The Role of Heavy Metals and Environmental Toxins in Psychiatric Disorders

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).

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References:

1. Braun et al (2006). Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environmental Health Perspectives, 114(12), 1904-1909.

2. Cecil et al. (2008). Decreased Brain Volume in Adults with Childhood Lead Exposure. PLoS Medicine, 5(5), PLoS Medicine, 2008, Vol.5(5).

3. Engel et al. (2010). Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environmental Health Perspectives, 118(4), 565-71.

4. Evans et al. (2014). Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. Neurotoxicology, 45, 91-99.

5. Kicinski et al. (2015). Neurobehavioral function and low-level metal exposure in adolescents. International Journal of Hygiene and Environmental Health, 218(1), 139-146.

6. Kim et al. (2009). Phthalates Exposure and Attention-Deficit/Hyperactivity Disorder in School-Age Children. Biological Psychiatry, 66(10), 958-963.

7. 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.

8. Ritz, et al. (2012). Phosphate additives in food--a health risk. Deutsches Ärzteblatt International, 109(4), 49-55.

9. Roberts & Karr. (2012). Pesticide exposure in children. Pediatrics, 130(6), E1765-88.

10. 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.

11. Sioen et al. (2013). Prenatal exposure to environmental contaminants and behavioural problems at age 7–8years. Environment International, 59, 225-231.

12. Suarez-Lopez et al. (2013). Acetylcholinesterase activity and neurodevelopment in boys and girls. Pediatrics, 132(6), E1649-58.

13. 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.

14. 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.

15. 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.

16. 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

17. 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.

Integrative Treatments for Behavioral Problems in Children

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.

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References

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.

Lithium: The Untold Story of the Magic Mineral That Charges Cell Phones and Preserves Memory

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.

Low-Dose Lithium

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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References

Bech P. The full story of lithium. Nord J Psychiatry. 2007;61(46):35–39. 
Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2.
Diniz BS, Machado-Vieira RM, Forlenza OV. Lithium and neuroprotectin: translational evidence and implications for the treatment of neuropsychiatric disorders. Neuropsychiatr Dis Treat.2013;9:493–500.
Farah R et al. Lithium's gene expression profile, a cDNA microarray study. Cell Mol Neurobiol. 2013;33:411–420. 
Mauer S, Vergne D, Ghaemi NS. Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Aust N Z J Psychiatry. 2014;48(9):809–818. 
Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res. 2013;10(1):104–107.
Shorter E. The history of lithium therapy. Bipolar Disord. 2009;11(2):4–9.
Schrauzer GN. Lithium: occurrence dietary intakes, nutritional essentiality. J Am Coll Nutr.2002;21(2):14–21.
Schrauzer GN, de Vroey E. Effects of nutritional lithium supplementation on mood. Biol Trace Elem Res.1994;40:89–101.
Schrauzer GN, Shrestha KP. Lithium in drinking water and the incidences of crimes, suicides and arrests related to drug addictions. Biol Trace Elem Res. 1990;25:105–113.
Strobasch AD, Jefferson JW. The checkered history of lithium in medicine. Pharm Hist.1980;22(2):72–76.
Young AH, Hammond JM. Lithium in mood disorders: increasing evidence base, declining use? Br J Psychiatry 2007;191:474–476.
Young W. Review of lithium effects on brain and blood. Cell Transplant. 2009;18:951–975.

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.com.

Lithium: The Cinderella Story about a Mineral That May Prevent Alzheimer’s Disease

James Greenblatt, MD and Kayla Grossman, RN

*Originally published in the December 2015 issue of The Neuropsychotherapist

Every four seconds, someone in the world develops dementia. Worldwide, an estimated 35.6 million people already live with a form of this neurodegenerative disorder, and these numbers are on a staggering rise. The World Health Organization has projected that the number of cases of dementia will double by 2030 (65.7 million) and triple by the year 2050 (115.4 million). Already in America the most common type of dementia, Alzheimer’s disease, is the sixth leading cause of death; one in three seniors passes with this type of crippling memory loss. (WHO, 2015)

Progressive memory loss that interferes with activities of daily living is not a normal part of aging. In fact, research is showing that cognitive decline is the result of pathophysiological processes deep within the brain beginning many years, even decades, before dementia symptoms start.

This knowledge is frightening. It brings attention to the pervasive and silent nature of these diseases. Neurodegenerative disorders have become an international public health issue with devastating medical, social and economic consequences. And yet, from the perspective of conventional medicine, relatively little is known about how to treat or stop them.

In the midst of a harrowing race to find answers, one unassuming prevention strategy has shown promise above the rest. This remedy is none other than the simple, brain-protecting mineral: lithium.

Understanding Alzheimer’s Disease
Chances are you’ve heard of Alzheimer’s disease before,or may even know someone who has suffered from it. Alzheimer’s disease is a tragic neurological malady characterized by a progressive and irreparable shrinking of brain tissue. The result is a devastating decline in memory, social abilities and communication skills in sufferers leading, eventually, to death.

Less than 5 percent of the time, Alzheimer’s disease results from a specific genetic combination that essentially guarantees a person will develop the disease. More commonly it is the result of a complex combination of subtle genetic, lifestyle and environmental factors that affect the brain over a lifetime. Scientists believe that Alzheimer’s disease is not an acute condition, but rather the result of numerous damages that occur over the years. This slow, cumulative patterning helps to explain why most patients with Alzheimer’s disease don’t present with symptoms until over the age of 65.

Pathologically, Alzheimer’s disease is the result of two trademark injuries or lesions that occur at the cellular level: plaques and tangles. Plaques are formed by deposits of small protein fragments called amyloid-B or beta-amyloid peptides. Clumps of these proteins block the synapses or spaces between brain cells or neurons. With the synapses barricaded, normal cell-to-cell signaling cannot occur and communication is essentially stopped in certain regions of the brain. Meanwhile, other lesions, called neurofibrillary tangles, develop within the neurons themselves. These tangles result from a disruption in the production of a different type of protein, called tau. Normally, tau protein filaments help to circulate nutrients and other essential supplies throughout the cell. In Alzheimer’s disease however, the strands destabilize, becoming twisted or “tangled”. Without this system to circulate vital compounds, neurons “starve” or die. The physiological processes required for memory and learning are halted, and symptoms begin to arise.

There is now evidence to show that these damaging beta-amyloid plaques and neurofibrillary tangles may actually be a relatively common malformation in the aging human brain. New research is revealing that plaques can appear a full 30-40 years before symptoms of cognitive decline even begin to show. (Langbaum et al., 2013) One recent study published in the Journal of the American Medical Association churned up the following statistics: 10% percent of healthy 50-year-olds have amyloid deposits. This figure swells to 33% by age 80, and 44% at age 90. (Visser et al., 2015). Individuals with a mental illness, specifically patients with depression or bipolar disorder, are at an even greater risk for developing these dementia-precursors in the brain. (DaSilva et al., 2013)

Nutrition and Brain Health
Currently there are no widely accepted preventative, or even ameliorative, treatments for most dementias including Alzheimer’s disease. A swarm of clinical trials have been launched in recent years, all with the goal of finding effective pharmaceutical interventions to stop or slow the progression of neurodegenerative disorders like Alzheimer’s disease. However between the years 2002 and 2012, 99.6% of drugs studies aimed at preventing, curing or improving Alzheimer’s symptoms were either halted or discontinued. (Devlin, 2013) Most of the tested drugs were making patients sicker, not better, and came with appalling side effects.

With pharmaceutical approaches failing, many clinicians and researchers are turning to nutrition to find their answers. Accumulating study results show that nutrition has profound effects on brain health. The brain functions at a high metabolic rate and uses a substantial portion of total nutrient intake. It relies on amino acids, fats, vitamins, minerals, and trace elements. These influence both brain structure and function. Nutrition also contributes to neuron plasticity and repair, key functions for mental health and well-being over the long term.

A collaborative research project funded by the National Institute on Aging recently found that individuals on a whole foods diet, rich in items like berries, leafy greens and fish, are at less of a risk for Alzheimer’s disease. (RUMC, 2015) Essential fatty acids such as omega-3s are also being studied at several large universities for their role in supporting brain health. Other experts have called Alzheimer’s disease “type 3 diabetes,” pointing to excess sugar intake as a major contributor to the disorder. The overlap between nutrition and cognitive function is becoming more widely accepted in the world of neurology.

Lithium: The Unlikely Treatment
One mineral that has shown great promise in the treatment of Alzheimer’s disease is the mineral lithium, a nutrient with established benefits for the treatment of mental health disorders.

Lithium salts have been used for centuries as a popular health tonic. Over the course of history this simple mineral has been applied to heal ailments as wide-ranging as asthma, gout, and migraines. Lithium springs were once sought-after health destinations, visited by authors, political figures and celebrities. Throughout the 19th and into the 20th century, lithium was used as a mineral supplement to fortify a variety of foods and beverages. The Sears, Roebuck & Company Catalogue of 1908 advertised Schieffelin’s Effervescent Lithia Tablets for a variety of afflictions. By 1907, The Merck Index listed 43 different medicinal preparations containing lithium. In 1929, a soft drink inventor named Charles Leiper Grigg even created a new lithiated beverage he called Bib-Label Lithiated Lemon-Lime Soda, now known as “7-Up.” The beverage contained lithium citrate until 1950, and was originally known and marketed for its potential to cure hang-overs after a night of drinking alcohol, and to lift mood.

Today lithium is still found naturally in food and water. The U.S. 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 like egg and milk providing the rest. Lithium has even been officially added to the World Health Organization’s list of nutritionally essential trace elements alongside zinc, iodine and others. 

In modern medicine, lithium is most widely acknowledged for its ability to encourage mood stability in patients with affective disorders. With years of research and clinical use to back it, a substantial body of evidence now exists to show that high-dose lithium restores brain and nervous system function, right down to the molecular level. This incredible mineral is now being considered for the treatment of cognitive decline.

Scientists first became interested in the use of lithium for treating neurodegenerative disorders when they observed that bipolar patients using lithium therapy seemed to have lower rates of cognitive decline than peers on other medications. In an attempt to figure out the legitimacy of this observation, one study compared the rates of Alzheimer's disease in 66 elderly patients with bipolar disorder and chronic lithium therapy, with the occurrence in 48 similar patients who were not prescribed the mineral. Findings in favor of lithium were staggering: patients receiving continuous lithium showed a decreased prevalence of Alzheimer’s disease (5%) as compared with those in the non-lithium group (33%). (Nunes et al., 2007) Two further studies in Denmark confirmed this phenomenon using different study designs, but achieving strikingly similar results. In this study series, investigators surveyed the records of over 21,000 patients who had received lithium treatment, and found that therapy was associated with decreased levels of both dementia and Alzheimer’s. (Kessing et al., 2008, 2010)

Unfortunately, the first clinical trials testing lithium with dementia patients proved disappointing. Researchers attempted to fit lithium into the same diagnostic treatment framework used by drug companies in the beginning: testing the therapy on patients who already had fully developed Alzheimer’s. At this point, the damages to the brain were simply too great to turn around.

One small, open-label study looked at low-dose lithium use in 22 Alzheimer’s disease patients over the course of one year. (MacDonald et al., 2008) While researchers concluded that prescription lithium salts were relatively safe in this population, there were no observed cognitive benefits. The small baseline sample size coupled with a high discontinuation rate, may have been to blame for these discouraging results. It may also have been too late for lithium to make a difference in these advanced stages of illness.

Another multi-center, single-blind study looked at the use of lithium sulfate in participants with mild Alzheimer’s disease over a 10 week period. (Hampel et al., 2009) They too failed to find significant effects of lithium treatment on cognitive performance or related biomarkers. One major issue with this trial however, was the length of observation. It likely takes months, not weeks, to see substantial cognitive shifts in patients.

A group led by Forlenza et al (2011), sought to correct for these initial design flaws. Focus was shifted away from the post-diagnosis period and settled on prevention. This unique study attempted to determine whether long-term lithium treatment could stop Alzheimer’s disease from occurring in high risk individuals. Forty-five participants with mild cognitive impairment (MCI), a precursor to Alzheimer’s, were randomized to receive lithium or a placebo. Over the 12-month trial, lithium dosages were kept at sub-therapeutic levels (150mg to 600mg daily) to minimize potential side effects. At the conclusion of the study, researchers discovered that those in the lithium group had a decreased presence of destructive tau proteins when compared to pre-study levels. This finding came in stark contrast to the the tau levels of the placebo group, which had increased steadily over the course of the study. What’s more, the lithium group showed improved performance on multiple cognitive scales. Overall tolerability of lithium was deemed good as patients reported limited side effects and the adherence rate to treatment was an impressive 91%. Researchers concluded that lithium had a significant disease-modifying impact on preventing dementia and Alzheimer’s disease when initiated early on in the disease progression.

The Promise of Low-Dose Lithium
Additional testing has found that lithium can be effective when used at low-doses or supplemental levels, similar to those found naturally in water and foods. Studies are beginning to show that the benefits of pharmaceutical lithium (used at an average of 600-1200 mg daily) can be achieved with much smaller and safer doses (between 1-20 mg). When lithium is used at these low or nutritional doses, the risks of side effects plummet.

Evidence pointing to the usefulness of low-dose lithium has come primarily from epidemiological studies conducted by geology specialists and other professionals. Eleven different studies have looked at lithium levels in the drinking water from various regions throughout the globe. Two dozen counties in Texas, the 100 largest American cities and 99 districts in Austria have been considered, alongside other locations in Greece and Japan.  (Dawson, 1970; Schrauzer & Shrestha, 1990; Kapusta et al., 2011 Kabacs et a., 2011; Giotakos et al., 2015; Sugawara et al., 2013) Lithium levels in the water have been compared to rates of behavioral issues (including psychiatric admissions, suicide, homicide, crimes), medical illnesses and overall mortality in these areas. Collectively the studies have analyzed outcomes in well-over 10 million subjects. In 9 of the 11 studies, a positive association between high lithium levels and beneficial behavioral, legal and medical outcomes has been observed. In each of the negative studies, levels of lithium were likely too low to yield any significant health effects. (Mauer et al., 2014)

These studies have spurred interest in the clinical applications of low-dose lithium, although trials have been slow coming. Because lithium is a naturally occurring mineral and is not patentable (and therefore not profitable), little financial backing has been put towards the cause. In one highly-regarded study published in Alzheimer’s Research however, a scant 0.3 mg of lithium was administered once daily to Alzheimer’s patients for 15 months. (Nunes, 2013) Those receiving lithium demonstrated stable cognitive performance scores throughout the duration of the study, while those in the control group suffered progressive declines.  Moreover, three months into the study, the seemingly impossible happened: the lithium treatment cohort began showing increasing mini-mental status scores.

Additional, high-quality trials using low-dose lithium are essential, especially in the realm of dementia and cognitive decline.

Key Neuroprotective Mechanisms
There is now clean scientific evidence to suggest not only that lithium protects the brain, but also how it does so. Lithium ions (at both high and low concentrations) have been shown to modify key cellular cascades that increase neuronal viability and resilience. Most prominently, lithium disrupts the key enzyme responsible for the development of the amyloid plaques and neurofibrillary tangles associated with Alzheimer’s disease. This enzyme is called Glycogen Synthase Kinase-3 (GSK-3)—a serine/threonine protein kinase that normally plays a major role in neural growth and development. In the healthy brain, GSK-3 is very important; it helps to carry out the synaptic remodeling that drives memory formation.

In Alzheimer’s disease however, GSK-3 becomes hyperactive in the areas of the brain that control cognition and behavior, including the hippocampus and frontal cortex. When “revved-up” in this way, GSK-3 phosphorylates, or activates, amyloid-B and tau proteins within the neurons. Eventually, these proteins accumulate and create the signature plaques and neurofibrillary tangles that disrupt brain function and result in symptoms of cognitive decline. Lithium works as a direct GSK-3 inhibitor to prevent this over-expression, halting inappropriate amyloid production and the hyper-phosphoryation of tau proteins before they become problematic. (Hooper et al., 2008; Wada, 2009)

In addition to protecting the brain from the development of plaques and tangles, lithium has been shown to repair existing damages brought on by the 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. (Leyhe et al., 2009) Patients on lithium have been found to have significantly higher gray matter volumes in the brain, hinting that lithium has powerful stimulatory effects on neurogenesis. One study has even directly demonstrated that damaged nerve cells exposed to lithium respond with increases in dendritic number and length. (Dwidivi & Zhang, 2014)

Conclusion
Alzheimer’s and dementia have become modern health problems of epidemic proportions. Nonetheless, relatively few pharmacological solutions have been discovered for preventing, treating and reversing associated cognitive decline. As conventional treatment approaches falter, clinicians and researchers have been turning more and more to natural alternatives. It has become increasingly evident that nutrition is a key factor when it comes to brain health.

Evidence suggests that the mineral lithium in particular, may play a major role in shifting the pathophysiological cascade associated with dementia and Alzheimer’s disease. In clinical studies, long-term lithium therapy has been found to decrease the problematic plaques and tangles leading to symptoms of cognitive decline. This powerful mineral acts by inhibiting damaging enzymes and stimulating the release of protective neurotrophic factors in the brain.

Lithium ions have been found to operate efficiently at low doses mimicking those found in nutritional sources. At these sub-pharmaceutical levels, lithium has been shown to be a beneficial and safe neuroprotective therapy across age groups and with minimal side effects.

The safety profile of low-dose lithium is particularly attractive, as prevention strategies for dementia are most effective when started early and continued for long periods of time. The dangerous plaques and tangles involved in Alzheimer’s disease start up to 40 years before the appearance of symptoms. What’s more, 10% of healthy 50 year olds already have amyloid deposits developing in the brain tissues. Thus, for optimal effectiveness, steps to protect the brain must be taken at a much younger age than previously thought.

When started early, low-dose lithium may be the key intervention to prevent cognitive decline. But first, we must move past the stigma that surrounds it. As psychiatrist Ana Fels wrote in her recent article for The New York Times, “[o]ne could make a case that lithium is the Cinderella of psychotropic medications, neglected and ill used.” Lithium is the single most proven substance to keep neurons alive, and yet it continues to be viewed in the public mind as a dangerous and scary drug. Lithium is found readily in our environment, food, water and each and every cell in the human body. It is time we change the conversation around one of nature’s most effective and powerful neuroprotective remedies.

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References

1. Da Silva, J., et al. 2013. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatry 202:177-186

2. Dawson, E.P., Moore, T.D. & McGanity, W.J. 1970. The mathematical relationship of drinking water lithium and rainfall on mental hospital admission. Dis Nerv Syst 31:1–10.

3. Devlin, H. 2015. Scientists find first drug that appears to slow Alzheimer’s Disease. The Guardian. Retrieved from: http://www.theguardian.com/science/2015/jul/22/scientists-find-first-drug-slow-alzheimers-disease.

4. Dwivedi, T. & Zhang, H. 2014. Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered apoptotic-regulatory proteins. Front Neurosci 8:1-8.

5. Fels, A. 2014. Should we all take a bit of lithium? The New York Times. Retrieved from: http://www.nytimes.com/2014/09/14/opinion/sunday/should-we-all-take-a-bit-of-lithium.html

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

7. Giotakos, O., et al. 2015. Lithium in the public water supply and suicide mortality in Greece. Biol Trace Elem Res 156(1–3):376–379.

8. Hampel, H., et al. 2009. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo- controlled, multicenter 10-week study. J Clin Psychiatry 70 (6): 922-31.

9. Hooper, C., Killick, R., Lovestone, S. 2008. The GSK3 hypothesis of Alzheimer’s Disease. J Neurochem 104, 1433-1439.

10. Kapusta N.D., et al. 2011. Lithium in drinking water and suicide mortality. Br J Psychiatry.198(5):346–350.

11. Kessing, L. V., et al. 2008. Lithium treatment and risk of dementia. Arch Gen Psychiatry 65(11):1331-1335.

12. Kessing, L.V., Forman, J.L., & Andersen, P.K. 2010. Does lithium protect against dementia? Bipolar Disord 12(1): 87-94.

13. Langbaum, J.B.S., et al. 2013. Ushering in the study and treatment of preclinical Alzheimer’s Disease. Nat Rev Neurol 9(7): 371-381.

14. Leyhe, T., et al. 2009. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s Disease. J Alzheimers Dis 16:649-656.

15. Macdonald, A., et al. 2008. A feasibility and tolerability study of lithium in Alzheimer’s disease. Int J Geriatr Psychiatry 23 (7): 704-11.

16. Mauer, S., Vergne, D., & Ghaemi, S. N. 2014. Standard and trace-dose lithium: A systematic review of dementia prevention and other behavioral benefits. Aust NZ J Psychiatry Retrieved from: http://anp.sagepub.com/content/early/2014/06/10/0004867414536932

17. Nunes, M. A., Viel, T. A., Buck, H. S. 2013. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s Disease. Curr Alzhiemer Res 10, 104-107.

18. Nunes, P. V., Forlenza, O. V., Gattaz, W. F. 2007. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 190:359-60.

19. Rush University Medical Center. 2015. Diet may help prevent Alzheimer’s: MIND diet rich in vegetables, berries, whole grains, nuts. Retrieved from: https://www.rush.edu/news/diet-may-help-prevent-alzheimers

20. Schruazer, G.N.., & Shrestha, K.P. 1990. Lithium in drinking water and the incidences of crimes, suicide and arrests related to drug addiction. Biol Trace Elem Res 25: 105-113.

21. Sugawara, N., et al. 2013. Lithium in tap water and suicide mortality in Japan. Int J Environ Res Public Health. 10(11):6044–6048.

22. Visser P.J., et al. 2015. Prevalence of cerebral amyloid pathology in persons without dementia. JAMA 313(19):1924-1938.

23. Wada, A. 2009. Lithium and neurpsychiatric therapeutics: neuroplascticity via glycogen synthase kinase-3B, B-catenin and neurotrohpin cascades. J Pharmacol Sci 110, 14-28.

24. World Health Organization. 2015. Facts and Figures: Dementia. Retrieved from: http://www.who.int/mediacentre/factsheets/fs362/en/.

Lithium Deficiency: Common in Mental Illness and Social Ills

William Shaw, PhD

Jim Adams found that in an evaluation of hair samples from children with autism that lithium values were significantly lower in young children of autism and their mothers. I have made similar observations on many children with autism tested through The Great Plains Laboratory. The lithium values of some children with autism are in the lowest one percentile. Ironically, the use of highly purified water to prevent ingestion of toxic chemicals may have deprived pregnant women of a trace amount of lithium found in tap water needed for normal brain development and this deficiency appears to be a significant autism risk factor. This switch to purified bottled water has taken place in the past 20 years during the same time as the surge in the autism epidemic.

The tenfold increase in bottled water consumption (image 1) coincides nearly exactly with an approximate ten-fold increase in autism incidence over the same time period. It is possible that this factor might in fact be equal in importance to mercury exposure as an autism risk factor.

In very small amounts lithium appears to be an essential element needed for good mental health. Areas of the country where lithium is present at high levels in the drinking water have less violence and crime. A study of 27 Texas counties found that the incidences of suicide, homicide and rape were significantly higher in counties whose drinking water supplies contained little or no lithium compared to counties with higher water lithium levels, even after correcting for population density.

Corresponding associations with the incidences of robbery, burglary and theft were also significant, as were associations with the incidences of arrests for possession of opium, cocaine and their derivatives. In addition, I have commonly found very low lithium values in hair samples of patients with schizophrenia. Furthermore, hair lithium has been shown to be a good indicator of lithium deficiency. Scalp hair lithium levels reflect the average intakes of bioavailable lithium over a period of several weeks to months and represent a noninvasive means of determining the dietary lithium intakes. Furthermore, lithium is needed to transport folate and vitamin B-12 into the brain. The common deficiencies of lithium may be one of the reasons children with autism require such high doses of certain forms of these vitamins.

A typical hair profile of a child with autism is shown in the adjoining diagram, demonstrating the extremely low lithium intakes common in autism. Blood tests done at conventional medical laboratories measure lithium but only are useful to measure the extremely high lithium levels associated with lithium drug therapy. Such tests are useless for the measurement of the very low lithium levels associated with nutritional lithium.

A provisional Recommended Daily Allowance (RDA) for a 70 kg adult of 1,000 mcg/day (about 1% of the dose of lithium commonly used as a pharmaceutical agent) has been suggested for a 70 kg adult, corresponding to 14.3 mcg per kg body weight. Note carefully that mcg stands for micrograms, not milligrams (mg)! Doses of lithium between 150-400 mcg per day (doses that are nutritional rather than pharmacological) resulted in improved mood in drug abusers, some of whom had a long history of drug abuse. The nutritional use of lithium is completely safe. No safety assessments or blood tests need to be done for nutritional supplementation of lithium in contrast to the use of lithium as a drug, which requires blood testing to prevent toxic overdose. If hair values are low or a person only drinks purified deionized or reverse-osmosis water, I think the person should take lithium supplements. New Beginnings Nutritionals has a convenient liquid that contains 50 mcg lithium per drop. I remember when the bottled water products were first launched and I was incredulous that people would pay for a product they could get for virtually nothing simply by turning on their faucets. Now I drink reverse-osmosis water, which is essentially free of trace elements (and toxic chemicals), and I take 500-mcg lithium daily by adding lithium drops to my orange juice.

Clinical References

• Moore GJ, et al. Lithium-induced increase in human brain grey matter. Lancet. 2000 Oct 7; 356(9237): 1241-2. http://www.ncbi.nlm.nih.gov/pubmed/11072948

• Schrauzer GN. Lithium: occurrence, dietary intakes, nutritional essentiality. J Am Coll Nutr. 2002 Feb;21(1):14-21.http://www.ncbi.nlm.nih.gov/pubmed/11838882

• Schrauzer G.N., Shrestha K.P., Flores-Arce M.P. Lithium in scalp hair of adults, students and violent criminals. Effects of supplementation and evidence for interactions of lithium with Vitamin B and other trace elements. Biological Trace Element Research, 1992 Aug 34 (2): 161 – 76. http://www.ncbi.nlm.nih.gov/pubmed/1381936

• J.B. Adams, C.E. Holloway, F. George, D. Quig. Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biological Trace Element Research. 110: 193-209, 2006.http://www.ncbi.nlm.nih.gov/pubmed/16845157

Porphyrin Testing and Heavy Metal Toxicity: Unresolved Questions and Concerns

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OXALATES CONTROL IS A MAJOR NEW FACTOR IN AUTISM THERAPY

Test Implications for Yeast and Heavy Metals
William Shaw, Ph.D.

What are Oxalates?

Oxalate and its acid form oxalic acid are organic acids that are primarily from three sources: the diet, from fungus such as Aspergillus, Penicillium, and possibly Candida (1-9), and also from human metabolism (10).

Oxalic acid is the most acidic organic acid in body fluids and is used commercially to remove rust from car radiators. Antifreeze (ethylene glycol) is toxic primarily because it is converted to oxalate. Two different types of genetic diseases are known in which oxalates are high in the urine. The genetic types of hyperoxalurias (type I and type II) can be determined from the Organic Acids Test (OAT) done at The Great Plains Laboratory. Foods especially high in oxalates include spinach, beets, chocolate, peanuts, wheat bran, tea, cashews, pecans, almonds, berries, and many others. Oxalates are not found in meat or fish at significant concentrations. Daily adult oxalate intake is usually 80-120 mg/d; it can range from 44-1000 mg/d in individuals who eat a typical Western diet.  A complete list of high oxalate foods is available at  http://patienteducation.upmc.com/Pdf/LowOxalateDiet.pdf.

High oxalate in the urine and plasma was first found in people who were susceptible to kidney stones. Many kidney stones are composed of calcium oxalate. Stones can range in size from the diameter of a grain of rice to the width of a golf ball. It is estimated that 10% of males may have kidney stones some time in their life. Because many kidney stones contain calcium, some people with kidney stones think they should avoid calcium supplements. However, the opposite is true. When calcium is taken with foods that are high in oxalates, oxalic acid in the intestine combines with calcium to form insoluble calcium oxalate crystals that are eliminated in the stool. This form of oxalate cannot be absorbed into the body. When calcium is low in the diet, oxalic acid is soluble in the liquid portion of the contents of the intestine (called chyme) and is readily absorbed from the intestine into the bloodstream. If oxalic acid is very high in the blood being filtered by the kidney, it may combine with calcium to form crystals that may block urine flow and cause severe pain.

Such crystals may also form in the bones, joints, blood vessels, lungs, and even the brain (10-13). In addition, oxalate crystals in the bone may crowd out the bone marrow cells, leading to anemia and immunosuppression (13). In addition to autism and kidney disease, individuals with fibromyalgia and women with vulvar pain (vulvodynia) may suffer from the effects of excess oxalates (14,15).

Oxalate crystals may cause damage to various tissues. The sharp crystals may cause damage due to their physical structure and may also increase inflammation. Iron oxalate crystals may also cause significant oxidative damage and diminish iron stores needed for red blood cell formation (10). Oxalates may also function as chelating agents and may chelate many toxic metals such as mercury and lead. Unlike other chelating agents, oxalates trap heavy metals in the tissues.

Many parents who told me of adverse vaccine reactions of their children reported that their child was on antibiotics at the time of vaccination. Yeast overgrowth, commonly associated with antibiotic usage, might lead to increased oxalate production and increased combination with mercury, slowing mercury elimination if oxalates were so high that they deposited in the bones with attached mercury. It would be interesting to see if increased elimination of heavy metals occurs after oxalate elimination by antifungal therapy and low oxalate diet. In addition, oxalates from the diet or from yeast/fungus in the gastrointestinal tract bind calcium, magnesium, and zinc, perhaps leading to deficiencies even when dietary sources should be adequate.

Oxalates and Autism

Oxalates in the urine are much higher in individuals with autism than in normal children (Figure 1). As a matter of fact, 36% of the children on the autistic spectrum had values higher than 90 mmol/mol creatinine, the value consistent with a diagnosis of genetic hyperoxalurias while none of the normal children had values this high. 84% of the children on the autistic spectrum had oxalate values outside the normal range (mean ± 2 sd). None of the ± 2 sd).  None of the children on the autistic spectrum had elevations of the other organic acids associated with genetic diseases of oxalate metabolism, indicating that oxalates are high due to external sources.

As shown in the table, both mean and median values for urine oxalates are substantially higher  in autism compared to the normal population. As a matter of fact the mean oxalate value of 90.1 mmol/mol creatinine is equal to the lower cutoff value for the genetic hyperoxalurias. The median value in autism is six times the normal median value and the mean value in autism is five times the normal mean value.

A brand new diet is being extensively used to treat children with autism and other disorders. Researcher named Susan Owens discovered that the use of a diet low in oxalates markedly reduced symptoms in children with autism and PDD. For example, a mother with a son with autism reported that he became more focused and calm, that he played better, that he walked better, and had a reduction in leg and feet pain after being on a low oxalate diet. Prior to the low oxalate diet, her child could hardly walk up the stairs. After the diet, he walked up the stairs very easily. Many hundreds of children with autism throughout the world are now being placed on this diet with good results.

Benefits Reported By Parents Using Low Oxalate Diet

Improvements in gross and fine motor skills
Improvements in expressive speech
Better counting ability
Better receptive and expressive language
Increased imitation skills
Increased sociability
Speaking in longer sentences
Decreased rigidity
Better sleep

Reduced self-abusive behavior
Increased imaginary play
Improved cognition
Loss of bed wetting
Loss of frequent urination
Improved handwriting
Improved fine motor skills
Improvement in anemia

... and many others

How Can High Oxalates Be Treated?

Use antifungal drugs to reduce yeast and fungi that may be causing high oxalate. Children with autism frequently require years of antifungal treatment. I have noticed that arabinose, a marker used for years for yeast/fungal overgrowth on the Organic Acids Test (OAT) at The Great Plains Laboratory, is correlated with high amounts of oxalates (Table 2 and Figure 2) and arabinose has been found to be an important fuel for fungal oxalate production (5). Candida organisms have been found surrounding oxalate stones in the kidney (9).

Give supplements of calcium citrate to reduce oxalate absorption from the intestine. Citrate is the preferred calcium form to reduce oxalate because citrate also inhibits oxalate absorption from the intestinal tract. The best way to administer calcium citrate would be to give it with each meal. Children over the age of 2 need about 1000 mg of calcium per day. Of course, calcium supplementation may need to be increased if the child is on a milk-free diet. The most serious error in adopting the gluten-free, casein-free diet is the failure to adequately supplement with calcium.

Try N-Acetyl glucosamine to stimulate the production of the intercellular cement hyaluronic acid to reduce pain caused by oxalates (16).

Give chondroitin sulfate to prevent the formation of calcium oxalate crystals (17).

Vitamin B6 is a cofactor for one of the enzymes that degrade oxalate in the body and has been shown to reduce oxalate production (18).

Increase water intake to help to eliminate oxalates.

Excessive fats in the diet may cause elevated oxalate if the fatty acids are poorly absorbed because of bile salt deficiency. Non-absorbed free fatty acids bind calcium to form insoluble soaps, reducing calcium’s ability to bind oxalate and reduce oxalate absorption (19). If taurine is low in the Amino Acids Test, supplementation with taurine may help stimulate bile salt production (taurocholic acid), leading to better fatty acid absorption and diminished oxalate absorption.

Probiotics may be very helpful in degrading oxalates in the intestine. Individuals with low amounts of oxalate-degrading bacteria are much more susceptible to kidney stones (20). Both Lactobacillus acidophilus and Bifidobacterium lactis have enzymes that degrade oxalates (21).

Increase intake of essential omega-3 fatty acids, commonly found in fish oil and cod liver oil, which reduces oxalate problems (22). High amounts of the omega-6 fatty acid, arachidonic acid, are associated with increased oxalate problems (23). Meat from grain fed animals is high in arachidonic acid.

Take supplements of vitamin E, selenium, and arginine which have been shown to reduce oxalate damage (24, 25).

Undertake a low oxalate diet. This may be especially important if the individual has had Candida for long periods of time and there is high tissue oxalate buildup. There may be an initial bad reaction lasting several days to a week after starting the diet since oxalates deposited in the bones may begin to be eliminated as oxalates in the diet are reduced.

Evaluate vitamin C intake. Vitamin C can break down to form oxalates. However, in adults, the amount of oxalate formed did not increase until the amount exceeded 4 g of vitamin C per day (26). A large study of more than 85,000 women found no relation between vitamin C intake and kidney stones (27). In addition, an evaluation of 100 children on the autistic spectrum at The Great Plains Laboratory revealed that there was nearly zero correlation between vitamin C and oxalates in the urine (Table 2). Megadoses (more than 100 mg/Kg body weight per day) of vitamin C were shown to markedly reduce autistic symptoms in a double blind placebo controlled study (28) so any restriction of vitamin C needs to be carefully weighed against its significant benefits.

Oxalate Metabolism

In the genetic disease hyperoxaluria type I and in vitamin B-6 deficiency, there is a deficiency in the enzyme activity of alanine glyoxylate amino transferase (AGT), leading to the accumulation of glyoxylic acid. The high glyoxylic acid can then be converted to glycolate by the enzyme GRHPR or to oxalate by the enzyme LDH. Thus, glycolate, glyoxylate, and oxalate are the metabolites that are then elevated in the Organic Acids Test (OAT) in hyperoxaluria type I and in vitamin B-6 deficiency.

In the genetic disease hyperoxaluria type II, there is a deficiency in an enzyme (GRHPR) that has two biochemical activities:  glyoxylate reductase and hydroxypyruvic reductase. This enzyme converts glyoxylate to glycolate and glycerate to hydroxypyruvate. When this enzyme is deficient, glycerate cannot be converted to hydroxypyruvate and glyoxylate cannot be converted to glycolate. In this disease, glyoxylate is increasingly converted to oxalate and glycerate is also very elevated.

External sources of oxalates include ethylene glycol, the main component of antifreeze. Antifreeze is toxic mainly because of the oxalates formed from it. In addition, some foods also contain small amounts of ethylene glycol. Vitamin C (ascorbic acid or ascorbate) can be converted to oxalates but apparently the biochemical conversion system is saturated at low levels of vitamin C so that no additional oxalate is formed until very large doses (greater than 4 g per day) are consumed. It is interesting that fungi can also produce vitamin C which may explain why many children with autism have high vitamin C even though they do not take supplements containing vitamin C. The high correlation between arabinose and oxalates indicate that intestinal yeast/fungal overgrowth is likely the main cause for elevated oxalates in the autistic spectrum population. The deposition of oxalates in critical tissues such as brain and blood vessels, the oxidative damage caused by oxalate salts, and the deposition of oxalate mercury complexes in the tissues may all be important factors in the core etiology of autism.

  [Insert OAT Sample Test Result – Oxalate Section]
 

Oxalate Interconversions

Oxalic acid undergoes many conversions depending on the acidity of the environment in which it is present. The acidity of a water solution is usually indicated by a value called the pH. A very low pH like 0 or 1 indicates a very acidic solution while a pH of 13 or 14 would represent a very alkaline solution. A pH of 7 indicates a condition of neutrality. Blood has a pH of 7.4 which is very slightly alkaline. The pH of urine varies between 4.5 to 8 with an average of 6. Oxalic acid can lose a positively charged hydrogen ion or proton at a very low pH. The first pK value for oxalic acid (1.27) indicates the pH in which there are equal amounts of oxalic acid and its form missing a proton called monobasic oxalate. At a higher pH, the monobasic oxalate converts to a dibasic oxalate form with two negative charges. The second pK value for oxalate (4.28) indicates the pH at which there are equal values of monobasic and dibasic oxalates.  At the pH of blood, which is extremely constant, virtually all oxalate is in the dibasic form. Because the pH of urine varies greatly, oxalate is mainly in the dibasic form in average urine while it is in both the monobasic and dibasic form in very acidic urine samples. When oxalates are tested, they are all converted to the same form before testing so they may be termed oxalates, oxalate, or oxalic acid.

Insolubility is a Key Factor in Oxalate Toxicity

Solubility of oxalate at body temperature is only approximately 5 mg/L at a pH of 7.0. The solubility of oxalic acid in water, in contrast, is approximately 106,000 mg/L. Thus, the oxalate form of oxalic acid is extremely insoluble. At most physiological pH values, oxalate salts are predominant. Oxalate has the ability to form salts with a wide variety of metals but each of these salts has a different solubility. A yardstick for measuring solubilities of different salts is called the solubility product constant or Ksp. The smaller the value of the Ksp, the greater the insolubility of a salt. Another way to express this is that the lower the Ksp, the greater the tendency of that salt to form insoluble crystals that may form in tissues. The table below lists the Ksp salts of oxalic acid in their order of solubility with the most insoluble salts listed at the top.

What is the importance of these solubility product numbers?

First, the Ksp for calcium oxalate indicates that whenever the product of the concentration of calcium and oxalate concentrations in blood exceeds the Ksp, calcium oxalate crystals may form and deposit in the tissues. Since the calcium concentration in blood hardly varies because of homeostatic mechanisms, it is the oxalate concentration in blood that varies widely and that determines whether or not calcium oxalate crystals form and deposit in the tissues. Zinc oxalate also has a very small Ksp so that if oxalates are present in high quantities in the intestinal tract, most of the zinc oxalate formed will not be absorbed because it is highly insoluble.

Second, mercury oxalate had the lowest Ksp of any oxalate salt that I could find. If an individual is exposed to inorganic mercury and has high oxalates in the blood or tissues, insoluble mercury oxalates may form in the blood and tissues that are unable to be eliminated.

The mercury used in vaccines as a preservative is an organic form that is converted to inorganic mercury. If an individual who is vaccinated is on antibiotics or was on antibiotics in the past, they may have extensive yeast/fungal overgrowth of the intestinal tract. They would absorb significant amounts of oxalates from these organisms that would trap mercury in the tissues and prevent its elimination. Many parents who talked with me indicated that their children had bad vaccine reactions while on antibiotics at the time of vaccination.

Third, magnesium oxalates are much more soluble than calcium oxalates. Thus, if magnesium supplements are given by themselves, oxalates from food or yeast/fungal sources that combine with magnesium are much more likely to be absorbed than calcium oxalates. However, transdermal magnesium or magnesium from Epsom salts baths that enters the blood and tissues through the skin might help to dissolve calcium or mercury oxalate crystals that had already formed in the blood or tissues.

Testing for Oxalates

The most convenient way of testing oxalates is with the Organic Acids Test (OAT) from The Great Plains Laboratory, Inc.

The Organic Acids Test checks for the presence of:

• Oxalic acid (oxalates) -Tests for all forms of oxalic acid and its salts or conjugate bases, oxalates

• Arabinose - Important Candida indicator which strongly correlates with oxalates

• Glycolic acid (glycolate)- Indicator of genetic disease of oxalate metabolism called Hyperoxaluria type I due to a deficiency in the enzyme activity of alanine glyoxylate amino transferase (AGT).

• Glyceric acid (glycerate) - Indicator of genetic disease of oxalate metabolism called Hyperoxaluria type II due to a deficiencyin an enzyme (GRHPR) that has two biochemical activities: glyoxylate reductase (GR) and hydroxypyruvic reductase (HPR).

• Ascorbic acid (ascorbate, vitamin C) - Indicates nutritional intake of vitamin C and/or excessive destruction. Vitamin C can be excessively converted to oxalates when free copper is very high. Evaluate further with copper/zinc profile from The Great Plains Laboratory.

• Pyridoxic acid - Indicator of vitamin B-6 intake. The enzyme activity alanine glyoxylate amino transferase (AGT) requires vitamin B-6 to eliminate glyoxylic acid or glyoxylate, a major source of excess oxalates.

• Furandicarboxylic acid, hydroxy-methylfuroic acid - Markers for fungi such as Aspergillus infection, one of the proven sources of oxalates

• Bacteria markers - A high amount of bacterial markers may indicate low values of beneficial bacteria such as Lactobacilli species that have the ability to destroy oxalates.

High Oxalate Food List

The foods below contain more than 10 mg oxalate per serving. A more detailed list is available online from the University of Pittsburgh Schools of the Health Sciences website.

Drinks
- Dark or "robust" beer
- Black tea
- Chocolate milk
- Cocoa
- Instant coffee
- Hot chocolate
- Juice made from high oxalate fruits (see below for high oxalate fruits)
- Ovaltine
- Soy drinks

Dairy
- Chocolate milk
- Soy cheese
- Soy milk
- Soy yogurt

Fats, Nuts, Seeds
- Nuts
- Nut butters
- Sesame seeds
- Tahini
- Soy nuts

Starch
- Amaranth
- Buckwheat
- Cereal (bran or high fiber
- Crisp bread (rye or wheat)
- Fruit cake
- Grits
- Pretzels
- Taro
- Wheat bran
- Wheat germ
- Whole wheat bread
- Whole wheat flour

Condiments
- Black pepper (more than 1 tsp.)
- Marmalade
- Soy sauce

Miscellaneous
- Chocolate
- Parsley

Fruit
- Blackberries
- Blueberries
- Carambola
- Concord grapes
- Currents
- Dewberries
- Elderberries
- Figs
- Fruit cocktail
- Gooseberry
- Kiwis
- Lemon peel
- Orange peel
- Raspberries
- Rhubarb
- Canned strawberries
- Tamarillo
- Tangerines

Vegetables
- Beans (baked, green, dried, kidney)
- Beets
- Beet greens
- Beet root
- Carrots

Vegetables Continued...

- Celery
- Chicory
- Collards
- Dandelion greens
- Eggplant
- Escarole
- Kale
- Leeks
- Okra
- Olives
- Parsley
- Peppers (chili and green)
- Pokeweed
- Potatoes (baked, boiled, fried)
- Rutabaga
- Spinach
- Summer squash
- Sweet potato
- Swiss chard
- Zucchini

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REFERENCES

1. Tsao, G. Appl Microbiol. 1963 May; 11(3): 249-254. Production of Oxalic Acid by a Wood-Rotting Fungus.

2. Takeuchi H Konishi T, Tomoyoshi T. Observation on fungi within urinary stones. Hinyokika Kiyo. 1987 May;33(5):658-61.

3. Lee SH, Barnes WG, Schaetzel WP. Pulmonary aspergillosis and the importance of oxalate crystal recognition in cytology specimens. Arch Pathol Lab Med. 1986 Dec;110(12):1176-9.

4. Muntz FH. Oxalate-producing pulmonary aspergillosis in an alpaca. Vet Pathol. 1999 Nov;36(6):631-2.

5. Loewus FA, Saito K, Suto RK, Maring E. Conversion of D-arabinose to D-erythroascorbic acid and oxalic acid in Sclerotinia sclerotiorum. Biochem Biophys Res Commun. 1995 Jul 6;212(1):196-203.

6. Fomina M, Hillier S, Charnock JM, Melville K, Alexander IJ, Gadd GM. Role of oxalic acid overexcretion in transformations of toxic metal minerals by Beauveria caledonica. Appl Environ Microbiol. 2005 Jan;71(1):371-81.

7. Ruijter, G.J.G., van de Vondervoort, P.J.I. & Visser, J. (1999) Oxalic acid production by Aspergillus niger: an oxalate-non-producing mutant produces citric acid at pH 5 and in the presence of manganese. Microbiology 145, 2569–2576.

8. Ghio AJ, Peterseim DS, Roggli VL, Piantadosi CA. Pulmonary oxalate deposition associated with Aspergillus niger infection. An oxidant hypothesis of toxicity. Am Rev Respir Dis. 1992 Jun;145(6):1499-502.

9. Takeuchi H, Konishi T, Tomoyoshi T. Detection by light microscopy of Candida in thin sections of bladder stone. Urology. 1989 Dec;34(6):385-7.

10. Ghio AJ, Roggli VL, Kennedy TP, Piantadosi CA. Calcium oxalate and iron accumulation in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2000 Jun;17(2):140-50.

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