Beyond the Gut: The Relationship Between Gluten, Psychosis, and Schizophrenia

JAMES GREENBLATT, MD & DESIREE DELANE, MS

Introduction

The National Institutes for Mental Health provide a succinct definition for schizophrenia as periods of psychosis characterized by disturbances in thought and perception and disconnections from reality; however, diagnosis is much less straightforward.  Schizophrenia represents a wide illness spectrum with symptomatic features and severity ranging from odd behavior to paranoia.  With a prevalence rate over the past century holding steady at 1% worldwide and immovably poor patient outcomes, schizophrenia delivers profound relational and societal burdens, proving to be a complex clinical challenge and an unyielding epidemiological obstacle.

Gluten as a Trigger for Psychosis

Although the role of food hypersensitivities in disease pathologies is highly controversial in the medical community, many recognize a parallel rise with dietary evolution in modern history.  Major shifts from ancestral diets largely absent of wheat or dairy to one with these as foundational components generate reasonable arguments on their implications for human health.  Industrialized food systems that streamline the way foods are grown, processed, and stored are often charged with altering their very nature down to its most infinitesimal molecules.  Yet, despite their diminutive size, micronutrients from food are essential to the complex processes and interactions that represent optimal health.

Intolerance to gluten represents one of the most prominent food hypersensitivities arising in recent history, delivering profound impacts to both physical and mental health.  As the most severe reaction to gluten, Celiac Disease (CD) affects a growing population of men and women in the United States.  Unfortunately, an estimated 83% of cases remain undiagnosed or wrongly diagnosed with other conditions. Like other autoimmune diseases, CD is a factor of underlying genetic susceptibility combined with environmental pressures.  Sometimes remaining non-symptomatic for years, CD progressively damages the lining of the intestine, eventually presenting with severe gastrointestinal symptoms including gas, bloating, diarrhea, and constipation.  One of the most dangerous consequences is that digestion and absorption become impaired, resulting in malnutrition and increasing requirements for several key nutrients.  Furthermore, chronic, subtle inflammation keeps the immune system on high alert, promoting an environment of oxidative stress in which free radicals wreak havoc throughout the body.  By elevating the body’s overall inflammatory status, CD and other immune-mediated food allergies trigger not only immediately apparent physical symptoms, but also biochemical imbalances that alter brain function.  Notably, data showing that CD is often incorrectly and inconsistently diagnosed suggests that mental symptoms are often misinterpreted or overlooked.

A separate byproduct of gluten metabolism poses another, possibly more dramatic and direct, threat to brain function.  Gliadorphin, a peptide fragment produced through the breakdown of gluten, directly accesses the brain and attaches to opiate receptors.  Neuropeptides including gliadorphin and casomorphin, a structurally similar byproduct of dairy, mimic and interfere with normal neurotransmitter communication, producing significant mental symptoms ranging from fatigue and brain-fog to hallucinations and aggression.  Like the opiate drugs morphine and heroin, food-derived opiates hold strongly addictive properties as they promote reward, sedation, and satiety.  Sensitive individuals are typically marked by excessive cravings and dependence on food sources of gliadorphin and casomorphin, that manifest in difficulties regulating mood and behavior when levels are depleted.  Fortunately, mental health practitioners have begun to recognize the contribution of neuropeptides in many psychiatric conditions.

Gluten, Gliadorphin, & Schizophrenia

Like Celiac disease, experts agree that schizophrenia has both genetic and environmental contributors, and evidence even suggests that overlapping genetic risk factors may underlie a shared susceptibility for schizophrenia and Celiac disease.  A 2004 Danish case-control study indicated that individuals with a history of Celiac disease may have a 3x greater risk of developing schizophrenia.  Additionally, short-term immune-related exposures during gestation or early life can have long-term consequences for the brain by inducing permanent DNA modifications.  Maternal or post-natal illnesses and infections have all been linked to a greater risk for psychosis and schizophrenia.  Excessive immune activation during these critical developmental periods can also influence the body’s response to potential food allergens.  From the other direction, schizophrenia and psychosis may invoke unique immune mechanisms influencing an individual’s reactivity to gluten. 

Remarkably, the relationship between gluten and psychosis appears to go beyond Celiac disease.  Elevated levels of gliadorphin have consistently been measured in patients with schizophrenia, autism, attention-deficit-hyperactivity disorder, depression, and other psychiatric conditions.  Abnormally low activity of the dipeptidyl peptidase IV (DPP-IV) enzyme, involved in the breakdown of gluten, offers a potential link.  A clinical study in roughly 60 patients with schizophrenia or depression suggested that significant alterations in DPP-IV activity characterized patients with schizophrenia.  The prevalence of elevated gliadorphin and other opiate peptides in psychosis patients has led some researchers to believe that these psychoactive substances carry unique information to the brain that influence disease development.

Without normal breakdown of gliadorphin by DPP-IV, neurotoxic levels accumulate and produce psychoactive effects.  Significant behavioral alterations in animal models given food-based neuropeptides reflect symptoms of psychosis that were reversible by pre-treatment with opiate-blocking drugs.  Human patients with elevated urinary gliadorphin also demonstrate clinical behavioral improvements when gluten and other sources of “dietary morphine” are removed from the diet.  DPP-IV also modulates the activation and proliferation of CD4+ immune cells, providing an additional mechanistic explanation for the excessive inflammation characteristic of both Celiac disease and schizophrenia.  Finally, normal DPP-IV activity depends on adequate zinc and other nutrients, common casualties of poor intestinal function.

A New Approach to Schizophrenia Treatment

Despite evidence-based attempts to address the diverse spectrum of physical and mental impairments associated with schizophrenia, weak progress has been made over the last 100 years.  The rapid, clear clinical responses of antipsychotic drugs introduced in the 1950s and 1960s once appeared to offer miraculous promise to those suffering with psychotic illness.  At least 70 different medications have been developed targeting similar biochemical pathways and are firmly established as first-line therapies.  Modern antipsychotics can be profoundly useful with skillful use in the initial stages of illness, particularly for severe cases.  But it is no secret that these medications are rarely, if ever, totally effective, have no influence on negative or cognitive symptom categories, and bring debilitating side effects requiring further drug interventions.

A growing wealth of theory and data links nutrition and mental health, yet mainstream psychiatry remains stubbornly fixated on the status quo.  Clinical studies suggest that nutrient requirements in schizophrenia patients exceed generally recommended levels, whether due to poor diet, impaired intestinal function, or genetically induced metabolic differences.  A 2018 systematic review by Firth, et al., of 11 studies in early-stage psychosis patients found deficiencies in antioxidants, amino acids, and polyunsaturated fatty acids.  This recent evidence lends significant support for assertive nutrient-based approaches to schizophrenia treatment, particularly as preventive strategies in high-risk patients.

Normal mental processes require tightly-controlled amounts of B-vitamins, antioxidants, lipids, and many other dietary nutrients as key enzymatic components for neural growth, communication, and protection.  On top of the potentially toxic effects of gluten and its byproducts on some individuals, malabsorptive conditions resulting from food sensitivities or Celiac disease further reduce the bioavailability of these critical nutrients to the brain and exacerbate the biochemical imbalances that drive psychiatric illness.  Resulting from this malnourished state, neurotransmitter dysfunction and miscommunication dramatically alter sensory perception and distort a patient’s experience of reality, manifesting in abnormal behavior and social dysfunction. 

Nutritional and other integrative therapies provide the body and brain with optimal and familiar tools for self-healing.  By addressing the origins of symptoms first, medications can be employed as second-tier strategies that support rather than direct treatment.  The treatment paradigm for schizophrenia must be expanded to adopt strategies for early recognition and prevention and incorporate holistic therapies that empower patients to be involved in their recovery.  Long-term dietary changes, including removal of gluten, and nutritional supplements facilitate recovery and promote resilience and self-care.  The integrative care model for mental health care aims not at just the absence of disease, but for healthy minds, bodies, and futures with hope for independence, happiness, and fulfillment.

---

References

1. Chien, W. T., & Yip, A. L. (2013). Current approaches to treatments for schizophrenia spectrum disorders, part I: an overview and medical treatments. Neuropsychiatric disease and treatment, 9, 1311.

2. Chong, H. Y., Teoh, S. L., Wu, D. B. C., Kotirum, S., Chiou, C. F., & Chaiyakunapruk, N. (2016). Global economic burden of schizophrenia: a systematic review. Neuropsychiatric disease and treatment, 12, 357.

3. Dauncey, M. J. (2013). Genomic and epigenomic insights into nutrition and brain disorders. Nutrients, 5(3), 887-914.

4. Ellul, P., Groc, L., Tamouza, R., & Leboyer, M. (2017). The clinical challenge of autoimmune psychosis: learning from anti-NMDA receptor autoantibodies. Frontiers in psychiatry, 8, 54.

5. Firth, J., Rosenbaum, S., Ward, P. B., Curtis, J., Teasdale, S. B., Yung, A. R., & Sarris, J. (2018). Adjunctive nutrients in first‐episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms. Early intervention in psychiatry.

6. Jungerius, B. J., Bakker, S. C., Monsuur, A. J., Sinke, R. J., Kahn, R. S., & Wijmenga, C. (2008). Is MYO9B the missing link between schizophrenia and celiac disease?. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147(3), 351-355.

7. Lennox, B. R., Palmer-Cooper, E. C., Pollak, T., Hainsworth, J., Marks, J., Jacobson, L., ... & Crowley, H. (2017). Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. The Lancet Psychiatry, 4(1), 42-48.

8. Liang, W., & Chikritzhs, T. (2012). Early childhood infections and risk of schizophrenia. Psychiatry research, 200(2), 214-217.

9. Maes, M., De Meester, I., Verkerk, R., De Medts, P., Wauters, A., Vanhoof, G., ... & Scharpé, S. (1997). Lower serum dipeptidyl peptidase IV activity in treatment resistant major depression: relationships with immune-inflammatory markers. Psychoneuroendocrinology, 22(2), 65-78.

10. Maes, M., Scharpé, S., Desnyder, R., Ranjan, R., & Meltzer, H. Y. (1996). Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs. Acta Psychiatrica Scandinavica, 93(1), 1-8.

11. NIMH. (2017). https://www.nimh.nih.gov/health/topics/schizophrenia/raise/what-is-psychosis.shtml. Accessed 09 April 2018.

12. Salim, S. (2014). Oxidative stress and psychological disorders. Current neuropharmacology, 12(2), 140-147.

13. Samaroo, D., Dickerson, F., Kasarda, D. D., Green, P. H., Briani, C., Yolken, R. H., & Alaedini, A. (2010). Novel immune response to gluten in individuals with schizophrenia. Schizophrenia research, 118(1), 248-255.

14. Sun, Z., Cade, J. R., Fregly, M. J., & Privette, R. M. (1999). β-Casomorphin induces Fos-like immunoreactivity in discrete brain regions relevant to schizophrenia and autism. Autism, 3(1), 67-83.

15. Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451-459.

Integrative Therapies for Obsessive Compulsive Disorder

James Greenblatt, MD

While it is human nature to occasionally ruminate or overanalyze important decisions, these thought patterns normally dissipate quickly freeing us of those fleeting moments of inner turmoil.  However, for those suffering from Obsessive Compulsive Disorder (OCD), letting go of repetitive thoughts is not so effortless.  Relentless ideas, impulses, or images inundate the brain leaving the individual mentally imprisoned to an existence of recurrent, irrational thought patterns.  These senseless obsessions often drive the individual to perform ritualistic behaviors or compulsions, in an effort to temporarily relieve their anxiety.  Sufferers stagger through life with a sense of pure powerlessness against their disorder; fully aware that the behavior is abnormal, yet unable to stop.

Psychotropic medications such as selective serotonin reuptake inhibitors (SSRI’s) and Anafranil and cognitive behavioral therapy are the conventional treatment options for Obsessive Compulsive Disorder. Sadly, the likelihood of complete recovery from OCD has not been shown to exceed 20% and relapse is quite common.  Inadequate treatment and limited biomedical options contribute to the high relapse rate as conventional medicine does not address underlying nutritional deficiencies or the root cause. Though unlikely to be caused by deficiencies alone, addressing vital nutrient depletions is a critical aspect of treating OCD since certain vitamins, minerals, and amino acids significantly impact serotonin neurotransmission.  Specifically, natural therapies including: 5-HTP, niacin (B3), pyridoxal-5-phosphate (B6), folate (5-MTHF), vitamin C, zinc, magnesium, inositol, and taurine are important to serotonin synthesis.  Therefore, the combination of aforementioned nutrients taken in therapeutic dosages should be part of integrative treatment approach for Obsessive Compulsive Disorder.

The fourth most common psychiatric illness in the United States, Obsessive Compulsive Disorder or “OCD” onset typically occurs by adolescence usually between the ages of 10-24, with one third of all cases appearing by age 15. In fact, OCD is said to be more common than asthma and diabetes (Schwartz, 1997). Despite its prevalence, it is often under diagnosed and under treated with more than half of those suffering receiving no treatment at all for their condition.  Gender does not affect susceptibility, as men and women are equally affected by this detrimental disorder. 

To fully grasp the inner workings of OCD, consider Jeffrey Schwartz’s description of “Brain Lock” (Schwartz, 1997) where four key structures of the brain become locked together sending false messages that the individual cannot interpret as false.  The brain is made up of two structures called the caudate nucleus and the putamen, which can be compared to a gearshift in a car.  According to Schwartz, “The caudate nucleus works like an automatic transmission for the front, or thinking part, of the brain…the putamen is the automatic transmission for the part of the brain that controls body movements… the caudate nucleus allows for the extremely efficient coordination of thought and movement during everyday activities.  In a person with OCD, however, the caudate nucleus is not shifting gears properly, and messages from the front part of the brain get stuck there.  In other words, the brain’s automatic transmission has a glitch.  The brain gets ‘stuck in gear’ and can’t shift to the next thought” (Schwartz, 1997).

It is clear that enhancing serotonin neurotransmission through psychotropic medications helps the brain “shift into gear” so to speak.   But what exactly causes this glitch that leads to serotonin deficiency syndrome? A number of factors including genes, diet, stress, neurotoxins, and inflammation are responsible for inadequate serotonin synthesis.  Amino acid availability for neurotransmitter synthesis is dependent upon certain digestive enzymes, and their activation is dependent on hydrochloric acid.  Without sufficient amino acid availability, neurotransmitter synthesis will suffer.  Specifically, availability of the essential amino acid L-tryptophan is required for serotonin production.  Because serotonin synthesis depends on the availability of L-tryptophan and essential cofactors including vitamin B3, folate (5-MTHF), vitamin B6, and zinc, serotonin levels will be less than optimal if any of the required building blocks are deficient.  The process of serotonin synthesis starts when L-tryptophan is converted into 5-hydroxytryptophan with the help of tryptophan hydroxylase (a vitamin B3 dependent enzyme), which requires 5-MTHF.  5-hydroxytryptophan (5-HTP) then converts to serotonin with the aid of decarboxylase, vitamin B6 dependent enzymes, and zinc.

Supplemental 5-hydoxytryptophan (5-HTP) can be beneficial for individuals as it essentially bypasses the need for L-tryptophan availability.  Easily crossing the blood brain barrier, 5-HTP works like a targeted missile directly increasing brain serotonin levels.  It does not require a transport molecule for crossing the blood brain barrier, and unlike L-tryptophan, it is shunted from incorporation into proteins and niacin conversion (Birdsall, 1998).  What’s more, promising research indicates that the therapeutic effect of 5-HTP compared to fluoxetine (Prozac), is actually equal (Jangid et al., 2013). Antidepressant effects are experienced in as little as two weeks with 5-HTP; effectively treating individuals with varying degrees of depression (Jangid et al., 2013).There has been four research studies looking at 5-HTP supplements specifically for OCD. Clinicians around the globe, for more than twenty years, have had success with amino precursors including 5-HTP for the treatment of OCD. I recommend starting all patients with 50 mg of 5-HTP and titrate slowly every 2 weeks up to a maximum of 200 mg per day. Side effects of 5-HTP include nausea, irritability, and possible anxiety.

In addition to the influence of digestive health on serotonin synthesis, absorption of vital minerals specifically zinc and magnesium, are also impacted by Hydrochloric Acid (HCL) availability.  Thus, if HCL and digestive enzyme production is low, mineral deficiencies will likely follow.  This is worth noting because optimal levels of zinc and magnesium are imperative to maintaining healthy serotonin levels, while moderating the activity of glutamate receptors. As stated previously, zinc is an important coenzyme required for decarboxylase activation and the conversion of 5-HTP to serotonin.  Magnesium also plays an essential role, aiding the conversion process of L-tryptophan to serotonin.

In addition to zinc and magnesium, folate plays a critical role in serotonin neurotransmission.  Specifically, the enzyme responsible for converting L-tryptophan to 5-HTP, requires 5-MTHF, also known as “L-Methylfolate.”  Without sufficient folate, L-tryptophan will struggle to convert to 5-HTP.  Research on depression and folate is extensive; hundreds of studies support the relationship between folate and depression.  Thus, it is imperative to consider folate status when treating OCD.   Specifically, low folate levels are associated with increased incidence of depression, poor response to antidepressants, and higher relapse rates.  Because dietary sources of folate are heat labile and easily oxidized (more than 50% is oxidized during food processing) folate malabsorption and deficiency is quite prevalent in our society.  To make matters worse, individuals taking certain medications such as anticonvulsants, oral contraceptives, antacids, antibiotics, and Metaformin are at increased risk of deficiency. 

Individuals that possess genetic polymorphisms in the gene coding for the methylenetetrahydrofolate reductase (MTHFR) gene are at high risk for low folate status due to reduced ability to convert folic acid to its active form. Folic acid requires a four step transformation process to be converted to L-methylfolate, where dietary folate requires three steps.  MTHFR polymorphisms reduce efficiency of this transformation process; severely impacting conversion of folic acid to L-methylfolate.  Since L-methylfolate is the active absorbable form of folate that crosses the blood brain barrier for use, inability to properly convert dietary or supplemental folic acid may cause folate deficiency (Lewis et al., 2006).

Inositol has proven particularly effective for SSRI resistant patients as well.  Specifically, OCD patients experiencing lack of response to SSRI’s or clomipramine have been examined.  There are research studies demonstrating dosages of 18/gms of inositol per day was effective in OCD treatment.  Improvement in symptoms had been reported at 6 weeks of treatment with no reported side effects (Fux et al., 1996).  A promising finding, inositol is an effective natural therapy for OCD treatment when taken on its own.  It is particularly helpful to individuals who are unresponsive to conventional SSRI treatment.  However, at this time use of inositol as an augmentation agent to improve SSRI function has not been proven effective (Fux et al., 1999).

Inositol’s effect on treatment resistant patients is likely due to its role in the neurotransmission process.  Operating as a secondary messenger, it enhances the sensitivity of serotonin receptors on the postsynaptic neuron using signal transduction.  Upon binding to its receptor, messages from serotonin are then translated into signals that are expressed through behaviors such as positive mood, relaxation, and reduced obsessions.  Due to its role in serotonin signaling, patients resistant to SSRI treatment may not necessarily have an issue with serotonin synthesis but rather decreased receptor sensitivity.

Controlled trials of inositol have confirmed therapeutic effects in a wide spectrum of psychiatric illnesses generally treated with SSRI’s including: OCD, Major Depressive Disorder, Panic Disorder, and Bulimia.  In particular, children exhibiting OCD symptoms have shown considerable life altering improvements with inositol treatment. For instance, “S.M.” a socially withdrawn, 11 year old child who obsessively feared fire and contamination, transformed into a “completely different child” with inositol treatment.  Similarly, “P.J.”, treated with inositol and 5-HTP, showed significant improvement in OCD symptoms.  A third clinical case, “C.K.” had suffered immensely with severe adverse side effects to Celexa and Prozac including aggressive thoughts of self-harm.  Upon treatment with inositol, no side effects were reported and minimal improvement was even displayed.  Even though research studies suggest 18 grams of Inositol per day, I start all patients with OCD on approximately 3 grams of Inositol per day (1/2 Tsp. 3 times per day).this minimizes GI side effects including bloating and nausea. If needed, Inositol dosages can be titrated up slowly with most patients responding below 12 grams per day.

Improving serotonin production and neurotransmission is integral to boosting serotonin levels and combating symptoms of OCD.  However, preventing over-activity of neurotransmitters should also be considered.  Taurine is an essential amino acid and precursor to GABA, an inhibitory neurotransmitter.  A regulatory agent, GABA helps maintain healthy serotonin levels and reuptake.  Widely known for its calming effect, taurine’s therapeutic use for anxiety and depression treatment has been explored.  In one study, animals fed a high taurine diet for 4 weeks exhibited anti-depressive behavior (Caletti, 2015).  Furthermore, a study on mice indicated a reduction in anxiety where taurine was administered 30 minutes before anxiety tests (Kong et al., 2006).  Though taurine does not directly target serotonin production, it is still worth noting as its inhibitory effect may reduce racing thoughts associated with anxiety disorders such as OCD.

Based on extensive scientific evidence supporting the relationship of aforementioned nutrients to serotonin production, as well as decades of clinical experience, I developed SeroPlus (https://www.nbnus.net/).   SeroPlus is a nutritional supplement to help patients with OCD and depression.   The formula provides serotonin building blocks including therapeutic doses of 5-HTP (direct precursor to serotonin), Inositol, and Taurine in addition to vital cofactors magnesium, vitamin C, pyridoxal-5- phosphate (activated B6), and Metafolin® (activated folate). Inositol elevates sensitization of serotonin receptors while taurine maintains healthy sympathetic nervous system tone and moderates serotonin activity and reuptake.  The formula also includes niacin and zinc picolinate which enhance availability of 5-HTP by reducing the amount of 5-HTP used for activation and absorption of these nutrients.  Synergistically, these ingredients work effectively together to optimize serotonin production and restore healthy serum levels of common deficiencies contributing to abnormalities in serotonin neurotransmission.

As with any psychiatric illness, treating OCD is complex and requires a comprehensive multi-prong approach beyond basic SSRI prescriptions and behavioral therapy.  Although directly enhancing serotonin production through natural therapies such as 5-HTP as well as correcting underlying B3, B6, zinc, magnesium, folate, and inositol deficiencies is at the heart of integrative treatment there are a number of alternative factors that may be contributing to the cause. Low levels of B12, DHA, and vitamin D must be addressed. 

A prisoner to their own thoughts, OCD sufferers are frustrated and searching for alternative treatment options.  The complex etiology of OCD includes genetics, inflammation, and the dysfunction of serotonin synthesis.  While SSRI’s may enhance serotonin synthesis, a number of OCD patients do not experience long term results.  Thus, identifying key nutrient depletions and replenishing them through dietary modification and supplementation is essential to increasing chances of long term recovery. 

James M. Greenblatt, MD, is the author of Finally Focused: The Breakthrough Natural Treatment Plan for ADHD (Harmony Books, 2017). He currently serves as Chief Medical Officer and Vice-President of Medical Services at Walden Behavioral Care, and he is an Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth Geisel School of Medicine. An acknowledged expert in integrative medicine, Dr. Greenblatt has lectured throughout the United States on the scientific evidence for nutritional interventions in psychiatry and mental illness. For more information, visit www.JamesGreenblattMD.com

---

References

1. Birdsall. (1998). 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. Aug; 3(4): 271-80.

2. Caletti. (2015). Antidepressant dose of taurine increases mRNA expression of GABAA receptor α2 subunit and BDNF in the hippocampus of diabetic rats. Behav Brain Res. 2015 Apr 15; 283:11-5.

3. Fux et al. (1996). Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry, Vol 153(9) 1219-1221.

4. Fux et al. (1999). Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: a double blind cross-over study. International Journal of Neuropsychopharmacology 2, 193-195.

5. Jangid et al. (2013) Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. Feb;6(1):29-34

6. Kong. (2006). Effect of taurine on rat behaviors in three anxiety models. Pharmacol Biochem Behav. Feb; 83(2):271-6.

7. Milner. (1963). Ascorbic acid in chronic psychiatric patients. Brit J Psychiatr 109; 294-299.

8. Schwartz, Jeffrey M. Brain Lock: Free Yourself from Obsessive-Compulsive Behavior . Harper Perennial; 1st edition, 1997.

DIETARY INFLUENCES ON BEHAVIORAL PROBLEMS IN CHILDREN

James Greenblatt MD, Author of Finally Focused (www.finallyfocusedbook.com), Chief Medical Officer and Vice President of Medical Services at Walden Behavioral Care

It is well known that our food choices play a role in our long-term physical health. It is less recognized that nutrition can have profound effects on our mental health and our behavior. Overall, malnutrition in childhood can affect the brain throughout the lifespan, while specific food components can affect our short-term well-being. Sugar, wheat, and milk are among the most common dietary triggers for ADHD symptoms. Fluctuating blood sugar levels and partially-digested foods can also cause a wide range of symptoms from fatigue to hyperactivity. This article will discuss the dietary influences on behavioral problems in children, review how laboratory testing can be critical in identifying food sensitivities, and how to enhance digestion for maximum absorption of nutrients.

One of the most debated treatments for ADHD is the Feingold Diet, introduced in the early 1970’s by pediatrician and allergist Ben Feingold, MD. He initially suggested that children who are allergic to aspirin (which contains salicylates) may react to artificial food colors and naturally occurring salicylates. The Feingold Diet eliminates artificial food additives like flavorings, preservatives, sweeteners, and colors to reduce hyperactivity. The research over the years on the Feingold Diet has been mixed – some studies show no behavior change and some show increases in hyperactivity when children consume artificial ingredients. A landmark study conducted in the UK on three hundred 3-year-old and 8/9-year-old children in the general population found artificial colors or a sodium benzoate preservative (or both) in the diet resulted in increased hyperactivity (McCann et al., 2007). This study led the European Union to ask manufacturers to voluntarily remove several artificial food colors from foods and beverages or to add a warning label that the artificial food color “may have an adverse effect on activity and attention in children” (Arnold et al., 2012). Conversely, in the US, the FDA reviewed the study and determined that a causal relationship between consumption of color additives and hyperactivity in children could not be definitively established (Arnold et al., 2012).

Genetics often play a role in how a child’s ADHD symptoms are exacerbated. The children most likely to be affected by food additives have a genetic inability to metabolize the compounds. Genetic tests were conducted on the 300 UK children from the artificial food color study. Children with specific variations in the HNMT gene, which helps break down histamine in the body, had stronger behavioral reactions to artificial food colors than children without this variation (Stevenson et al., 2010). This means that in some children, food additives spur the release of histamine that in turn affect the brain.

The Barbados Nutrition Study was a longitudinal case-control study that began in the late 1960’s and investigated the physical, mental, and behavioral developmental effects of infant malnutrition. The 204 participants of this study experienced a single episode of moderate to severe malnutrition during their first year of life. Data was collected on these children through adulthood and compared to data from healthy children. By the end of puberty, all children completely caught up in their physical growth. However, cognitive and behavioral issues persisted into adulthood.

The consequences of malnutrition in infancy manifested in many ways. IQ scores of the children with a history of malnutrition at age 5-11 were significantly lower than those of the control children. 50% of the malnourished children had scores at or below 90 while only 17% of the control children had scores this low (Galler et al., 1983). According to teacher reports, attentional deficits, including shorter attention span, poorer memory, and more distractibility and restlessness, were found in 60% of the malnourished children compared to only 15% of the controls. They also had worse social skills, general health, sleepiness in the classroom, and emotional stability (Galler et al., 1983). When the children were reassessed on these measures at age 9-15, a history of early malnutrition was still associated with behavioral impairment at school, especially attention deficits (Galler & Ramsey, 1989).

Behavior problems reported by teachers when the participants were aged 5-11 significantly predicted conduct problems at age 11-17 (Galler et al., 2012). Age at 5-11, children malnourished as infants had lower performance on 8 out of 9 academic subject areas. 37 children (36 malnourished, 1 control) were below the expected grade for their age (Galler, Ramsey, & Solimano, 1984). Compared to control children, previously malnourished children at age 5-11 had significantly worse scores on parent-rated measures of good behavior (no antagonism between mother and child, obedience), social skills, mother-child relationship, frustration level, eating habits, sleeping habits, and school avoidance. Compared to their siblings, previously malnourished children had significantly worse scores on social skills, good behavior, helpfulness, mother-child interaction, eating habits, toilet training, and language (Galler, Ramsey, & Solimano, 1985). When the children were reassessed on these measures at age 9-15, the same results were seen, especially for aggression and distractibility (Galler & Ramsey, 1989). Problems with self-regulation, displayed as reduced executive functioning and aggression toward peers, persisted through adolescence (Galler et al., 2011).

Years later when the subjects were aged 37-43, attention problems were assessed using an adult ADHD scale and a computerized test of attention-related problems. There was a higher prevalence of attention deficits in the previously malnourished group relative to controls. 69% of the previously malnourished participants had at least one test score that fell within the clinical range for attention disorders (Galler et al., 2012). Previously malnourished participants also had worse educational attainment and income across the entire 40-year study (Galler et al., 2012).

Multiple connections have been made between sugar, hyperactivity, and the risk for ADHD. In group of almost 400 school-age children, researchers found that children with the greatest “sweet” dietary pattern had almost four times greater odds of having ADHD compared to those who ate sweets (ice cream, refined grains, sweet desserts, sugar, and soft drinks) less often (Azadbakht & Esmaillzadeh, 2012). In a similar study on 1,800 adolescents, having a “Western” dietary pattern (higher intakes of total fat, saturated fat, refined sugars, and sodium) more than doubled the odds of an ADHD diagnosis (Howard et al., 2011). Likewise, a study on 986 children, average age 9 years, found a high intake of sweetened desserts (ice cream, cake, soda) was significantly associated with worse inattention, hyperactivity-impulsivity, aggression, delinquency, and externalizing problems. In contrast, a high-protein diet was associated with better scores on these measures. A high level of sweetened dessert consumption was also associated with lower scores on tests of listening, thinking, reading, writing, spelling, and math (Park et al., 2012).

Certain foods may not only influence behavioral and physical symptoms, but may also modify brain activity. When children aged 6-15 with food-induced ADHD consumed provocative foods, they showed an increase in beta activity in frontotemporal regions during EEG topographic mapping of brain electrical activity (Uhlig et al., 1997). Beta waves are involved in normal waking consciousness and tend to have a stimulating effect; while too much beta can lead to anxiety.

A food sensitivity to a protein found in milk or a protein found in wheat is a prevalent but neglected cause of ADHD. Milk and milk products like cheese and butter contain a protein called casein. Casein is different from lactose which is a milk sugar. Grains like wheat, rye, and barley contain a protein called gluten. During digestion, casein becomes casomorphin and gluten becomes gliadorphin. For most people, these proteins are further broken down into basic amino acids. For some with ADHD, they have inactive dipeptidyl peptidase IV, a zinc-dependent enzyme that breaks down both casein and gluten, leaving these opioid peptides substances to build up.

Children with ADHD who have high levels of casomorphin or gliadorphin often have severe, uncontrolled symptoms. Both casomorphin and gliadorphin are morphine-like compounds which attach to opiate receptors in the brain. These substances can act like an addicting drug in susceptible children and cause fatigue, irritability, and brain fog. A child with high levels of casomorphin may have strong cravings for milk products (ice cream, yogurt) and may become irritable when he or she doesn’t eat these types of foods. The Gluten/Casein Peptide Test is a simple urine test that can measure levels of casomorphin and gliadorphin. If a child has high levels of casomorphin or gliadorphin, they should try to eliminate casein or gluten. Supplementation with DPP-IV enzymes can also be beneficial and often required for clinical improvement.

Malnutrition can negatively affect behavior and cognition, but certain nutrients can have detrimental effects on children as well. Louise Goldberg, pediatric dietitian, put it succinctly: “Food allergies and sensitivities can come at children with a one-two punch - first making them agitated, and next robbing them of nutrients that might rein in their behavior” (Peachman, 2013). We are biochemically unique and have different physiological and psychological responses to different foods. The right food for one child may the wrong food for another. For instance, peanut butter on whole wheat toast may be a nutritionally-balanced, energy-boosting snack for one child, while this snack would be harmful to a child who cannot tolerate neither nuts nor wheat. Medical testing can clarify which nutrients a child is sensitive to. Fortunately, eliminating offending substances can rapidly improve physical and behavioral symptoms.

References:

Arnold, et al. (2012). Artificial food colors and attention-deficit/hyperactivity symptoms: Conclusions to dye for. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 9(3), 599-609.

Azadbakht & Esmaillzadeh. (2012). Dietary patterns and attention deficit hyperactivity disorder among Iranian children. Nutrition, 28(3), 242-249.

Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development I. Degree of impairment in intellectual performance. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 8-15.

Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development II. Classroom behavior. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 16-22.

Galler & Ramsey. (1989). A follow-up study of the influence of early malnutrition on development: Behavior at home and at school. Journal Of The American Academy Of Child And Adolescent Psychiatry, 28(2), 254-261.

Galler, Ramsey, & Solimano. (1984). The influence of early malnutrition on subsequent behavioral development III learning disabilities as a sequel to malnutrition. Pediatric Research, 18(4), 309-313.

Galler, Ramsey, & Solimano. (1985). Influence of early malnutrition on subsequent behavioral development: V. child’s behavior at home. Journal Of The American Academy Of Child Psychiatry, 24(1), 58-64.

Galler et al. (2011). Early malnutrition predicts parent reports of externalizing behaviors at ages 9-17. Nutritional Neuroscience, 14(4), 138-144.

Galler et al. (2012). Infant malnutrition predicts conduct problems in adolescents. Nutritional Neuroscience, 15(4), 186-192.

Galler et al. (2012). Infant malnutrition is associated with persisting attention deficits in middle adulthood. The Journal Of Nutrition, (4), 788.

Galler et al. (2012). Socioeconomic outcomes in adults malnourished in the first year of life: a 40-year study. Pediatrics, (1), 1.

Howard et al. (2011). ADHD Is Associated with a "Western" Dietary Pattern in Adolescents. Journal of Attention Disorders, 15(5), 403-411.

Lacy. (2004). Hyperactivity/ADHD-- new solutions. AuthorHouse.

Langseth & Dowd. (1978). Glucose tolerance and hyperkinesis. Food And Cosmetics Toxicology, 16(2), 129-133.

McCann et al. (2007). Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: A randomised, double-blinded, placebo-controlled trial. The Lancet, 370(9598), 1560-1567.

Niederhofer. (2011). Association of Attention-Deficit/Hyperactivity Disorder and Celiac Disease: A Brief Report. Primary Care Companion For CNS Disorders, 13(3), pii: PCC.10br01104.

Park et al. (2012). Association between dietary behaviors and attention-deficit/hyperactivity disorder and learning disabilities in school-aged children. Psychiatry Research, 198, 468-476.

Stevenson et al. (2010). The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms. The American Journal of Psychiatry, 167(9), 1108-15.

Uhlig et al. (1997). Topographic mapping of brain electrical activity in children with food-induced attention deficit hyperkinetic disorder. European Journal of Pediatrics, 156(7), 557-61.

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.

---

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/.

A Primer on Natural Antifungal Agents: Evidence and Rationale for Their Use

Jessica Bonovich RN, BSN

Guidelines for the treatment of yeast have been documented in the literature for nearly every major organ system (Pappas). Yet, a standard of care for gastrointestinal yeast treatment is surprisingly absent despite the large body of work demonstrating that pathogenic yeast causes harm to various aspects of the gastrointestinal tract (Zwolinska, Brzozowski). Clinicians suspicious of GI yeast overgrowth typically perform a fecal analysis with culture and sensitivity. While this method is ideal for the effective treatment of yeast, it is poorly understood why patients with yeast overgrowth often test negative upon laboratory examination of stool (Maaroufi, Shaw). Up to 50% of stool analysis negative for yeast species returned positive on PCR (Maaroufi). Metabolites of yeast detected in The Great Plains Laboratory Organic Acids Test are a very reliable method of detecting yeast (Shaw). However, this test cannot determine the exact organism and therefore its susceptibility to antifungals (Shaw). It also cannot determine the exact location of the yeast overgrowth but clinical experience has shown that the majority of cases are in fact GI related. The documentation set forth is based broadly on in vivo and in vitro studies on the antifungal properties of the natural agents, documentation of yeast infections involving organ systems other than the GI tract, and yeast overgrowth in the GI of the irritable bowel patient population.

Probiotic Support

Evidence:

Candida: Promising data by several small studies has demonstrated the use of probiotics as effective against numerous pathological conditions caused by Candida. In these studies, Lactobacillus GG, L. acidophilus, and Saccharomyces boulardi were the predominant probiotics shown to be effective with L. GG demonstrating the ability to induce antibody formation against Candida in immune deficient mice. Probiotics have been shown to accelerate the healing of various pathological conditions in the gastro-intestinal tract when Candida is present (Zwolinska 2006 & 2009, Hatakka). Probiotics have also been shown to accelerate immune response to Candida in several murine simulations (Wagner, Zwolinska 2006 & 2009).

Aspergillus: Data on the effectiveness of probiotics against Aspergillus infection is not available. Aspergillus infections are thought to be rare in comparison to other yeast species such as Candida. However, a recent study indicated a high percentage of Aspergillus in stool samples of patients with Crohn's disease. (Li) Aspergillus infections are usually associated with pulmonary infection and or post-surgical complications that are often very acute. The severity of the Aspergillus complications and small numbers of infection are presumably responsible for the lack of research in this regard. The relative safety of Lactobacilli, bifidobacteria, and lactococci has been demonstrated extensively in the literature. Incorporation of these probiotics into a protocol for Aspergillus treatment may be considered appropriate in many cases.

Studies on the use of probiotics for gastrointestinal healing have been aimed at a wide range of populations. To date, the most promising studies have been in the treatment and prevention of acute infectious diarrhea, viral gastroenteritis, antibiotic associated diarrhea, ulcerative colitis, and necrotizing enterocolitis in preterm infants (Manzoni, Zwolinska, Szajewska). In all of these conditions, inflammation is of a primary concern.

Risks: Reports of bacteremia and even a few isolated cases of sepsis have been documented in the literature from the Lactobacillus genera including L. rhamnosis, L. plantarum, L. casei, L. paracasei, L. salivarius, L. acidophilus (Snydman, Borriello). Cases of sepsis have also been documented for the usually beneficial yeast Saccharomyces boulardi. In some cases, the cultures were linked to a probiotic supplement, in others, the bacteria were found to be intrinsic to the patient's own microflora (Snydman, Borriello). In all of the cases, the patients were severely immunocompromised and often had feeding tubes, short gut syndrome, and/or a central line (Snydman, Borriello, Munoz, Herbrecht). The cases of sepsis have most commonly been associated with S. boulardi (Munoz, Herbrecht). However, fungemia from S. boulardi infection is rare in comparison to the population believed to be taking the supplement (Herbrecht, Munoz). In one study, increase in bacteremia from Lactobacillus did not increase over a decade, despite the 6 fold increase in probiotic use (Borriello). These data indicate that individuals taking probiotics are not at any greater risk than the general population for bacteremia associated with Lactobacillus. Regardless, the practitioner should exercise caution in severely immunocompromised patient populations to reduce any risk to the patient.

Rationale:

Promote the immune response against intestinal yeast overgrowth. To promote healing and reduce inflammation in the intestinal mucosa during yeast overgrowth.

Dosing:

The strain most commonly championed in the literature is that of Lactobacillus GG in doses of 10 billion colony forming units (CFU's) taken early in treatment. Saccharomyces thermophilus and S. boulardi were found to be effective in some studies and less effective in others. A daily intake of 10^6 to 10^9 CFUs is reportedly the minimum effective dose for therapeutic purposes.

Allicin

Evidence:

Allicin is the active ingredient found in garlic. The most commonly understood mode of action for allicin is linked to its ability to cross cell membranes and combine with sulfur-containing molecular groups in amino acids and proteins, thus interfering with cell metabolism (Davis, Singla). The antimicrobial properties of allicin have been demonstrated in numerous in vitro and in vivo murine models (Davis, Guo, Shadkchan). The antifungal properties of allicin have been shown to potentiate the effectiveness of fluconazole, the synergistic combination being the most effective at killing Candida species in kidney cells (Guo). Human studies have been targeted largely toward cardiovascular and antihypertensive effects and little has been done to demonstrate the antimicrobial properties (Fugh-Berman, NACAM). However, a study in China reports successful use of intravenous allicin against invasive fungal infections (Davis).

The strength of the supplement is affected by the preparation of garlic. Studies have shown that water, oil, and high temperatures can degrade allicin content (Singla). Interestingly powdered garlic is found to be the highest in allicin (Singla). Interestingly, powdered preparations of garlic for cooking were found to have a greater allicin content than nine supplement tablets studied (PDR). There are also pure allicin extracts available on the market for use.

Risks: Studies have demonstrated that allicin can inhibit platelet aggregation in blood and several cases of bleeding complications have been documented. All of which were following an invasive procedure (Fugh-Berman). Allicin may also increase production of insulin by pancreatic cells causing the potential for hypoglycemia in some patient populations. Allicin may also inhibit cholesterol synthesis in the liver causing exacerbation of developmental delay in children with low cholesterol levels. Physicians should use caution in patients with bleeding conditions, on blood thinners, with hypoglycemia, or diabetics who are insulin dependent. Cholesterol testing is advised for children with developmental disorders prior to supplementation with allicin.

Rationale:

Mild antifungal therapy when prescriptive agents are unavailable or contraindicated and where dosing by weight is required (such as for children). Promote the synergistic modulation of antifungal therapy with fluconazole.

Dosing:

Insufficient evidence exists in US literature for dosing recommendations, especially for children. However, there are several governing bodies outside of the US that regulate supplementation and provide a guideline for dosing. According to the National Center for Complementary and Alternative Medicine in the US, allicin is considered safe for most adults. Use of allicin for antifungal treatment may be appropriate in doses as high as one milligram per kilogram of body weight. Human studies have demonstrated that doses of allicin effectively potentiated the effects of antifungal treatment in doses of 7.8 - 27 mg per dose. The European Scientific Cooperative on Phytotherapy (ESCOP) recommends 3 to 5 milligrams allicin daily (1 clove or 0.5 to 1.0 gram dried powder) for the prevention of atherosclerosis. The World Health Organization (WHO) recommends 2 to 5 grams fresh garlic, 0.4 to 1.2 grams of dried powder, 2 to 5 milligrams oil, 300 to 1,000 milligrams of extract, or other formulations that are equal to 2 to 5 milligrams of allicin daily. The European Scientific Cooperative on Phytotherapy (ESCOP) recommends 2 to 4 grams of dried bulb or 2 to 4 milliliters of tincture (1:5 dilution in 45% ethanol), by mouth three times a day for upper respiratory tract infections.

MCT Oil/ Caprylic Acid/Monolauren/Coconut Oil

Evidence:

There are numerous in vitro and in vivo animal studies that demonstrate the effectiveness of coconut oil and/or its medium chain fatty acid constituents (Caprylic Acid, Capric Acid, and Lauric Acid) against Candida and other pathogens (Bergsson, Batovska, Huang, Dayrit). Human trials are much more limited. Therefore the evidence for treating yeast with this substance is based on the clinical observation of physicians who commonly treat yeast conditions. Physicians who routinely treat patients for Candida report very good success with using MCT oil/Caprylic acid. In his book, The Yeast Connection, Dr. Crook sites numerous examples of physicians who have reported this supplement as clinically useful (Crook).

Immunomodulating Properties: Like Omega-3 fatty acids, MCT's produce fewer inflammatory eicosanoids of the two- and four-series (Wan). Several in vivo studies have demonstrated anti-inflammatory properties of MCT oil and antipyretic and analgesic properties have also been documented (Canela, Intahphuak). In vivo MCTs may reduce intestinal injury and protect from hepatotoxicity which is a concern in patients taking fluconazole and itraconazole antifungal therapy (Berit, Kono). Human studies are few but promising as many of the studies are on severely immunocompromised patients who require total parernteral nutrition (TPN) and the HIV/AIDS patient population (Wanke, Dayrit, Craig, Wolfram, Chen). This patient population has responded well to the addition of MCT's. The degree to which these results apply to the general population is unclear. However, the safety of this supplement can be inferred given its effective use in severely immune compromised patient populations.

Risks: Acute toxicity tests conducted in several species of animal demonstrate that MCTs are essentially non-toxic. Ninety-day toxicity tests did not result in notable toxicity, whether the product was administered in the diet up to 9375mg/kg body weight/day or by intramuscular injection (up to 0. 5ml/kg/day, rabbits). Levels of up to 1g/kg/day have been confirmed safe in several clinical human trials (Traul). The use of MCT is only contraindicated in patients with impaired states of fat metabolism such as ketosis, acidosis, and cirrhosis (Bach).

Rationale:

Mild antifungal therapy when prescriptive agents are unavailable or contraindicated and where dosing by weight is required (such as for children).

Dosing:

Caprylic acid: PDR for nutritional supplements indicate dose as 300-1200 mg daily
Monolauren: 240 – 720 mg three times daily (adults)
Virgin coconut Oil: 2 ml/kg/day of virgin coconut oil in children
MCT: levels of up to 1g/kg/day have been confirmed safe in several clinical human trials.

Clinical References:

• Bach, AC., Babayan, VK. (1982). Medium Chain Triglycerides: un update. American Journal of Clinical Nutrition, 36(5); 950-962

• Batovska, D., et al. (2009). Antibacterial study of the medium chain fatty acids and their 1-monoglycerides: individual and synergistic relationships. Polish journal of Microbiology, 58(1); 43-7.

• Bergsson, G., et al. (2001). In vitro killing of Candida albicans by fatty acids and monoglycerides. Antimicrobial Agents and Chemotherapy, 45(11); 3209-12.

• Berit, M., Pfeuffer, M., Schrezenmeir, J., (2006). Medium Chain triglicerides. International Dairy Journal, 16(11) 1378-1382.

• Borriello, S., et al. (2003). Saftey of Probiotics that Contain Lactobacilli or Bifidobacteria. Clinical Infectious Disease, 36(6); 775-780. Doi 10.1086/368080

• Brzozowski, T., et al (2005). Influence of gastric colonization with Candida albicans on ulcer healing in rats: Effect of ranitidine, asprin and probiotic therapy. American Journal of Gastroenterology, 40(3); 286-296.

• Canani, R., et al. (2007). Probiotics for treatment of acute diarrhea in children: randomized clinical trial of five different preparations. BMJ, 335-340. Doi 10.1136/bmj.39272.581736.55

• Canela, GO., (2007). Anti-inflammatory activity of virgin coconut oil. The Philippine Journal of Internal Medicine, 45(2) 85-88.

• Craig, GB., et al. (1997). Decreased fat and nitrogen losses in patients with AIDS receiving medium chain triglyceride-enriched formula vs those receiving long-chain-triglyceride containing formula. Journal of the American Dietetic Association, 97(6); 605-11.

• Chen, FM., et al. (2005). Efficacy of medium-chain triglycerides compared with long-chain triglycerides in total parenteral nutrition in patients with digestive tract cancer undergoing surgery. The Kaohsiung Journal of Medical Sciences, 21(11); 487-94.

• Crook, W. (2000). The Yeast Connection Handbook. Jackson, TN: Woman's Health Connection.

• Davis, S. (2005). An overview of the antifungal properties of allicin and its breakdown products-the possibility of a safe and effective antifungal prophylactic. Mycoses, 48(2); 95-100. DOI: 10.1111/j.1439-0507.2004.01076.

• Dayrit, C. (2000). Coconut oil in Health and Disease: Its and Monolauren's potential as cure for HIV/AIDS. Read at the XXXVII Cocotech Metting Chennai, India July 25, 2000. http://coconutresearchcenter.org/article10526.pdf

• Fugh-Berman, A., (2000). Herbs and Dietary Supplements in the Prevention and Treatment of Cardiovascular Disease. Preventive Cardiology, 3(1); 24-32. Doi:10.1111/j.1520-037X.2000.80355.

• Guo, N., Wu, X.,, et al. (2010). In vitro and in vivo interactions between fluconazole and allicin against clinical isolates of fluconazole-resistant Candida albicans determined by alternative methods. FEMS Immunology and Medical Microbiology, 58(2); 193-201. Doi: 10.1111/j.1574-695X.2009.00620.

• Hatakka, K., et al. (2007). Probiotics Reduced the Prevalence of Oral Candida in the Elderly – a Randomized Controlled Trial. Journal of Dental Research, 86 (2); 125-130. doi: 10.1177/154405910708600204

• Herbrecht, R., Nivoix, Y., (2005). Saccharomyces cervisiae Fungemia: an adverse effect of Saccharomyces boulardi probiotic Administration. Clinical Infectious Disease, 40(11); 1635-1637. Doi 10.1086/429926

• Huang, CB., Alimova, Y., Myers, TM., Ebersole, JL. (2011). Short and medium chain fatty acids exhibit antimicrobial activity for oral microorganisms. Archives of Oral Biology, 56(7); 650-4.

• Intahphuak, S. et al. (2010). Anti-inflammatory, analgesic, and antipyretic activities of virgin coconut oil. Pharmaceutical Biology, 48(2); 151-7.

• Khodavandi, A., Alizadeh, F., et al. (2011). Comparison between efficacy of allicin and fluconazole against Candida albicans in vitro and in a systemic candidiasis mouse model. FEMS Microbiology Letters, 315. Kono, H., et al. (2003). Protective effects of medium-chain triglycerides on the liver and gut in rats administered endotoxin. Annals of Surgery, 237(2); 246-55.

• Li, Qiurong., et al. (2014). Dysbiosis of Gut Fungal Microbiota is Associated with Mucosal Inflammation in chrohn's Disease. Journal of Clinical Gastrointerology, 48:513-523.

• Maaroufi, Y., Heymans, C., De Rune, J., Duchateau, H. (2003). Rapid Detection of Candida albicans in Clinical Blood Samples by Using a TaqMan-Based PCR Assay. Journal of Clinical Microbiology, 41; 3293-3298.

• Manzoni, P., et al. (2006). Oral Supplementation with Lactobacillus casei Subspecies rhamnosus Prevents Enteric Colonization by Candida Species in Preterm Neonates: a Randomized Study. Clinical Infectious Diseases, 42(12); 1735-1742. doi: 10.1086/504324

• Munoz, P., et al. (2005). Saccharomyces cerevisiae fungemia: and emerging infectious disease. Clinical Infectious Disease, 40(11); 1625-34.

• National Center for Complimentary and Alternative Medicine (NCCAM). Herbs at a Glance: Garlic. Retrieved on 3/3/2014 from http://nccam.nih.gov/health/garlic/ataglance.htm

• Snydman, D. (2008). The Safety of Probiotics. Clinical Infectious Diseases, 46(2); S104-S111. Doi 10.1086/523331

• Pappas, P., et al. (2004). Guidelines for Treatment of Candidiasis. Clinical Infectious Diseases. 38; 161-189

• Shadkchan, Y., Shemesh, E., et al. (2004). Efficacy of allicin, the reactive molecule of garlic, in inhibiting Aspergillus spp. In vitro, and in a murine model of disseminated aspergillosis. Journal of Antimicrobial Chemotherapy, 53; 832-836. doi: 10.1093/jac/dkh174.

• Shaw ,W., (2008) Biological Treatments for Autism and PDD. Publisher: Author.

• Singla, V., Bhaskar, R, (2011). Garlic: a review. International Journal of Drug Formulation, 2. Retrieved from http://www.ordonearresearchlibrary.org/Data/pdfs/IJDFR80.pdf

• Szajewska, H., Skorka, A., Dylag, M. (2006) Meta-analysis: Saccharomyces boulardii for treating acure diarrhea in children. Alimentary Pharmacology and Theraputics, 25(3); 257-264. Doi 10.1111/j.1365-2036.2006.03202.x

• Szajewska, et al., (2006). Probiotics in Gastrointestinal Diseases in Children: Hard and Not-So-Hard Evidence of Efficacy. Journal of Pediatric Gastroenterology and Nutrition, 42(5); 454-475. Doi 10.1097/01.mpg.0000221913.88511.72

• Wagner, D., et al. (2000). Effects of probiotic bacteria on humoral immunity to Candida albicans in immunodeficient bg/bg-nu/nu and bg/bg-nu/+ mice. Journal of Microbiology/Immunology, 17; 55-59. Pdf http://www.reviberoammicol.com/2000-17/055059.pdf

• Traul, KA., Driedger A., Ingle DL., Nakhasi, D. (2000). Review of the toxicologic properties of medium-chain triglycerides. Food and Chemical Toxicology, 38(1), 79-98.

• Wan, JM., TEO, TC., Babayan, VK., Blackburn GL. (1988). Invited Comment: lipids and the development of immune dysfunction and infection. Journal of Parenteral and Enteral Nutrition, 12(6 supplment); 43s-52s.

• Wanke, CA., et al. (1996). A medium chain triglyceride-based diet in patients with HIV and chronic diarrhea reduces diarrhea and malabsorbtion: a prospective, controlled trial. Nutrition, 12(11-12); 766-71.

• Wolfram, G., (1986). Medium Chain Triglicerides for Total Parenteral Nutrition. World Journal of Surgery, 10; 33-37.

• Zwolinska, M., et al. (2009). Effect of Candida colonization on Human Ulcerative Colitis and the Healing of Inflammatory Changes of the Colon in the Experimental Model of Colitis Ulcerosa. Journal of Physiology and Pharmcology, 60(1); 107-108. Pdf http://jpp.krakow.pl/journal/archive/03_09/pdf/107_03_09_article.pdf

• Zwolinska-Wcislo, M., et al. (2006). Are probiotics effective in the treatment of fungal colonization of the gastrointestinal tract? Eperimental and clinical studies. Journal of Physiology and Pharmcology, 57(9); 35-49. Pdf http://www.jpp.krakow.pl/journal/archive/11_06_s9/pdf/35_11_06_s9_article.pdf

A New Generation of Organic Acid Testing: Pushing the Limits of Detection with New Technology

Shaw, William Ph.D

More than 50 phenotypically different organic acidemias have been discovered since the first known disease of this type, isovaleric academia, was described in 1966. An organic acid is any compound that generates protons at the prevailing pH of human blood. Although some organic acidemias result in lowered blood pH, other organic acidemias are associated with relatively weak organic acids that do not typically cause acidosis.

Organic acidemias are disorders of intermediary metabolism that lead to the accumulation of toxic compounds that derange multiple intracellular biochemical pathways, including glucose catabolism (glycolysis), glucose synthesis (gluconeogenesis), amino acid and ammonia metabolism, purine and pyrimidine metabolism, and fat metabolism. The accumulation of an organic acid in cells and fluids (plasma, cerebrospinal fluid, or urine) leads to a disease called organic academia, or organic aciduria.

Although this technology has commonly been used for diagnosing genetic disease in children, genetic diseases in adults have also been detected with it. New applications of organic acid testing include detection of factors in psychiatric disorders, mitochondrial disease and dysfunction, and exposure to a wide variety of toxic chemicals from the environment, and assessment of inflammation due to overproduction of quinolinic acid from tryptophan.

Testing now includes markers for the following metabolites:

• Glycolysis

• Krebs Cycle

• Amino acid Metabolism

• DNA, RNA metabolism

• Neurotransmitter metabolism

• Organophosphate metabolism

• Yeast, fungal markers

• Markers for beneficial bacteria

• Oxalate markers for kidney stones, genetic disease

• Specific marker for ammonia toxicity

• Markers of fatty acid catabolism

• Metabolic diseases causing autism spectrum disorders

• Phthalates

• Solvents

• Pyrethrins

• Dry cleaning solvents

• Preservatives

• Vinyl chloride

• Specific Clostridia marker

• Specific mitochondrial disease markers

• Vitamin deficiency markers

• Phosphate marker of bone function

• Marker for glutathione precursor

• Genetic screening with extremely sensitive markers

Organic acids are most commonly analyzed in urine because they are not extensively reabsorbed in the kidney tubules after glomerular filtration. Thus, organic acids in urine are often present at 100 times their concentration in the blood serum and thus are detected in urine with greater accuracy and precision than with blood samples. The number of organic acids found in urine is enormous: over 1000 have been detected since this kind of testing started 25 years ago. The challenge of dealing with so many compounds led to the use of gas chromatography-mass spectrometry (GC/MS) to analyze these complex body fluids.

With GC/MS, organic acids are chromatographically separated on the basis of their polarity and volatility and then bombarded by an electron beam that fragments the eluting molecules in a characteristic pattern. The patterns, or spectra, are stored by a computer system and then compared with known spectra that are compiled in a spectral "library." The software then compares an unknown spectrum to all the spectra on the hard drive and prints out those with the best fit. Since a single organic acid analysis generates over 1000 spectra, and each spectrum may consist of 600 ions, the software must be optimized to analyze the data in the most efficient and clinically relevant manner. Recently, the Great Plains Laboratory Inc. increased the sensitivity of this technology by approximately 1000-fold with the use of new triple-quadrupole MS technology so that a large number of toxic compounds can be measured at levels of micromoles/mole creatinine compared with urine compounds, such as vanillylmandelic (VMA), which is measured at levels of millimoles/mole creatinine.

The scope of organic acid testing has been markedly widened by commercial laboratories such that it can monitor physiological changes in nongenetic diseases and offer tremendous help in diagnosis and treatment of most chronic illnesses. Some examples are given below:

An adult with a movement disorder and bilateral temporal arachnoid cysts by brain imaging was found to have very elevated glutaric acid, indicating the presence of the genetic disease glutaric aciduria type 1.1Symptoms of this potentially fatal disorder include headaches, ataxia, memory loss, and many other neurological effects. Treatment with high doses of carnitine may be helpful in relieving symptoms in such cases, and of course such information is important for genetic counseling.

High levels of urine oxalates in an adult with frequent kidney stones led to a closer examination of the patient's dietary history. The patient ate a large spinach salad with pecans almost every day. Spinach is one of the foods highest in oxalates, and all nuts are high in oxalates as well. Treatment is directed at reducing dietary oxalates as well as calcium citrate and vitamin B6 supplementation.

After organic acid testing, a child with autism was found to have very high values (more than four times the upper limit of age-appropiate normals) of the catecholamine metabolites VMA and HVA, indicating a possible neuroblastoma. Follow-up imaging near the spine confirmed the presence of a previously undiagnosed neuroblastoma, likely saving the child's life.

Another child thought to have autism had very low amino acids, and the neurologist recommended high doses of amino acid supplements, which made the child severely ill. Organic acid testing revealed a massive excretion of methylmalonic acid, indicating that the child had methlmalonic aciduria, a severe genetic disorder. Treatment of this disorder requires extensive supplementation with vitamin B12 and a low-protein diet. Continued amino acid supplementation or a high-protein diet might have been fatal.

A person with severe depression was found to have low amounts of the serotonin metabolite 5-hydroxy-indoleacetic acid, which is derived from tryptophan. Depression is associated with decreased brain serotonin. However, the tryptophan metabolite by an alternate pathway, quinolinic acid, was much higher. Quinolinic acid is associated with inflammation such as arthritis and is considered to be neurotoxic, with a probable role in Parkinson's syndrome, Alzheimer's disease, Huntington's disease, and schizophrenia.2,3 The condition eosinophilia myalgia syndrome (EMS), associated with excessive tryptphan intake, is probably not due to tryptophan itself but to the inflammatory effects of its major metabolite quinolinic acid. Quinolinc acid administered by itself generated all of the symptoms of EMS.4,5 This research indicates that various conspiracy theories about contaminated tryptophan batches as the cause of EMS are unnecessary and probably wrong. 100% pure tryptophan at high enough doses will produce significant quantities of toxic quinolinic acid and EMS in susceptible individuals. Administration of 5-hydroxytryptophan (5-HT or 5-HTP) is a much safer option than tryptophan since 5-HT cannot be converted to the neurotoxic quinolinic acid, whereas only about 1% of tryptophan is converted to serotonin.6 Both the serotonin metabolite and quinolinic acid are measured by organic acid testing (Figure 1).

I recently proved that the dibiosis marker 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), the predominant dihydroxy-phenylpropionic acid isomer in urine measured in the organic acid test, is due to a combination of human metabolism and the metabolism by a group of Clostridia species, including but not limited to C. difficile.7 The same article indicates that 3,4-dihydroxyphenylpropionic acid (DHPPA) is a marker for beneficial bacteria in the gastrointestinal tract such as Lactobacilli, Bifidobacteria, and E. coli. The exception is one species of Clostridia orbiscindens that can convert the flavonoids luteolin and eriodictyol (which occur only in a relatively small food group that includes parsley, thyme, celery, and sweet red pepper) to DHPPA. The quantity of C. orbiscindens in the gastrointestinal tract is negligible (approximately 0.1% of the total bacteria) compared with the predominant flora of Lactobacilli, Bifidobacteria, and E. coli.7 DHPPA is an antioxidant that lowers cholesterol, reduces proinflammatory cytokines, and protects against pathogenic bacteria.

Outdated literature has referred to HPHPA as due to dietary origin based mainly on conjecture, but this conjecture was clearly disproved by my 2010 article which indicates that the metabolite is abolished by the antibiotic metronidazole.8 DHPPA, a different isomer, has been claimed to be a metabolite of Pseudomonas species, but the literature indicates that this compound is formed by the in vitro action of these species on quinolone, a component of coal tar – a substance missing from the diet of virtually all humans.9

HPHPA has been one of the most useful clinical markers in recent medical history. Treatment of individuals with high urinary values with metronidazole, vancomycin, or high doses of probiotics has led to significant clinical improvements or remissions of psychosis, tic disorders, seizures, autistic behaviors, hyperactivity, chronic fatigue syndrome, and obsessive compulsive behavior.

One of the newest aspects of organic acid testing is the screening for 74 different toxic chemicals in the environment by testing their organic acid metabolites. Solvents such as benzene, toluene, styrene, and others may be present for only short periods in body fluids and may also be lost in transit due to their volatility, but their metabolites are very stable. Using this screening technique, most metabolites of different organophosphates and pyrethrins can be measured as well as trichloroethylene, tetrachloroethylene, and vinyl chloride. Phthalates, an extremely toxic group of compounds implicated in infertility and abnormal sexual development in both males and females, can be measured by their metabolite phthalate, a specific chemical entity.

The chemical structure of phthalic acid (or phthalates) is nearly identical to quinolinic acid. A toxic effect occurs when phthalic acid competitively inhibits the reaction by which quinolinic acid is converted to the beneficial coenzyme NAD. High concentrations of phthalic acid or quinolinic acid may be associated with increased toxicity due to phthalate blockage of NAD formation and potential mitochondrial dysfunction due to deficient NAD for mitochondrial energy production.

One of the most important advances in the organic acid test is the addition of a biochemical marker, tiglylglycine, as a specific indicator for mitochondrial dysfunction.11 Mitochondrial dysfunction has been implicated in Parkinson's and Alzheimer's syndromes, diabetes, autism, chronic fatigue syndrome, aging, and many others. Tiglylglycine has been shown to be elevated in the urine in mitochondrial disorders involving defects of complexes I, II, III, and IV, protein complexes attached to the mitochondrial membrane that are involved in energy production. In addition to mutations in mitochondrial or nuclear DNA, mitochondrial dysfunction may also be due to exposures to toxic chemicals such as organophosphates and the solvent trichloroethylene. The advantage of the organic acid test is that if a mitochondrial dysfunction is detected, a number of different toxic chemicals implicated in mitochondrial damage can be reviewed to find the potential cause. Trichloroethylene has been found as a contaminant in the municipal water supply of many cities in both the US and Canada, and is used as a degreaser military bases and as a common solvent throughout the chemical industry. Mitochondrial disorders can be treated with a cocktail of nutritional substances including coenzyme Q10, carnitine, riboflavin, and others, when chemical exposure is not detected. If toxic chemicals are found, treatment with the Hubbard protocol can be highly successful for the removal of a wide array of toxic substances.12

Clinical References:

• 1. Martinez-Lage J et al. Macrocephaly, dystonia, and bilateral temporal arachnoid cysts: glutaric aciduria type 1. Childs Nerv Sys. 1994;10(3): 198-203.

• 2. Guillemin GJ et al. Quinolinic acid in the pathogenesis of Alzheimer's disease. Adv Exp Med Biol. 2003;527:167-176.

• 3. Stoy N et al. Tryptophan metabolism and oxidative stress in patients with Huntington's disease. J Neurochem. 20015;93:611-623.

• 4. Silver RM et al. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med. 1990;322(13):874-881.

• 5. Noakes R, Spelman L, Williamson R. Is the L-tryptophan metabolite quinolinic acid responsible for eosinophilic fasciitis? Clin Exp Med. 2006;6(2):60-64.

• 6. Shah GM et al. Biochemical assessment of niacin efficiency among carcinoid cancer patients. Am J Gastroenterol. 2005;100:2307-2314.

• 7. Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia species in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010;13(3):1-10.

• 8. Kumps A, Duez P, Mardens Y. Metabolic, nutritional, latrogenic, and artifactual sources of urinary organic acids: a comprehensive table. Clin Chem. 2002,48:708-717.

• 9. Shukla OP. Microbial transformation of quinolone by a pseudomonas sp. Appl Environ Microbiol. 1986;51(6):1332-1342.

• 10. Fukuwatari T et al. Phthalate esters enhance quinolinate production by inhibiting alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarbocylase (ACMSD), a key enzyme of the tryptophan pathway. Toxicol Sci. 2004;81:302-308.

• 11. Bennett M et al. Tiglylglycine excreted in urine in disorders of isoleucine metabolism and the respiratory chain measured by stable isotope dilution GC-MS. Clin Chem. 1994;40(10):1879-1833.

• 12. Shaw W. The unique vulnerability of the human brain to toxic chemical exposure and the importance of toxic chemical evaluation and treatment in orthomolecular psychiatry. J Orthomol Med. 2010;25(3).

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

---

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.

11. Ott SM, Andress DL, Sherrard DJ. Bone oxalate in a long-term hemodialysis patient who ingested high doses of vitamin C. Am J Kidney Dis. 1986 Dec;8(6):450-4.

12. Hall BM, Walsh JC, Horvath JS, Lytton DG. Peripheral neuropathy complicating primary hyperoxaluria. J Neurol Sci. 1976 Oct;29(2-4):343-9.

13. Sahin G, Acikalin MF, Yalcin AU. Erythropoietin resistance as a result of oxalosis in bone marrow. Clin Nephrol. 2005 May;63(5):402-4.

14. Sarma AV, Foxman B, Bayirli B, Haefner H, Sobel JD. Epidemiology of vulvar vestibulitis syndrome: an exploratory case-control study. Sex Transm Infect. 1999 Oct;75(5):320-6.

15. http://www.thevpfoundation.org/effective_treatment.htm

16. Shirane Y, Kurokawa Y, Miyashita S, Komatsu H, Kagawa S. Study of inhibition mechanisms of glycosaminoglycans on calcium oxalate monohydrate crystals by atomic force microscopy. Urol Res. 1999 Dec;27(6):426-31.

17. Chetyrkin SV, Kim D, Belmont JM, Scheinman JI, Hudson BG, Voziyan PA. Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria.

18. Sangaletti O, Petrillo M, Bianchi Porro G. Urinary oxalate recovery after oral oxalic load: an alternative method to the quantitative determination of stool fat for the diagnosis of lipid malabsorption. J Int Med Res. 1989 Nov-Dec;17(6):526-31.

19. Kumar R, Mukherjee M, Bhandari M, Kumar A, Sidhu H, Mittal RD. Role of Oxalobacter formigenes in calcium oxalate stone disease: a study from North India. Eur Urol. 2002 Mar;41(3):318-22.

20. Azcarate-Peril MA, Bruno-Barcena JM, Hassan HM, Klaenhammer TR. Transcriptional and functional analysis of oxalyl-coenzyme A (CoA) decarboxylase and formyl-CoA transferase genes from Lactobacillus acidophilus. Appl Environ Microbiol. 2006 Mar;72(3):1891-9.

21. Baggio B, Gambaro G, Zambon S, Marchini F, Bassi A, Bordin L, Clari G, Manzato E. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996 Apr;7(4):613-20.

22. Gambaro G, Bordoni A, Hrelia S, Bordin L, Biagi P, Semplicini A, Clari G, Manzato E, Baggio B. Dietary manipulation of delta-6-desaturase modifies phospholipid arachidonic acid levels and the urinary excretion of calcium and oxalate in the rat: insight in calcium lithogenesis. J Lab Clin Med. 2000 Jan;135(1):89-95.

23. Santhosh Kumar M, Selvam R. Supplementation of vitamin E and selenium prevents hyperoxaluria in experimental urolithic rats. J Nutr Biochem. 2003 Jun;14(6):306-13.

24. Pragasam V, Kalaiselvi P, Sumitra K, Srinivasan S, Varalakshmi P. Pragasam V, Kalaiselvi P, Sumitra K, Srinivasan S, Varalakshmi P. Counteraction of oxalate induced nitrosative stress by supplementation of l-arginine, a potent antilithic agent. Clin Chim Acta. 2005 Apr;354(1-2):159-66. Epub 2005 Jan 19.

25. Takenouchi KAso K, Kawase K, Ichikawa H, Shiomi T. On the metabolites of ascorbic acid, especially oxalic acid, eliminated in urine, following administration of large amounts of ascorbic acid. J Vitaminol (Kyoto). 1966 Mar 10;12(1):49-58.

26. Curhan, G. C., Willett, W. C., Speizer, F. E., Stampfer, M. J. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 10:4:840-845, Apr 1999

27. Dolske MC, Spollen J, McKay S, Lancashire E, Tolbert L. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog. Neuropsycho-pharmacol Biol Psychiatry. 1993 Sep;17(5):765-74.