, researchers measured vitamin D levels at age 9.8 years and assessed psychotic experiences at age 12.8 years. Vitamin D concentrations during childhood were associated with psychotic experiences during early adolescence. If psychotic experiences are related to the development of schizophrenia, this supports a possible protective association of higher vitamin D concentrations with schizophrenia (Tolppanen et al., 2012).
Vitamin D deficiency is associated with more severe symptoms. Cross sectional analyses were carried out on mentally ill adolescents aged 12-18 who required either inpatient or partial hospitalization. Of the 104 patients evaluated, 72% had insufficient vitamin D levels. Vitamin D status was related to mental illness severity. Those with vitamin D deficiency were 3.5 times more likely to have hallucinations, paranoia, or delusions (Gracious et al., 2012). A second study supports this finding. Vitamin D was analyzed from 20 patients with first-episode schizophrenia. Greater severity of negative symptoms (blunted affect, emotional withdrawal, poor rapport, passive-apathetic social withdrawal, abstract thinking, and stereotyped thinking) was strongly correlated with lower vitamin D status. Lower vitamin D levels were also associated with more severe overall cognitive deficits (Graham et al., 2015).
McGrath et al. (2010) investigated the relationship between neonatal vitamin D status and later risk of schizophrenia. They identified 424 cases with schizophrenia from the Danish Psychiatric Central Register and analyzed their neonatal dried blood spots. Not surprisingly they found a significant seasonal variation in vitamin D status and significantly lower levels of vitamin D in the offspring of mothers who immigrated to Denmark. They also found that those with lower neonatal concentrations of vitamin D had an increased risk of schizophrenia. The researchers estimated that if all these neonates had optimal vitamin D levels, over 40% of schizophrenia cases could have been averted.
The same group of researchers also discovered that taking vitamin D supplements during the first year of life is associated with a reduced risk of schizophrenia in males. They looked at a Finnish birth cohort and collected data about the frequency and dose of vitamin D supplementation during infancy. Males who regularly took vitamin D supplements had an 88% decreased risk of schizophrenia compared to those who never took supplements (McGrath et al., 2004).
The mechanism underlying this nutrient-illness relationship can only be speculated upon. Those with schizophrenia commonly have elevated markers of inflammation. Cells that are low in vitamin D produce high levels of inflammatory cytokines while cells with adequate vitamin D release significantly less of these cytokines. Thus there may be an anti-inflammatory mechanism (Chiang et al., 2016). Vitamin D regulates the transcription of many genes involved in pathways implicated in schizophrenia, including genes involved in synaptic plasticity, neuronal development, and protection against oxidative stress (Graham et al., 2015). Animal studies show that vitamin D deficiency in the gestational period affects dopamine metabolism and alters the dopamine system in the developing brain. Dopamine has been implicated in the pathogenesis of schizophrenia. Vitamin D deficiency during the gestational period can also affect brain structures that are associated with schizophrenia (Valipour, Saneei, & Esmaillzadeh, 2014).
While there is a lack of trials analyzing vitamin D supplements in the treatment of psychosis and schizophrenia, individuals with low levels of vitamin D within this patient population will tend to benefit from supplementation. Based on over 25 years of clinical experience, I have observed significant improvement in treatment outcomes utilizing vitamin D 5,000 to 10,000 i.u. once daily as an adjunct therapy. Serum vitamin D levels should be re-evaluated every two months until optimal levels are achieved.
- Chiang, M., Natarajan, R., & Xiaoduo, F. (2016). Vitamin D in schizophrenia: a clinical review. Evidence Based Mental Health, 19(1), 6-9.
- Cieslak, K., Feingold, J., Antonius, D., Walsh-Messinger, J., Dracxler, R., Rosedale, M., & ... Malaspina, D. (2014). Low vitamin D levels predict clinical features of schizophrenia.
- Crews, M., Lally, J., Gardner-Sood, P., Howes, O., Bonaccorso, S., Smith, S., & ... Gaughran, F. (2013). Vitamin D deficiency in first episode psychosis: A case–control study. Schizophrenia Research, 150(Special Section: Negative Symptoms), 533-537.
- Graham, K., Lieberman, J. , Lansing, K., Perkins, D., Calikoglu, A., & Keefe, R. (2015). Relationship of low vitamin D status with positive, negative and cognitive symptom domains in people with first-episode schizophrenia. Early Intervention In Psychiatry, 9(5), 397-405. Schizophrenia Research, 159(2/3), 543-545.
- Hedelin, M., Löf, M., Olsson, M., Lewander, T., Nilsson, B., Hultman, C. M., & Weiderpass, E. (2010). Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population. BMC Psychiatry, 10,38.
- Humble, M. B., Gustafsson, S., & Bejerot, S. (2010). Low serum levels of 25-hydroxyvitamin D (25-OHD) among psychiatric out-patients in Sweden: Relations with season, age, ethnic origin and psychiatric diagnosis. Journal Of Steroid Biochemistry And Molecular Biology, 121(Proceedings of the 14th Vitamin D Workshop), 467-470.
- Itzhaky, D., Bogomolni, A., Amital, D., Arnson, Y., Amital, H., & Gorden, K. (2012). Low serum Vitamin D concentrations in patients with schizophrenia. Israel Medical Association Journal, 14(2), 88-92.
- McGrath, J., Saari, K., Hakko, H., Jokelainen, J., Jones, P., Järvelin, M., & ... Isohanni, M. (2004). Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophrenia Research, 67, 237-245.
- McGrath, J. J., Eyles, D. W., Pedersen, C. B., Anderson, C., Ko, P., Burne, T. H., & ... Mortensen, P. B. (2010). Neonatal Vitamin D status and risk of schizophrenia: a population-based case-control study. Archives Of General Psychiatry, (9), 889.
- Menkes, D., Marsh, R., Lancaster, K., Grant, M., Dean, P., & du Toit, S. (2012). Vitamin D status of psychiatric inpatients in New Zealand's Waikato region. BMC Psychiatry, 12, 68.
- Shivakumar, V., Kalmady, S. V., Amaresha, A. C., Jose, D., Narayanaswamy, J. C., Agarwal, S. M., & ... Gangadhar, B. N. (2015). Serum vitamin D and hippocampal gray matter volume in schizophrenia. Psychiatry Research, 233(2), 175-179.
- Tolppanen, A., Sayers, A., Fraser, W. D., Lewis, G., Zammit, S., McGrath, J., & Lawlor, D. A. (2012). Serum 25-Hydroxyvitamin D3 and D2 and Non-Clinical Psychotic Experiences in Childhood. Plos ONE, 7(7), 1-8.
- Valipour, G., Saneei, P., & Esmaillzadeh, A. (2014). Serum vitamin D levels in relation to schizophrenia: a systematic review and meta-analysis of observational studies. The Journal Of Clinical Endocrinology And Metabolism, 99(10), 3863-3872.
- Yüksel, R. N., Altunsoy, N., Tikir, B., Cingi Külük, M., Unal, K., Goka, S., … Goka, E. (2014). Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation. Therapeutic Advances in Psychopharmacology, 4(6), 268–275.
This is a radio show interview with Dr. William Shaw on local New York station WBAI 99.5 from April 15, 2016. Take Charge of Your Health hosts Corinne Funari, RPA, CCN and Linda Segal interviewed Dr. Shaw about the dangers of glyphosate, the world's most widely used herbicide being sprayed on our crops. To listen to the show, click here. Dr. Shaw's interview starts at 13:00.
William Shaw, PhD
In response to the inaccurate, unscientific article by Thomas Lodi, M.D. on oxalates1 in the December 2015 issue of Townsend Letter, I will make the following point by point responses:
(1)Cartoons about Popeye.
I will not use any cartoons in my response. Anyone interested in cartoons should immediately stop reading this article and start reading their local paper’s comic section.
The tone for accuracy of the author is set in the very first paragraph of his article in which his first reference, #23, has nothing to do with my green smoothie article, which is reference #24. A better reference would actually be #2 from my article2. When the clock strikes 13, the accuracy of the other 12 hours of the clock is in serious question.
(3)Inaccuracy about the contribution of endogenous production to total oxalate load.
Lodi states that 80-90% of oxalates in the body are endogenously produced. Unfortunately, the best scientific study refutes his assertion. According to Holmes et al3, who did extremely well-controlled studies on every aspect of oxalate metabolism and has publishedforty-one scientific articles on oxalates in the peer reviewed literature, the mean dietary oxalate contribution to total oxalate in the diet is 52.6 % on a high oxalate diet which was defined as a diet of 250 mg oxalate per day. The person drinking a green smoothie with 2 cups of raw spinach ingests 1312 mg of oxalates or over five times the level of what Holmes considers a high-oxalate diet, just in the spinach consumption alone and over 26 times the amount of oxalates in a low oxalate diet (50 mg per day)4. The estimated human production of oxalates is 40 mg per day3. On a green smoothie diet with two cups of spinach, the diet in normal humans contains 33 times the endogenous human production of oxalates just based on the spinach alone.
All of Lodi’s assertions about the benefits of a vegetarian diet are meaningless since there is no single vegetarian diet; there are as many vegetarian diets as there are vegetarians.
(4)Inaccuracy about the availability of calcium and magnesium in spinach.
Lodi states that “every plant, green and otherwise (including spinach) has abundant magnesium and calcium and potassium”. Unfortunately, none of the calcium and magnesium in spinach or other high oxalate plants is bioavailable since it is strongly bound to oxalates. Furthermore, the average oxalate value of spinach is 7.5 times its calcium content, making spinach a very poor choice for someone to maintain adequate calcium stores5. According to Kohmani, who added a good deal of spinach, similar to the diet of a person ingesting a daily green smoothie or a large daily spinach salad, to the diet of rats to determine its effects5:
“If to a diet of meat, peas, carrots and sweet potatoes, relatively low in calcium but permitting good though not maximum growth and bone formation, spinach is added to the extent of about 8% to supply 60% of the calcium, a high percentage of deaths occurs among rats fed between the age of 21 and 90 days. Reproduction is impossible. The bones are extremely low in calcium, tooth structure is disorganized and dentine poorly calcified. Spinach not only supplies no available calcium but renders unavailable considerable of that of the other foods. Considerable of the oxalate appears in the urine, much more in the feces.”
(5)Lodi argues that his patients haven’t complained about kidney stones while drinking a lot of green smoothies so oxalates must not be problematic.
Lodi’s contention that his patients on a high oxalate diet don’t have kidney stones is anecdotal. He presents no data from active chart review of his patients to determine if questions about kidney stones were ever asked. Furthermore, it is doubtful that his patients would have even have connected their diet with their kidney stones. I have had numerous seminars on the connection between oxalates and kidney stones and it is common to get feedback from the audience members that they had kidney stones shortly after starting either a diet including a spinach green smoothie or a large spinach salad on a regular basis. Since these comments were not even solicited, it is likely that even a larger number of individuals may have experienced kidney stones but were shy to voice their experiences. A neurologist friend attributes his recent severely-disabling stroke to the dietary changes encouraged by his wife that placed him on a daily green spinach smoothie for a considerable time.
Furthermore, Lodi seems to think that a lack of kidney stones indicates a lack of oxalate problems. However, oxalates may form in virtually every organ of the body including the eyes, vulva, lymph nodes, liver, testes, skin, bones, gums, thyroid gland, heart, arteries, and muscles6-7. Oxalates may occur in these other organs without appearing in the urinary tract at all and in individuals without genetic hyperoxalurias7. Oxalates have been implicated in heart disease7, stroke, vulvodynia, and autism8-10. Women of child-bearing age need to be especially careful of the spinach green smoothie diet because of the autism oxalate connection and the negative effects of spinach containing oxalates on fertility5. Prisoners in the state prisons in Illinois were encouraged by the Weston-Price Nutrition Foundation to file a lawsuit against the state because of their deteriorating health due to a high amount of soy protein in the prison diet11. Soy protein is tied with spinach as the highest oxalate foods4. Oxalates are especially toxic to the endothelial cells of the arteries, leading to atherosclerosis12. Oxalate crystals are concentrated in the atherosclerotic lesions7. Such lesions have commonly been overlooked by the use of stains of atherosclerotic lesions that make the oxalate crystals difficult to visualize. The relatives of people consuming the green smoothie diet would only know of their loved ones’ oxalate deposits throughout their organs on the day of their autopsies which employed pathological examinations that can detect oxalates.
Primary genetic hyperoxaluria is not the major cause of kidney stones in adults since 80% of individuals died of this disorder before age 20 and it is so rare that it could not possibly be the cause of most cases of oxalate kidney stones13. However, a genetic polymorphism present in up to 20% of Caucasian groups called P11L codes for a protein with three times less activity of alanine: glyoxylate aminotransferase (AGT) than the predominant normal activity polymorphism, leading to excessive endogenous production of oxalates14. This substantial group of individuals would be even more susceptible to the harm of a high oxalate diet. Kidney stones were rampant in the United Kingdom during the World Wars when rhubarb, another high oxalate food, was recommended as a substitute for other low oxalate but unavailable vegetables13.
In summary, those who do not care for their health can eat or drink whatever they want. But they should realize that their diets are fad-based and/or based on quasi-religious ( “feasts” as part of the “awakening” according to Lodi) reasons, not based on hard scientific evidence. Furthermore, they should be aware that their diet may kill them15. The green smoothie fad will go down in medical history with the AMA journal allowing cigarette advertising with physician endorsements and the use of mercury-containing teething powder for babies as one of the greatest health follies in a considerable time.
1. Lodi, T. Green smoothie bliss: Was Popeye secretly on dialysis? Townsend Letter for Doctors. Dec 2015 pgs 28-39
2. Shaw, W. The Green Smoothie Health Fad: This Road to Health Hell is Paved with Toxic Oxalate Crystals. Townsend Letter for Doctors. Jan 2015 Available online at: http://www.townsendletter.com/Jan2015/green0115.html
3. Holmes RP, Goodman HO, and Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney International, Vol. 59 (2001), pp. 270–276
4. Harvard T.H. Chan School of Public Health Nutrition Department's File Download Site on oxalates in the diet. https://regepi.bwh.harvard.edu/health/Oxalate/files Accessed December 1,2015
5. Kohmani,EF. Oxalic acid in foods and its fate in the diet. Journal of Nutrition 18(3):233-246,1939
6. Jessica N. Lange, Kyle D.Wood, John Knight, Dean G. Assimos, and Ross P. Holmes. Glyoxal Formation and Its Role in Endogenous Oxalate Synthesis. Advances in Urology Volume 2012, Article ID 819202, 5 pages doi:10.1155/2012/819202
7. G.A. Fishbein, R. G. Micheletti, J. S. Currier, E. Singer, and M. C. Fishbein, Atherosclerotic oxalosis in coronary arteries, Cardiovascular Pathology, vol. 17, no. 2, pp. 117–123, 2008.
8. Giuseppe Di Pasquale, , Mariangela Ribani, Alvaro Andreoli, , Gian Angelo Zampa, and Giuseppe Pinelli, Cardioembolic Stroke in Primary Oxalosis With Cardiac Involvement. Stroke 1989, 20:1403-1406
9. Solomons CC, Melmed MH, Heitler SM.Calcium citrate for vulvar vestibulitis. A case report. J Reprod Med. 1991 Dec;36(12):879-82.
10. Konstantynowicz J, Porowski T, Zoch-Zwierz W, Wasilewska J, Kadziela-Olech H, Kulak W, Owens SC, Piotrowska-Jastrzebska J, Kaczmarski M. A potential pathogenic role of oxalate in autism. Eur J Paediatr Neurol. 2012 Sep;16(5):485-91.
11. Monica Eng, Chicago Tribune reporter. Soy in Illinois prison diets prompts lawsuit over health effects. December 21, 2009. http://articles.chicagotribune.com/2009-12-21/news/0912200121_1_soy-protein-soy-cheeses-soyfoods-association. Accessed December 2,2015
12. RI Levin, PW Kantoff and EA Jaffe Uremic levels of oxalic acid suppress replication and migration of human endothelial cells. Arterioscler Thromb Vasc Biol 1990, 10:198-207
13. A. J. Chaplin Histopathological occurrence and characterization of calcium oxalate: a review. J. Clin. Path., 1977, 30, 800-811
14. Michael J. Lumb and Christopher J. Danpure. Functional Synergism between the Most Common Polymorphism in Human Alanine:Glyoxylate Aminotransferase and Four of the Most Common Disease-causing Mutations. Journal of Biological Chemistry Vol. 275, No. 46, November 17, pp. 36415–36422, 2000
Sanz P, Reig R: Clinical and pathological findings in fatal plant oxalosis. Am J Forensic Med Pathol 13:342–345, 1992
Matthew Pratt-Hyatt, PhD
Personalized medicine has been called the future of medicine since the inception of the Human Genome Project (HGP) in the early 90s, which was a project set up by the United States government to sequence the complete human genome. The HGP was completed in 2003.(1) This new wealth of knowledge allowed scientist to develop tests that sequence the 3 billion base pairs and the 20-25 thousand genes in the human genome.(2) Over those 25 thousand genes there are over 80 million variants in the human genome.(3) These variations include single nucleotide polymorphisms (SNPs) as well as small deletions and insertions throughout the genome and many of those variants play a significant role in patient health. The dream of personalized healthcare is to use genetic testing to understand a patient’s predisposition for developing different conditions, and then undergo molecular diagnostic tests to determine how the environment is interacting with these genes.
At The Great Plains Laboratory, Inc., we have been primarily focused on looking at the second half of this equation -- finding the root cause of patient symptoms in a wide variety of chronic disorders. We have developed tests that look at hundreds of different analytes and have worked with doctors to help them interpret how these data can be used to personalize treatment for patients. Even though traditional medicine has mostly followed the philosophy that one size fits most, functional medicine says that each person is unique and deserves unique care. That is why we have developed our new genetic test, GPL-SNP1000, which now allows us to have a more complete picture of what contributes to a patient’s health status.
The first generation of genetic sequencing was first published in 1977 by Frederick Sanger. This technology first used radiolabeling and then later fluorescent labeling for sequencing reactions. This technology uses these labeled nucleotides and the length of the copied DNA in order to arrange the nucleotide sequence. The Sanger method is good for sequencing short (300-1000 nucleotides long) amounts of DNA in a single reaction.(4) There are some benefits and drawbacks to this type of sequencing. The Sanger technology allowed scientists to sequence one stretch of DNA and then compare it to a database and look for differences. This technology was useful if you had a suspected mutation in a known gene, because you could sequence the whole gene in a small number of reactions. However, there are also drawbacks to this technology, such as only being able to sequence a low number of both genes and patients at one time.
The next major advance in genotyping technology was the advent of the TaqMan Allelic Discrimination assay. This assay uses a fluorescent reporter that is generated during the Polymerase chain reaction (PCR).(5) The TaqMan assay uses DNA probes that differ at the polymorphic SNP site. One set of probes is complementary to the wild-type allele and another set is complementary to the variant allele. These probes only bond to sequences of DNA that are 100% complementary. These probes, which are bonded to fluorescent reporter dyes, are also bonded to quencher dyes. The quencher dye prevents the reporter from becoming fluorescent when both are attached to the reporter. The probes hybridize to the complementary strands. When DNA is copied during the PCR reaction by Taq polymerase the probe is degraded and the dyes are released. The DNA is then genotyped by determining the signal intensity ratio of the dyes bonded to the wild-type probe and the mutant variant.(6)
The most recent advance in sequencing technology has been the advent of Next Generation Sequencing (NGS). There are several companies that use different means to accomplish this, but NGS machines are able to monitor what nucleotide is added at each place during the DNA chain prolongation reaction. This principle has been labeled “sequencing-by-synthesis.” This new technique allows for sequencing to move from about 1000 nucleotides long to about 1000 billion bases per run. This gives researchers the ability to perform a very in-depth sequence for one patient, or sequence several dozen patients at a time using more pinpointed analysis.(7)
Using NGS, our scientists at The Great Plains Laboratory, Inc., in partnership with the genetic company Courtagen, have developed what we think will be the next great tool for personalized medicine. Our new test GPL-SNP1000 is a genetic screen that covers 1048 SNPs over 144 different genes. These genes are broken up into nine different groups, which are: DNA methylation, mental health, drug metabolism/chemical detoxification, autism risk, oxalate metabolism, cholesterol metabolism, acetaminophen toxicity, and the transporter genes.
The GPL-SNP1000 test report (see figure 1) is programmed to only depict the SNPs that are mutated. We are including the gene symbol, the RS number (or reference SNP number), which indicates which SNP is mutated (so that you can look up new research on that mutation), a pathogenicity number (we look at all available research on each SNP and predict how severe a mutation at that SNP would be) genotype (what is the change in nucleotide), phenotype (whether the patient is heterozygous or homozygous [one of two mutated copies], and the disease(s) associated with that mutation (we have listed the most common conditions associated with every SNP in our assay). The report also has interpretations that are auto-generated for genes that are found to be mutated in the assay. One additional feature our report has is hyperlinks to the references on Pubmed used to make the interpretations. This allows both patients and healthcare practitioners to review the literature about those particular mutations, without having to search the Internet for these articles.
We were also very strategic about selecting the nine specific groups of genes and SNPs that our test evaluates. We talked to dozens of functional medicine professionals and asked them what groups of genes would help them the most in their practices. The top answer was the DNA methylation pathway, which was not surprising because the most utilized genetic tests on the market are currently the MTHFR tests. The MTHFR pathway is a process by which carbons are added onto folic acid from amino acids and redistributed onto other compounds throughout the body. This process is responsible for the formation of methionine, S-Adenosyl methionine (SAMe), and thymidylate monophosphate (dTMP). These compounds play critical roles in nucleotide synthesis, neurotransmitter function, detoxification, and numerous other processes.(8) We believed that we could provide better coverage of these genes than previously done by other genetic tests. We knew that no other test had more than 35 SNPs in their assay for the MTHFR gene, so we redesigned our existing DNA Methylation Profile by increasing the number of SNPs from 32 to 105. One reason why this test is so popular is the very common occurrence of one of the more serious SNPs of the MTHFR gene, rs1801133 (C667T). This mutation has mutant allele frequency of 39% for the heterozygous genotype and a 17% frequency for the homozygous mutant. It can decrease the enzyme’s functionality by 90%, causing patients to have an increased risk of developmental delay, mental retardation, vascular disease, and stroke.(9)
Our second most requested group of genes was those that correlate with mental health. Mutations to these genes can predispose patients to a variety of ailments including depression, schizophrenia, anxiety, and bipolar disorder. We designed this group to include the nine genes and 53 SNPs that are most commonly the cause of mental disorders. One of the more important genes in this group is the catechol-o-methyltransferase (COMT) gene. This enzyme is responsible for the degradation of catecholamines, which include dopamine, epinephrine, and norepinephrine. Mutations to COMT can lead to bipolar disorder, anxiety, obsessive compulsive disorder, and attention deficit disorder. One of the more common mutates of COMT is the Val108Met mutation (rs4680), which can cause a heightened risk of developing anxiety.(10)
The next gene group we focus on is the group for drug metabolism/chemical detoxification. These enzymes include the cytochrome P450s, sulfur transferases, glutathioine transferases, and the methyltransferases. The P450s are important for multiple molecular functions including drug metabolism, hormone production, toxicant detoxification, and more. The P450s are expressed throughout the body, but primarily in the liver. There are 57 different genes for the cytochrome P450 enzymes, however eight are responsible for most of the drug metabolism done by the body. The P450 enzymes are responsible for 75% of all drug metabolism.(11) Mutations to P450s can cause changes in the rate of metabolism of some medications, causing decreased effectiveness and other dangerous complications. Some medications known to be affected by drug mutations include but are certainly not limited to warfarin, Diazepam, antiarrhythmic drugs, antidepressants, and antipsychotics.(12-13) P450s that are known to have alleles in the population that dramatically affect drug metabolism include CYP2C9, CYP2C19, and CYP2D6.(14) Besides the P450s,which are considered phase I detoxification, GPL-SNP1000 covers phase II detoxification enzymes that include glutathione S-transferse, Sulfotranferase 1a1, betaine-homocysteine methyltransferase 2, and UDP glucuronosyltransferease 1A1 .
The next group of genes we analyze tells parents if they or their children may have a mutation that is commonly found in autistic patients. It has been reported that the prevalence of autism has increased dramatically in the last two decades.(15) We looked at many different studies to determine what mutations are more commonly found in autistic patients, but not found in the neurotypical, non-autistic public. Three large studies that were done using over 3000 participants were very useful in developing this panel.(16-18) We selected 252 SNPs that cover 33 genes that were found in these three studies. These genes cover many different pathways including glucose metabolism, ion and calcium channels, DNA transcription regulation, and nervous system genes.
Next, we included a group of genes that are involved with oxalate metabolism. Oxalate and its acidic form, oxalic acid, are formed from diet, human metabolism, and yeast/fungal. Oxalates are known to combine with calcium to form crystals that can cause kidney stones. These crystals may also form in the bones, joints, blood vessels, lungs, and even the brain.(19) The oxalate group from our test analyzes 32 SNPs that cover five different genes. One of these genes is Alanine-glyoxylate aminotransferase (AGXT). Mutations to AGXT can lead to kidney stones and primary hyperoxaluria.(20)
In addition to these groups of genes, our new test also looks at genes for cholesterol metabolism, as well as transporters. Both of these pathways are important for the body to regulate itself properly. Cholesterol is important because it is critical for producing cellular membranes, hormones, and bile acids. There are numerous recent articles discussing the importance of these cholesterol-produced molecules that regulate sugar metabolism and our metabolic rate. Transporters are also necessary because they move large molecules and other chemicals into and out of the cell, which are not able to move across cellular membranes without assistance. Without transporters, cells are not able to attain the proper building blocks necessary for optimum functionality or dispose of toxic cellular waste.
Truly personalized medicine may not be a reality today; however I believe the recent developments in genetic testing are the biggest leaps we’ve had in a long time. GPL-SNP1000 helps healthcare professionals know what problems their patients may have now or in the future due to genetic mutations, as well as what specific treatments may be beneficial. The Great Plains Laboratory, Inc. offers cutting-edge diagnostic tools that help identify underlying causes of many chronic conditions and provides recommendations for treatment based on test results. In addition to our new genetic test, we offer other comprehensive biomedical testing, including our Organic Acids Test (OAT), IgG Food Allergy Test, GPL-TOX (our Toxic Organic Chemical Profile), and many more. Utilizing a combination of our genetic and molecular diagnostics, we can now see a more complete picture of a patient’s overall health, both at present and potential problems for the future, which can all be addressed now. I think the sun is rising on a new horizon of health.
1. Biello D, Harmon K. Tools for Life. Sci Am. 2010;303:17-18.
2. Marian AJ. Sequencing your genome: what does it mean? Methodist Debakey Cardiovasc J. 2014;10(1):3-6.
3. McCarthy DJ, Humburg P, Kanapin A, et al. Choice of transcripts and software has a large effect on variant annotation. Genome Med. 2014;6(3):26.
4. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977;74(12):5463-5467.
5. Livak KJ, Flood SJ, Marmaro J, Giusti W, Deetz K. Oligonucleotides with fluorescent dyes at opposite ends provide a quenched probe system useful for detecting PCR product and nucleic acid hybridization. PCR Methods Appl. 1995;4(6):357-362.
6. Shi MM, Myrand SP, Bleavins MR, de la Iglesia FA. High throughput genotyping for the detection of a single nucleotide polymorphism in NAD(P)H quinone oxidoreductase (DT diaphorase) using TaqMan probes. Mol Pathol. 1999;52(5):295-299.
7. Lin B, Wang J, Cheng Y. Recent Patents and Advances in the Next-Generation Sequencing Technologies. Recent Pat Biomed Eng. 2008;2008(1):60-67.
8. Wiemels JL, Smith RN, Taylor GM, et al. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci U S A. 2001;98(7):4004-4009.
9. Deloughery TG, Evans A, Sadeghi A, et al. Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease. Circulation. 1996;94(12):3074-3078.
10. Craddock N, Owen MJ, O'Donovan MC. The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol Psychiatry. 2006;11(5):446-458.
11. Guengerich FP. Mechanisms of drug toxicity and relevance to pharmaceutical development. Drug Metab Pharmacokinet. 2011;26(1):3-14.
12. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5(1):6-13.
13. Ingelman-Sundberg M. Genetic susceptibility to adverse effects of drugs and environmental toxicants. The role of the CYP family of enzymes. Mutat Res. 2001;482(1-2):11-19.
14. Kalra BS. Cytochrome P450 enzyme isoforms and their therapeutic implications: an update. Indian J Med Sci. 2007;61(2):102-116.
15. Rutter M. Incidence of autism spectrum disorders: changes over time and their meaning. Acta Paediatr. 2005;94(1):2-15.
16. Sanders SJ, He X, Willsey AJ, et al. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron. 2015;87(6):1215-1233.
17. Iossifov I, O'Roak BJ, Sanders SJ, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216-221.
18. De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209-215.
19. Hall BM, Walsh JC, Horvath JS, Lytton DG. Peripheral neuropathy complicating primary hyperoxaluria. J Neurol Sci. 1976;29(2-4):343-349.
20. Poore RE, Hurst CH, Assimos DG, Holmes RP. Pathways of hepatic oxalate synthesis and their regulation. Am J Physiol. 1997;272(1 Pt 1):C289-294.
William Shaw, PhD
Calcium is one of the most tightly regulated substances in the body. In addition to the role of calcium as a structural element in bones and teeth (99% of the body’s calcium is in the bones), calcium is critically needed for nerve function. When calcium in the plasma drops about 30%, the person may develop tetany, a condition that is often fatal due to overstimulation of the nerves in both the central nervous system and peripheral nervous system, leading to tetanic contraction of the skeletal muscles. The concentration of calcium in the plasma is one of the most constant laboratory values ever measured. In the great majority of normal people, calcium only varies from 9-11 mg per dL, regardless of the diet (1). The reason is a complex hormonal system that utilizes the bones as a source of calcium. This regulatory system employs the parathyroid gland that secretes parathyroid hormone or parathormone to digest the bones and release calcium when there is only a small decrease in the plasma calcium. Parathormone also increases the absorption of calcium from the gastrointestinal tract and the kidney tubules. When calcium rises in the plasma, parathormone secretion decreases, depositing more calcium in the bones while renal and gastrointestinal absorption are decreased. Calcitonin, a polypeptide hormone produced by the thyroid gland, opposes the effects of parathyroid hormone. In addition, vitamin D increases the absorption of calcium from the gastrointestinal tracts and the kidney tubules like parathyroid hormone but has little effect on digesting bones to release calcium. One of the most controversial and misunderstood topics is what is the optimum nutritional intake of calcium and vitamin D. In the center of the controversy is the role of calcium in the initiation of plaque in the arteries, leading to atherosclerosis and cardiovascular disease.
An average adult ingests about 750 mg per day of calcium and secretes about 625 mg of calcium in the intestinal juices. If all the ingested calcium is absorbed, there would be a net absorption of 125 mg per day of calcium. Since the average person excretes about 125 mg calcium per day in the urine, the average person has a zero net calcium balance except when bone is being deposited. If bone is being deposited due to the stress of exercise or following a fracture, the regulation of the amount of urinary calcium excretion is the major factor to allow for bone growth. One of the major factors that prevents calcium absorption is the presence of high amounts of oxalates in the diet. The human body has the ability to make some oxalate endogenously, perhaps about 40 mg per day in individuals with a favorable genetic makeup. A low oxalate diet contains less than 50 mg per day of oxalates while a high oxalate diet with two cups or more of spinach, nuts, and berries in a smoothie or salad per day could easily contain 1500 mg per day of oxalates. Such high amounts of oxalates readily use up the 125 mg of available calcium, forming insoluble calcium oxalate salts which can deposit in every organ of the body. These deposits can easily initiate endothelial damage that can lead to strokes and myocardial infarctions (heart attacks) and such oxalate deposits have been detected in atherosclerotic lesions. The person on a high oxalate diet will have a much greater need for calcium and/or magnesium than the person on a low oxalate diet.
Since urine is the major controlling element for maintaining calcium balance that is under tight hormonal control, it appears to me that urine calcium is the best indicator of adequate dietary calcium. The most common reasons for low urine calcium are inadequate dietary calcium and/or a high oxalate diet. Other reasons for calcium deficiency include hypoparathyroidism, pseudohypoparathyroidism, vitamin D deficiency, nephrosis, nephritis, bone cancer, hypothyroidism, celiac disease, and malabsorption disorders.
The most common reason for high urine calcium is a diet high in calcium. Other reasons for calcium excess are vitamin D intoxication, hyperparathyroidism, osteolytic bone metastases, myeloma, excessive immobilization, Cushing’s syndrome, acromegaly, distal renal tubular acidosis, thyrotoxicosis, Paget’s disease, Fanconi’s syndrome, schistosomiasis, breast and bladder cancers, and sarcoidosis.
Magnesium is an essential element like calcium and is also in the bones (66% of the body’s magnesium is in the bones). It is a cofactor with many enzymatic reactions especially those requiring vitamin B6. Like extremely low calcium, extremely low magnesium can also cause tetany of the muscles.
The most common reason for low urine magnesium is low magnesium in the diet. Low magnesium in the diet may increase the incidence of oxalate crystal formation in the tissues and kidney stones. Less common causes of low magnesium include celiac disease, other malabsorption disorders, dysbiosis, vitamin D deficiency, pancreatic insufficiency, and hypothyroidism. Early signs of magnesium deficiency include loss of appetite, nausea, vomiting, migraine headaches, fatigue, and weakness. As magnesium deficiency worsens, numbness, tingling, muscle contractions and cramps, seizures, personality changes, anxiety, depression, attention deficit, abnormal heart rhythms, and coronary spasms can occur. Low urinary magnesium for long time periods is associated with increased risk of ischemic heart disease.
The most common reason for high urine magnesium is high magnesium in the diet. Less common causes of high urine magnesium include alcoholism, diuretic use, primary aldosteronism, hyperthyroidism, vitamin D excess, gentamicin toxicity, and cis-platinum toxicity. Increased urinary magnesium excretion can occur in people with insulin resistance and/or type 2 diabetes. Symptoms of marked magnesium excess can include diarrhea, hypotension, nausea, vomiting, facial flushing, retention of urine, ileus, depression, lethargy before progressing to muscle weakness, difficulty breathing, extreme hypotension, irregular heartbeat, and cardiac arrest.
- Guyton, Arthur. Textbook of Medical Physiology,3rd edition. WB Saunders Co, Philadelphia, 1966,pgs1100-1118.
- Fleming, CR, et al. The importance of urinary magnesium values in patients with gut failure. Mayo Clinic Proceedings. 1996 Jan;71(1):21-4.