Contents

Foreword

Chapter 1. Biochemical Individuality and Mental Health

Chapter 2. Brain Chemistry 101

Chapter 3. The Decisive Role of Nutrients in Mental Health

Chapter 4. Epigenetics and Mental Health

Chapter 5. Schizophrenia

Chapter 6. Depression

Chapter 7. Autism

Chapter 8. Behavioral Disorders and ADHD

Chapter 9. Alzheimer’s Disease

Chapter 10. The Clinical Process

Appendix A. Methylation

Appendix B. Oxidative Stress

Appendix C. Metallothionein

Chapter 1. Biochemical Individuality and Mental Health

The Birth of Neurotransmitters

In the 1970s, low serotonin activity was associated with clinical depression, elevated norepinephrine with anxiety, and elevated dopamine with schizophrenia.

The Power of Nutrients

Serotonin is produced from the amino acid tryptophan, and the final reaction step requires vitamin B6 as a cofactor. Dopamine can originate from either of two amino acids with iron and folate also involved in the process. Norepinephrine is produced from dopamine with copper (Cu) having a decisive role. Zinc (Zn) and B6 are required for the synthesis and regulation of GABA.

The population of reuptake transporters generally has a more dominant effect on synaptic activity than the number of neurotransmitters present. Transporters are continuously produced in the brain by genetic expression, the process by which information in a gene is used to produce a protein. The rate of production of transporters is enhanced by certain nutrients and inhibited by others.

• Methylation (addition of a CH3 chemical group) of DNA is a primary mechanism for “silencing” (switching off) genes that produce neurotransmitter transporters. The net result is that undermethylated persons generally have reduced serotonin activity and a tendency for depression.
• Overmethylated persons may have excessive dopamine activity and a tendency for anxiety and paranoid schizophrenia.

Biochemical Individuality

The number of different genetic combinations possible in a child from the same two parents exceeds 40 million. Human beings are not a combination of their mother and father but possess physical characteristics and traits from a genetic lottery involving many ancestors.

Abnormal levels of key nutrients can have an adverse effect on brain chemistry and mental health. Because of these abnormalities, some individuals have a predisposition for conditions such as clinical depression, oppositional defiant disorder (ODD), and attention-deficit/hyperactivity disorder (ADHD), while others are quite invulnerable to these disorders.

Biochemistry can be affected by diet and stressful life events, but the dominant factor often goes back to genetics or, additionally, epigenetics. The environment (e.g., diet, toxins, lifestyle) can affect the expression of a person’s genes, and this alteration in gene expression is called epigenetics.

Chapter 2. Brain Chemistry 101

The Neurotransmitter Life Cycle

• Step 1: Synthesis: Most neurotransmitters are produced in the axon terminus near the synapse. The reactants consist of (a) amino acids and other nutrients that enter the cell through the cell membrane, and (b) enzymes that are produced by gene expression in the nucleus and make the long journey down the axon via microtubule tunnels.
• Step 2: Packaging into vesicles: Vesicles are formed in the nucleus and travel down the axon via microtubule tunnels. Neurotransmitters are loaded into vesicles through proteins called vesicular monoamine transporters (VMAT) that are embedded in vesicle membranes. About 20 to 200 neurotransmitter molecules can be stored within each vesicle. Some of the vesicles attach to the neuron’s membrane at docking sites where they can launch their neurotransmitters into the synapse.
• Step 3: Release into a synapse: When a brain cell fires, calcium ions rush into the cell, causing vesicles to be ripped open and neurotransmitter molecules sprayed into the synapse. The ruptured vesicles are either absorbed into the cell membrane or returned to the cytosol liquid for formation of new vesicles.
• Step 4: Interaction with an adjacent cell: A fraction of the neurotransmitter molecules travel across the synapse to receptors of nearby cells and transmit a chemical message that either promotes or inhibits cell firing. After a brief interaction, the neurotransmitter molecule is released from the receptor back into the synapse.
• Step 5: Reuptake: Neurotransmitter molecules can be quickly returned to the original cell through transmembrane transporter proteins and packaged into new vesicles for reuse. This reuptake process usually dominates neurotransmitter activity at synapses, and transporters are the target of most psychiatric medications. For example, SSRI antidepressants directly interact with transporters to inhibit serotonin reuptake and increase serotonin concentrations in the synapse.
• Step 6: Death: Neurotransmitter molecules eventually undergo chemical degradation that removes them from the scene. Some neurotransmitter molecules diffuse away from the synapse and are lost by that mechanism.

SSRI medications include Prozac, Zoloft, Paxil, Luvox, Celexa, and Lexapro. Effexor, Cymbalta, and Pristiq are selective serotonin and norepinephrine inhibitors (SNRIs) that increase synaptic activity of both serotonin and norepinephrine. Another class of antidepressants are the monoamine oxidase inhibitors (MAOIs), which reduce levels of monoamine oxidase, a natural biochemical that destroys a fraction of the serotonin molecules in the synapse.

Benefits of Biochemical Therapy

For most patients, the benefits of biochemical therapy result from the following:

• Normalizing the concentration of nutrients needed for neurotransmitter synthesis
• Epigenetic regulation of neurotransmitter activity using targeted nutrient therapy
• Reducing free-radical oxidative stress

Many patients suffering from depression exhibit low levels of vitamin B6, an important cofactor in the last chemical step in serotonin synthesis.

Methylating nutrients such as S-adenosylmethionine (SAMe) can inhibit gene expression of serotonin transporters and, therefore, increase serotonin activity.

For many patients, antioxidant nutrients can assist in normalizing activity at GABA, N-methyl-D-aspartate (NMDA), and other receptors.

Chapter 3. The Decisive Role of Nutrients in Mental Health

The Brain – A Chemical Factory

Most of our brain’s serotonin is synthesized in the raphe nuclei along the brainstem and transported by axons to areas throughout the brain. Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area.

Database Studies, Early Nutrient Therapies, and Beyond: Examples from Schizophrenia

Abram Hoffer recommended a protocol involving the combined use of niacin, folic acid, vitamin B12, vitamin C, essential oils, and special diets for schizophrenic patients.

• New epigenetics research indicates that folates and niacin can powerfully reduce dopamine activity by enhancing acetylation of histones
• He reported that 90% of schizophrenics fit into one of the three major biochemical types that he called histapenia, histadelia, and pyroluria, with an additional 4% suffering from wheat gluten allergy. He also identified several low-incidence disorders that could cause schizophrenia symptoms, including porphyria, homocysteinuria, hypothyroidism, and polydipsia.

Carl Pfeiffer believed that histamine deficiency (histapenia) and copper overload were responsible for classic paranoid schizophrenia that usually involved auditory hallucinations. He treated this condition with folic acid, vitamin B12, niacin, zinc, and augmenting nutrients. In contrast, Pfeiffer’s histadelia (histamine overload) biotype typically involved delusions or catatonic behaviors that he treated with methionine, calcium, and sometimes with antihistamines.

• Another 20% of schizophrenia patients fit into Pfeiffer’s pyroluria biotype that was often characterized by both auditory hallucinations and delusions. Pfeiffer treated the pyrolurics with strong doses of vitamin B6 and zinc.
• The author amassed evidence that methyl and folate levels had a far greater impact on mental health than histamine and concluded that histamine was not a decisive factor in schizophrenia. Today, blood histamine is used as a marker for methylation status but not for mental status. Histamine and methyl groups are present in measurable levels throughout the body and an inverse relationship exists between them.
• Pfeiffer’s terms histadelia and histapenia were replaced by undermethylation and overmethylation, with the understanding that serotonin, dopamine, and norepinephrine activities are influenced by methyl status. However, this approach did not explain why a powerful methylating treatment (folic acid and vitamin B12) caused dramatic worsening in undermethylated schizophrenics. This problem was resolved in 2009 with the discovery that methyl and folate have opposite epigenetic impacts on neurotransmitter reuptake at synapses.

The genetic expression of transporters is inhibited by methylation and enhanced by acetylation. Acetylation is the process of adding an acetyl group (CH3CO) to a molecule. The relative amounts of methyl and acetyl attached to DNA and histone tails impact the synaptic concentration of reuptake proteins and the activity of dopamine, serotonin, and norepinephrine.

• By different mechanisms, folates and niacin promote dominance of acetylation at DNA and histones.
• Methionine and SAMe produce the opposite effect by promoting methylation of DNA and histones. The net result is that activities of serotonin, dopamine, and other neurotransmitters are strongly influenced by the methyl/folate ratio.

Coping with Biochemical Imbalances

Counseling and a good environment may be effective in mild-to-moderate behavioral disorders, but a severe chemical imbalance must focus on correcting brain chemistry. Similarly, a mild genetic tendency for depression may be overcome by factors such as a good environment, exercise, and counseling, whereas a severe tendency may require aggressive biochemical intervention.

The Repeat Offenders

Copper overload is present in most cases of hyperactivity, learning disability, postpartum depression, autism, and paranoid schizophrenia.

Undermethylation is often present in antisocial personality disorder, clinical depression, anorexia, obsessive-compulsive disorder, and schizoaffective disorder.

• Antisocial personality disorder associated with criminality usually involves the combination of zinc deficiency, oxidative overload, undermethylation, and elevated toxic metals.
• Paranoid schizophrenia usually involves overmethylation, folate deficiency, and elevated blood copper.
• Because of genetic variations, a particular chemical imbalance may have a variety of outcomes for different persons.

The primary repeat offenders are the following:

• Copper overload
• Vitamin B6 deficiency
• Zinc deficiency
• Methyl/folate imbalances
• Oxidative stress overload
• Amino acid imbalances

These all have a direct role in the synthesis or functioning of a major neurotransmitter.

Remediating the Repeat Offenders

Copper Overload:

• Copper plays an important role in the synthesis of neurotransmitters, respiration, immune function, energy metabolism, and growth. In most persons, blood copper levels are kept in a narrow range through the action of metallothionein (MT), ceruloplasmin, and other proteins. Unfortunately, many persons have a genetic inability to regulate copper levels and a serious copper overload can result.
• Copper is a cofactor in the synthesis of norepinephrine. Norepinephrine is formed in the brain by the addition of a hydroxyl group to a dopamine molecule.
• This reaction occurs in dopamine storage vesicles and is enabled by the enzyme dopamine β-hydroxylase (DBH) together with doubly-charged copper ions, vitamin C, and O2 cofactors. DBH is a complex molecule containing 576 amino acids that binds to several copper ions. Vitamin C protects the DBH enzyme from oxidative reactions and supplies electrons for the reaction. The O2 cofactor provides the oxygen atom for creation of the hydroxyl group.
• Copper overloads tend to lower dopamine levels and increase norepinephrine in the brain. Imbalances in these important neurotransmitters have been associated with paranoid schizophrenia, bipolar disorder, postpartum depression, ADHD, autism, and violent behavior.
• Most persons with elevated blood copper also exhibit depressed zinc and excessive oxidative stress. In healthy persons, copper levels are regulated by MT and other proteins that bind to excess copper and carry it out of the body. However, MT activity can be significantly reduced by either zinc deficiency or elevated oxidative stress. Many persons diagnosed with mental illness have an inborn tendency for elevated copper levels, and this predisposes them to psychiatric disorders.

Vitamin B6 Deficiency:

• B6 concentrations in the brain are about 100 times higher than levels in blood, and has important roles in mental functioning. Severe deficiency of vitamin B6 has been associated with irritability, depression, poor short-term memory, and psychosis. It is required for efficient synthesis of serotonin, dopamine, and GABA.
• There are three different chemical forms of B6, the most common being pyridoxine hydrochloride, which converts to pyridoxal-5-phosphate (PLP, which is also known as P5P), the activated form of B-6 in the body and brain. PLP is a strong aldehyde that has the ability to remove carboxyl groups (COOH) from molecules. An important example is the conversion of 5-HTP to serotonin (5-HT).
• PLP links to the enzyme aromatic L-amino-acid decarboxylase (AADC) and enables the removal of the OH- group from 5-HTP. Persons with a genetic or acquired B6 deficiency tend to produce insufficient amounts of brain serotonin and are prone to clinical depression, OCD, and other mental problems.
• Vitamin B6 in the form of PLP is also required for the synthesis of dopamine (L-Dopa + L-amino acid decarboxylase + PLP ->Dopamine) and GABA (Glutamic acid + L-glutamic acid + PLP -> GABA) in the brain. A genetic or acquired deficiency of B6 can result in abnormally low levels of these neurotransmitters and problems, including ADHD, depression, anxiety, and sleep disorders. 
• Vitamin B6 is involved in more than 80 biochemical reactions in the body. Deficiency can result in nervousness, insomnia, muscle weakness, and difficulty walking. The gold standard test for B6 status is the transaminase stimulation blood test. However, most B6 deficient people exhibit elevated pyrroles that can be detected by an inexpensive urine test. 
• Many slender malabsorbers diagnosed with schizophrenia failed to respond to the standard form of B6 (pyridoxine hydrochloride) but improved significantly after receiving supplements of PLP.

Zinc Deficiency:

• Dietary zinc is transported to the liver by albumin, transferrin, and L-histidine proteins in the portal bloodstream. Once in the liver, most of the zinc is converted to zinc metallothionein that acts as a chaperone carrying zinc to cells throughout the body. Zinc is quite nontoxic when bound to a protein, and cases of zinc overload and poisoning are extremely rare.
• More than 90% of persons diagnosed with depression, behavioral disorders, ADHD, autism, and schizophrenia exhibit depleted plasma zinc levels, ranging from low-normal to severe deficiency. One explanation for this is that most mental disorders involve oxidative stresses that deplete zinc stores in the body. In addition, zinc has a special role in activation and inhibition of NMDA receptors that are essential to good mental health.
• Zinc deficiency has been associated with delayed growth, temper control problems, poor immune function, depression, poor wound healing, epilepsy, anxiety, neurodegenerative disorders, hormone imbalances, and learning problems. Zinc is a component of more than 200 enzymes and is present in RNA polymerase, zinc fingers, and other special proteins that have key roles in cell division and genetic expression.
• Zinc has many important roles in brain function:
  • Zinc metallothionein is a key component of the blood-brain barrier that prevents harmful chemicals from entering the brain.
  • Zinc proteins in the brain combat oxidative free radicals that could destroy brain cells, harm the myelin sheath, and alter neurotransmitter levels.
  • Zinc is required for the efficient conversion of dietary B6 into PLP, which is needed for efficient synthesis of serotonin, dopamine, GABA, and other neurotransmitters.
  • Zinc deficiency can cause copper overloads that can alter brain levels of dopamine and norepinephrine.
  • Zinc deficiency results in altered brain levels of GABA.
  • Zinc is a neurotransmitter that is stored in vesicles and ejected into synapses.
  • Zinc has a special role in the activation and inhibition of NMDA receptors.
• Increasing blood zinc levels results in higher production of MT and other zinc-bearing proteins that drive toxins out of the body. Special caution must be taken for persons with a cadmium overload since rapid removal can damage kidney tubules (gradually correct over a few months).
• Many neuroscientists regard zinc as unimportant in mental illness for the following reasons:
  • Most persons receive sufficient zinc from their diet.
  • Homeostatic processes regulate blood zinc levels in most humans.
  • Zinc is not directly involved in rate-controlling steps in the synthesis of most neurotransmitters.
• He believes lab testing for plasma zinc should be mandatory for all patients diagnosed with a behavioral disorder, ADHD, autism, or a mental illness.

Methyl/Folate Imbalances:

• Low serotonin depressives thrive on methylating agents such as methionine or SAMe but are intolerant to folates. In contrast, patients with excessive activity of dopamine and norepinephrine (e.g., paranoid schizophrenia) thrive on folic acid and react adversely to SAMe and methionine.
• Folate deficiency results in reduced production of transporters and elevated synaptic activity. Undermethylation has the opposite effect, resulting in excessive gene expression of transporters and reduced synaptic activity.
• The nutrient SAMe is a natural reuptake inhibitor for serotonin, dopamine, and norepinephrine. Folic acid is a natural reuptake enhancer that can combat excessive dopamine activity. The individual levels of methyl and folate in the brain are not as important as the methyl/folate ratio. Genetic or acquired imbalances in methyl and folate may be responsible for more than 50% of all mental illness.

Oxidative Stress:

• The role of oxidative stress in schizophrenia was first noticed when researchers in the 1960s observed elevated pyrrole levels in these patients. Pyrrole is a natural organic chemical containing a five-membered ring with the formula C4H4NH. The term pyrrole is also used for several organic compounds containing a pyrrole ring. Pyrroles are involved in the synthesis of heme, the primary constituent of hemoglobin. Except for a role in the production of biochemicals, pyrroles are of minor importance and are efficiently excreted in urine. They have an affinity for binding with PLP and zinc, resulting in these valuable nutrients being transported out of the body together with the pyrroles.
• Some persons have a genetic (or acquired) tendency for very elevated levels of pyrroles, which can result in a deficiency of both PLP and zinc.
• Classic symptoms of pyrrole disorder include high anxiety, frequent mood swings, poor short-term memory, reading disorder, morning nausea, absence of dream recall, and frequent anger and rages.
• Most mental disorders involve oxidative stress, and elevated pyrroles may be secondary to a number of other biochemical conditions. However, psychiatric symptoms often recede or disappear after B-6 and zinc therapy and normalization of pyrrole levels. A genetic pyrrole disorder can result in low serotonin and GABA levels.
• Persons born with pyrrole disorder may have a lifetime tendency for deficiencies of B6, zinc, and for high oxidative stress. Any source of oxidative stress can elevate urinary pyrrole levels. Many persons have elevated pyrroles resulting from factors such as physical accidents, illnesses, infections, emotional trauma, and toxic metals. Oxidative overloads from any source can cause psychosis in sensitive individuals by lowering glutamate neurotransmitter activity at NMDA receptors in the brain. Oxidative stresses deplete levels of glutathione (GSH) needed for efficient NMDA function.
• Incidence of Pyrrole Overload in Clinical Populations
  • ADHD 18 %
  • Behavioral Disorder 28 %
  • Autism 35 %
  • Depression 24 %
  • Bipolar Disorder 35 %
  • Schizophrenia 30 %
  • Post-Traumatic Stress 12 %
  • Alzheimer’s Disease 14 %
  • Healthy Controls 8 %

Amino Acid Disorders:

• Tryptophan is the initial starting point (substrate) for the synthesis of serotonin. 
• Dopamine and norepinephrine are synthesized from either phenylalanine or tyrosine, and supplements of these amino acids may assist in elevating levels of these neurotransmitters.
• Glutamine is an amino acid that is a substrate for glutamic acid and the neurotransmitter GABA.
• GABA is both an amino acid and a neurotransmitter, and depressed levels have been associated with anxiety, depression, and psychosis.
• Aspartate is the starting point for the synthesis of the neurotransmitter aspartic acid.
• L-histidine is a precursor of the neurotransmitter histamine.
• Methionine is the precursor for SAMe that has a strong influence on genetic expression of several enzymes required for neurotransmitter synthesis and reuptake.

Fatty Acid Imbalance:

• Unsaturated fatty acids are especially important because they provide fluidity to cell membranes and assist in communication between brain cells. At brain synapses where the action is, four fats make up more than 90% of the lipid content: docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA), and dihomo-gammalinolenic acid (DGLA). Of these, DHA (an omega-3 fatty acid) is found in the highest concentration and appears to have the greatest impact on brain function.
  • DHA deficiency has been associated with depression, ADHD, schizophrenia, bipolar disorder, and dementia. Second in importance may be EPA, another omega-3 fatty acid.
  • DHA and EPA are essential fatty acids (EFAs) that have become very popular nutritional supplements. Seafood and fish oils are excellent omega-3 dietary sources.
  • AA and DGLA are omega-6 EFAs and are at excessive levels in most persons who consume a junk food diet.
• Most persons with severe pyrrole disorder have sufficient levels of omega-3 oils but are very deficient in AA. These patients thrive on primrose oil, which is rich in omega-6; however, they may deteriorate if they supplement with omega-3 alone. In contrast, most depressives and schizophrenics are deficient in DHA and EPA and thrive on omega-3 supplements.
• Most mental disorders involve elevated oxidative stress that can be quite lethal to EFAs. Fortunately, phosphatidyls are fatty acids that provide a safe haven for DHA, EPA, AA, and DGLA in the presence of oxidative free radicals. The four major phosphatidyls have choline, serine, inositol, or ethanolamine attached to the end of the molecule.

Glucose Dysregulation:

• Some patients exhibit chronic low blood glucose levels and require glucose stabilizing nutrients, like chromium and manganese, as well as frequent small meals with complex carbohydrates.
• Typical symptoms include drowsiness after meals, irritability, craving for sweets, trembling, anxiety, and intermittent poor concentration and focus.

Toxic Overload:

• Persons with depressed levels of zinc, glutathione, selenium, or metallothionein are especially sensitive to toxic metals. A high percentage of overmethylated mental patients exhibit severe sensitivities to pesticides and toxic industrial chemicals.
• Effective treatment of a toxic overload requires a three-part approach:
  • Avoidance of additional exposures
  • Biochemical treatment to hasten the exit of the toxins from the body
  • Correction of underlying chemical imbalances to minimize future vulnerability to toxins

Malabsorption:

• Although only 10% of mental illness cases involve serious malabsorption, more than 90% of autistics exhibit this problem.
• There are three primary classes of absorption problems:
  • Stomach problems, including excessive or insufficient levels of hydrochloric acid
  • Incomplete digestion in the small intestine
  • Problems at the brush-border of the intestine where most nutrients are absorbed into the portal blood stream
• The consequences can include nutrient deficiencies, inflammation in the intestinal tract, Candida, and many other gastrointestinal (GI) disorders.
• Elevated oxidative stress can destroy digestive enzymes needed for processing protein and is a frequent cause of malabsorption. A high percentage of malabsorbing patients have a compromised and, thus, ineffective intestinal barrier, allowing toxic metals and other undesirable substances to enter the body and access the brain. Treatment depends on the type of malabsorption present and may involve the adjustment of stomach acid levels, administration of digestive enzymes that survive stomach acid, administration of antioxidants, and use of special diets.

Other Nutrient Imbalances:

• Selenium, vitamin C, vitamin E, and other natural antioxidants combat inflammation and free radicals in the brain and indirectly increase glutamate activity at NMDA receptors. Vitamin D deficiency has been associated with depression, schizophrenia, ADHD, and other mental disorders. Vitamin D levels increase during exposure to sunlight, and it’s not a surprise that northern Scandinavia, with its relatively low amount of sunlight, has an extremely high incidence of schizophrenia.

The Interface with Psychiatric Medication

The goal is not to eliminate psychiatric medication but to identify the dosage needed for maximum benefits.

Their internal outcome studies indicate that more than 70% of behavior, ADHD, and depression patients report they are at their best with zero medication after six months of biochemical therapy. The remaining 30% state that some medication support is needed to prevent a partial return of symptoms.

The situation is very different for patients diagnosed with schizophrenia or bipolar disorder, with only 5% able to completely discontinue psychiatric medication after successful biochemical therapy. Many of these patients report elimination of psychosis and a return to independent living after a combination of nutrient therapy and greatly reduced medication levels.

Nutrient Therapy Response Times

Several weeks or months are usually needed to achieve the full effect. In contrast, most psychiatric medications can affect symptoms within a few hours or days.

SSRI antidepressants quickly bind to transporters, resulting in a rapid increase in serotonin activity at the synapse. Methylation therapy for depression using SAMe or methionine reduces genetic expression of transporters, resulting in a slow and gradual increase in serotonin activity over a period of several months. In another example, nutrient therapy to eliminate copper overloads in the blood usually requires about 60 days.

The chemical imbalance with the fastest response is pyrrole disorder, with significant progress often reported during the first week. This rapid response

results from the ability to normalize vitamin B-6 levels in a short time.

Zinc deficiency usually can be corrected within 60 days.

Treatment of overmethylation usually entails no improvement the first two weeks, with gradual progress over the next four to eight weeks.

Undermethylation is the slowest chemical imbalance to resolve, with three to nine months often required for the full effect.

The Value of Counseling

Behavior-disordered teens may have a negative self-image and poor habits that cannot be corrected by chemistry alone. Many anorexic patients have reported nice improvement from nutrient therapies but needed effective counseling to achieve complete recovery.

Chemical Classification of Mental Illnesses

More than 30% of depressives are not low-serotonin patients, and for them an SSRI will likely be either neutral or harmful.

The most common phenotype of schizophrenia involves elevated dopamine activity, and most current antipsychotic medications are aimed at lowering activity of this neurotransmitter. Unfortunately, this is the wrong approach for schizophrenics with different brain chemistry.

Chapter 4. Epigenetics and Mental Health

The chemical environment in the womb can determine which genes are expressed and which are silenced in the various tissues and organs. In addition, environmental factors can alter genetic expression throughout life. Many mental disorders result from environmental factors that cause genes to behave (or express themselves) improperly. Nutrient imbalances or toxic exposures can alter gene expression rates and may be the root cause of numerous psychiatric disorders. It’s not a coincidence that methylation is a dominant factor in epigenetics, and methylation abnormalities are common in mental illnesses.

Epigenetics 101

Epigenetics provides the blueprint that specifies the combination of proteins to be manufactured in each tissue.

The acidic DNA strand gently adheres to millions of histones which are slightly alkaline. The histone-DNA beads are called nucleosomes, and an array of nucleosomes is termed chromatin.

A histone consists of eight linear proteins clumped together like a ball of yarn, with several protein tails protruding from the array. The DNA ribbon wraps around each of the millions of histones slightly less than two times (146 base pairs).

Researchers recently established that genes can be turned on or off, depending on which chemicals react with the histone tails. Abnormal histone modifications are common in mental illness, and nutrient therapy can assist in normalizing histone chemistry.

DNA methylation involves addition of methyl groups to some of the cytosine molecules along the double helix. In most cases, methylation in the vicinity of a gene tends to silence expression of that gene. This process is a crucial part of human development that helps determine which proteins are produced in different tissues and organs. DNA methylation also prevents expression of viruses and other junk genes that have been implicated in disease conditions.

• If tails are predominantly acetylated, genetic expression (protein production) is promoted. Highly methylated histones generally result in silencing of genetic expression.
• Acetyl groups lower the pH of alkaline histones, thus reducing the electrostatic attraction to DNA and allowing the array to open up and promote genetic expression. Methyl groups produce the opposite effect by increasing compactness of chromatin and silencing genetic expression.

After conception, all of the methyl, acetyl, and other regulating chemicals from the parents’ DNA are removed from the DNA of the fetus and a new set of chemicals attached during early fetal development. These chemicals are called bookmarks (or marks) since they regulate the expression of every gene and can remain in place through a lifetime of cell divisions. Deviant marks that develop in utero can result in a variety of diseases and developmental disorders. Most deviant marks associated with mental illnesses are believed to involve inappropriate placement of methyl and acetyl groups on DNA or histone tails.

Acetyl and methyl levels dominate the expression/silencing of many genes, but other chemical factors such as phosphate, biotin, ubiquitin, and citrullin can react with histones and influence gene expression. In addition, transcription factors are recruited by specific combinations of histone proteins and reactants and interact with the local DNA to influence cell expression. There may be more than 2,000 transcription factors, indicating there are a great multitude of different histone reactions that can occur.

Transcription Factors

Transcription factors are proteins that bind to specific areas of DNA and regulate the access of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA). A defining feature of transcription factors is that they contain one or more DNA-binding domains, which attach to specific sequences of DNA adjacent to the genes that they regulate.

Some transcription factors promote gene expression, while others are inhibitory. The enormous diversity of these proteins may be essential to development of in utero tissue differentiation. They have several mechanisms, including regulation of acetyl and methyl levels at CpG islands (genomic regions that contain a high frequency of cytosine-phosphate-guanine sites) and histones.

The Methyl-Acetyl Competition

Methyl groups are delivered to histones by SAMe and acetyl groups by acetyl coenzyme A. Both of these chemical factors are in high concentration throughout the entire body.

• SAMe is a natural protein produced in the liver from dietary methionine. SAMe provides methyl groups for dozens of important biochemical reactions in the body and is conserved by a process called the methylation cycle or one-carbon cycle.
• Acetyl coenzyme A is formed from the metabolism (breakdown) of protein, fats, and carbohydrates and delivers high energy acetyl groups to the mitochondria for processing in the citric acid cycle.

Attachment or removal of methyl and acetyl at histone tails is dominated by enzymes called methylases, acetylases, demethylases, and deacetylases—NOT by the amounts of methyl and acetyl present.

Niacinamide (vitamin B3) reduces the activity of sirtuin, an important deacetylase enzyme.

Folic acid impacts methyl levels at histones. It’s interesting to note that folates increase methyl levels in tissues and the bloodstream, but they reduce methylation at certain histones that regulate gene expression.

Neurotransmitter Transporter Proteins

Gene expression of serotonin, dopamine, and norepinephrine transporters is dominated by a competition between methyl and acetyl groups at the histone tails. If acetylation dominates, the production of transporters is increased and neurotransmitter activity is reduced. If methylation wins the battle, gene expression of transporters is inhibited, resulting in higher neurotransmitter activity. In essence, nutrients that promote histone methylation are natural serotonin reuptake inhibitors.

Placing acetyl groups on histones is enabled by enzymes called histone acetyltransferases (HATs). Acetyl groups can be readily removed by chemicals called histone deacetylases (HDACs). Several HAT and HDAC enzymes have been identified. Enzymes called histone methyltransferases (HMTs) promote the transfer of one to three methyl groups from SAMe to specific amino acid locations along the linear histone proteins.

Epigenetics and Brain Functioning

Proper synaptic activity depends on:

• The amount of neurotransmitter produced in brain cells
• The amount of synaptic neurotransmitters lost by diffusion or reaction with chemicals
• The availability of transporters that return synaptic neurotransmitters back into the original brain cell (reuptake)

Epigenetics research has identified several nutrient factors that have a powerful impact on transporters at neurotransmitter synapses, including methionine, SAMe, folic acid, niacinanide, and zinc.

Two Types of Epigenetic Disorders

Epigenetic disorders can result from either (a) fetal programming errors or (b) deviant gene bookmarks that develop later in life.

Environmental insults are believed responsible for the deviant marks that can persist throughout the remainder of life. Fetal programming errors can result in developmental disorders that are evident from birth. However, deviant fetal programming may also produce predisposition for disorders that appear after birth such as cancer, heart disease, and regressive autism. Epigenetic disorders that appear before age three may result in brain structure abnormalities that are irreversible. In contrast, deviant epigenetic marks that cause brain chemistry imbalances are likely to be reversible.

Two Types of Epigenetic Therapy

Except for recent cancer research, all epigenetic treatments have been the temporary type in which gene expression rates are modified without changes in the marks. These treatments cause one of two outcomes: (1) uncoiling DNA from histones to enhance gene expression rates or (2) tighter compaction of DNA and histones to reduce expression rates.

Epigenetics and Nutrient Therapy

Methionine and SAMe:

• Undermethylated persons were prone to depression that usually could be lessened by SSRIs. Overmethylated persons were prone to high-anxiety depression that usually worsened after SSRIs.
• Methionine and SAMe increase histone methylation, which can inhibit gene expression of serotonin transport proteins. The result is increased serotonin in synapses and higher serotonin activity. In effect, methionine and SAMe are natural serotonin reuptake inhibitors.

Folic Acid:

• Overmethylated schizophrenic patients thrive on folic acid, whereas methyl-deficient patients exhibit intolerance.
• In effect, folic acid increases genetic expression of transporters, causing reduced activity of dopamine and serotonin.
• Folate and methyl produce opposite effects on neurotransmission. Folic acid is a serotonin reuptake enhancer, whereas methionine and SAMe are serotonin reuptake inhibitors. Giving folic acid to an undermethylated depression patient results in improved methyl levels (SAMe) throughout the body and brain but reduced methyl levels at key histones and CpG islands that regulate neurotransmitter activity.
• Folic acid supplements can either increase or decrease methylation at histone tails and CpG islands, depending on the portion of the DNA strand that is involved. With respect to mental health, folic acid supplements generally must be avoided for undermethylated patients and emphasized for overmethylated patients.

Vitamin B3 (niacin):

• Niacinamide inhibits sirtuins, a class of proteins that effectively remove acetyl groups from histones and promote methylation. By this mechanism, increased intake of vitamin B3 (niacin or niacinamide) results in higher gene expression of transporters and reduced dopamine activity. This is especially useful for paranoid schizophrenics who have excessive dopamine activity.

Other Nutrients:

• Biotin and phosphates can covalently bind to histones and impact gene expression. Zinc enhances the gene expression of metallothionein, an important antioxidant protein. Many other nutrients affect the production and functioning of enzymes and cofactors that govern epigenetic processes. Pantothenic acid, tryptophan, choline, and dimethylaminoethanol (DMAE) enhance acetylation of histones.

Identification of Epigenetic Disorders

Autism usually involves poor immune function; altered brain structure; digestive abnormalities; odd, repetitive movements; etc., all of which form a distinctive syndrome that is typical of an epigenetic disorder.

• Abnormal methylation, non-Mendelian heritability, and a syndrome of distinctive symptoms and traits.

Since deviant marks survive many cell divisions, the condition doesn’t just go away. Future epigenetic therapies aimed at correcting aberrant gene expression have great potential for benefitting these patients.

Autism:

• Undermethylation is a distinctive feature of autism spectrum disorders. Both the autistic regression event and the persistence of autism symptoms are also consistent with a gene expression disorder.

Schizoaffective Disorder:

• This condition is a mixed thought, mood, and perceptual disorder consisting of delusional thinking, moods ranging from depression to mania, and perceptual hallucinations and illusions.
• Many of these patients also exhibit obsessive-compulsive tendencies, internal anxiety, and catatonic tendencies. Typically, this is an adult-onset condition featuring a mental breakdown after a history of high achievement.
• A review of the chemistry database for 500 persons with this diagnosis revealed that virtually all had evidence of undermethylation.

Paranoid Schizophrenia:

• Usually involves auditory hallucinations and paranoia along with other symptoms.
• More than 85% exhibited overmethylation. This condition is often misdiagnosed, and a careful study of 250 patients with classic symptoms indicated overmethylation in 94% of the patients. With more accurate diagnosis, the incidence of this chemical imbalance could approach 100%. A typical feature of this illness is a mental breakdown after age 15.

Obsessive-Compulsive Disorder (OCD):

• His chemistry database contains 92 individuals diagnosed with severe OCD. Many reported that the condition appeared quite suddenly and has been a chronic problem since that time. All but five exhibited severe undermethylation.

Antisocial Personality Disorder (ASPD):

• Examination of data for more than 400 persons diagnosed with ASPD indicated a high incidence of zinc deficiency, pyrrole disorder, toxic metal overload, and glucose dyscontrol. However, more than 96% also exhibited undermethylation, suggesting this condition may be epigenetic in origin and involve aberrant brain development and altered neurotransmitter activity. Future treatments that modify methyl and acetyl levels at histones and DNA CpG sites may represent an effective way to reduce crime and violence.

Anorexia:

• Examination of chemistry information for 145 persons diagnosed with anorexia revealed that all but five were undermethylated.

Paraphilias:

• In most cases, they first became aware of their condition between the ages of 14-16. More than 90% were undermethylated, suggesting that paraphilias may be epigenetic in origin. The terms obsessive-compulsive perversion or OCP are probably more appropriate than paraphilia. It’s well known that child molesters rarely reform regardless of medications, counseling interventions, or the threat of imprisonment.

Transgenerational Epigenetic Inheritance (TEI)

Animal experiments have clearly shown that certain epigenetic errors can be transmitted to future generations, without changing DNA sequence. There is growing evidence that this mechanism also occurs in humans. This means that the harmful effects of a toxic exposure can be passed on to one’s children and grandchildren.

Imprinting of abnormal methylation of the genome is believed to be one of the major TEI mechanisms.

TEI defects could also cause abnormal brain development, chemical imbalances, weakened immune function, and an inborn predisposition for a mental illness. In addition, TEI may have contributed to the mysterious recent epidemics in ADHD, autism, breast cancer, and other conditions that have a strong heritable component.

Nature, Nurture, and Epigenetics

Schizophrenia and many other mental illnesses involve inherited predispositions but violate classic laws of Mendelian genetics, thereby indicating a strong influence of environment.

Gene expression can go awry due to toxic chemicals, emotional trauma, chronic personal failures, oxidative stress, medication side effects, nuclear radiation, and abnormal nutrient levels. The good news is that deviant gene marks may be normalized by future epigenetic therapies.

Chapter 5. Schizophrenia

Schizophrenia typically develops between the ages of 15-25 for males and 16-35 for females. The symptoms, especially hallucinations, delusions, paranoia, and radical changes in personality. 

Biological Psychiatry

Atypical antipsychotic medications usually result in impressive benefits, but most patients remain handicapped compared to their pre-breakdown condition, experience serious side effects that may become permanent, and may experience gradual loss of brain cortex volumes.

Dopamine Theory:

• Symptoms of paranoid schizophrenia could be produced in normal persons by increasing dopamine activity through the use of amphetamines.
• This theory can explain psychosis and other positive symptoms of schizophrenia, but it cannot explain the cognitive, socialization, and other negative symptoms that are classic features of the disorder. 

Glutamate Theory:

• Phencyclidine hydrochloride (PCP) administered to normal persons can induce psychosis that closely resembles schizophrenia. The main action of PCP is to reduce glutamate activity at NMDA receptors. This theory received strong support when it was learned that increasing NMDA activity (using glycine supplements) was effective in reducing schizophrenia symptoms. NMDA receptors are unique in that neurotransmission requires simultaneous docking of both glutamate and glycine molecules.
• Early research indicates that D-serine and Dcycloserine are most effective for undermethylated schizophrenia, with sarcosine better suited for overmethylated patients. In addition, D-serine has become a promising treatment for addictions to opiates, cocaine, alcohol, and other substances.

Oxidative Stress Theory:

• Glutathione (GSH) levels are depleted by oxidative free radicals and are low in brains of those with schizophrenia. Moreover, low GSH reduces glutamate activity at NMDA receptors, a condition that can produce hallucinations, delusions, and other classic symptoms of schizophrenia.
• The many sources of oxidative stress in the brain include heavy metals, viruses, bacteria, injury, inflammation, emotional stress, nuclear radiation, and high iron levels.
• Fortunately, the brain is protected by several antioxidant factors including GSH, metallothionein, selenium, superoxide dismutase (SOD), catalase, vitamin C, and cysteine.
• The strong heritable predisposition for schizophrenia suggests that weak antioxidant protection is the culprit in most cases.

Epigenetics Theory:

• A study of identical twins discordant for schizophrenia found epigenetic DNA methylation abnormalities in the schizophrenics but not in their twin brothers. In other studies, schizophrenics had higher levels of methylation than depressive controls, resulting in lower gene expression of GAD67, an enzyme that produces the neurotransmitter GABA; the researchers found that methionine worsened symptoms, while valproic acid increased histone acetylation and provided benefits.

Excessive dopamine activity associated with an elevated methyl/folate ratio involves underproduction of a complex chemical called dopamine active transporter (DAT). This transporter removes dopamine from synapses, sending it back to the original cell for reuse. Overmethylation results in reduced expression of DAT and excessive dopamine activity. This biochemical abnormality is a hallmark of paranoid schizophrenia.

In contrast, the epigenetic effect of undermethylation is to reduce activity of serotonin, dopamine, and norepinephrine. In addition, undermethylation appears to influence synaptic NMDA receptor activity and is associated with schizoaffective disorder and delusional disorders. Reduced activity of norepinephrine usually coincides with reduced adrenaline activity that may contribute to catatonic symptoms that are characteristic of schizoaffective disorder and delusional disorder.

Viral insult may alter gene expression and contribute to the illness and impact of schizophrenia.

Biochemical Classification of the Schizophrenias

90% of the cases: overmethylated schizophrenia (42%), undermethylated schizophrenia (28%), and a condition of severe oxidative stress termed pyrrole schizophrenia (20%).

Differential Diagnosis Factors

Patients who are overmethylated or pyroluric usually exhibit warning signs of the disease before the age of 10, but undermethylated patients may be symptom-free until the breakdown. Chemical analyses of blood and urine provide about 50% of the information required for accurate diagnosis. Symptoms, traits, physical signs, medical history, and family history are equally useful in identifying a patient’s schizophrenia biotype.

Symptoms during initial breakdown:

• Persons who become more physically active and report hearing voices are likely to be overmethylated.
• Patients who shut down with catatonic symptoms usually exhibit undermethylation.
• Schizophrenics who exhibit wild mood swings, great fears, and deteriorate under stress are likely to have pyrrole disorder.

Response to psychiatric medications:

• Dramatic worsening of psychiatric symptoms after serotonin-enhancing SSRIs suggests folate insufficiency and methyl overload. Similarly, worsening of psychosis after a benzodiazapine medication suggests a low methyl/folate ratio.

Family History:

• More than 50% of schizophrenia patients have at least one relative with a serious mental illness.

Dominance of hallucinations or delusions:

• Most patients exhibiting severe delusions are undermethylated, whereas most patients with a dominant symptom of auditory hallucinations are overmethylated. Most pyrrole disorder patients exhibit both delusions and auditory hallucinations.

Psychiatric medication issues:

• Recovered schizophrenics who completely eliminate psychiatric medication are likely to relapse within a year.
• After several months of nutrient therapy, some patients report great improvement in psychosis symptoms, anxiety, depression, socialization, and cognition while simultaneously experiencing extreme physical tiredness and reduced energy.

Recovery Timeline:

• Mentally ill patients with pyrrole disorder usually improve significantly during the first two to four weeks of nutrient therapy, with progress continuing for two to four months.
• Most overmethylated psychotics are greatly troubled during the first three weeks of treatment, with clear improvement beginning during week four.
• Delusional undermethylated patients usually report little or no progress over the first four to six weeks and then experience a gradual recovery during the next six months. Many of these patients report a return to a normal life.

Overmethylation Biotype of Schizophrenia

Laboratory indications include whole blood histamine levels below 40 ng/ml, absolute basophil levels below 30, and serum copper higher than 120 mcg/dl. This schizophrenia phenotype involves excessive activity at dopamine and norepinephrine receptors, possibly caused by epigenetic inhibition of dopamine active transporters (DATs) and norepinephrine transporters (NETs) and elevated copper levels. Primary symptoms usually include auditory hallucinations, paranoia, agitation, and extreme anxiety. The most common diagnosis is paranoid schizophrenia.

Judy – 26 (Overmethylation):

• High anxiety, auditory hallucinations, mother had severe anxiety and depression, Judy loved art and music but didn’t do well in school. However, she had plenty of friends.
• Depressed blood histamine level of 10 ng/ml, and she was diagnosed with overmethylation. Elevated copper and depressed zinc levels.
• Judy was treated with folic acid, zinc, niacin and vitamins B-6, B-12, C, and E, which she took along with her medication. Her nutrient therapy was aimed at reducing norepinephrine and dopamine levels while increasing GABA. She reported a worsening of anxiety the first three weeks, followed by clear improvement during month two. Within six months, her symptoms had nearly disappeared and she returned to work after a year’s absence. Her psychiatrist has weaned her from Tegrerol and Zoloft, and she continues on a low dose of Zyprexa.

Robert – 25 (Overmethylation):

• High anxiety and auditory hallucinations. No family history of mental illness, he had food and chemical sensitivities and allergy treatment as a child.
• He had been very sociable prior to his psychosis symptoms but had become a loner. He exhibited several overmethylation symptoms including difficulty sleeping, low libido, nervous legs, and ringing in the ears (tinnitus). He had a heavy beard, and his chest was covered with thick black hair.
• Robert’s testing indicated overmethylation (depressed blood histamine of 26 ng/ml), and he was placed on a regimen of folic acid, vitamins B-3, B-6, B-12, C, and E together with supplements of zinc, manganese, and chromium. At his annual follow-up visit, Robert reported that the voices had disappeared and he felt in good health.

Undermethylation Biotype of Schizophrenia

Severely depressed methyl/folate ratio is present in about 28% of the schizophrenia population. The dominant symptom is usually delusions, although mild hallucinations are sometimes present. Laboratory indications are whole blood histamine above 70 ng/ml, elevated blood basophils, and depressed SAMe/SAH ratio.

Most undermethylated persons in the general population are high achievers in good mental health. However, most mentally ill persons exhibiting this imbalance respond to methylation therapies. This form of schizophrenia involves low activity of serotonin, dopamine, and norepinephrine, possibly caused by epigenetic overexpression of SERT (serotonin transporter), DAT, and NET transporters at synapses. Low glutamate activity at NMDA receptors is also suspected. Typical symptoms include delusions, OCD behaviors, high internal anxiety, and catatonic tendencies.

Common symptoms include belief that the CIA or FBI is following them, that their parents are aliens, or that a satellite in outer space is beaming painful rays into their brain. Most undermethylated schizophrenics have ritualistic behaviors and strong obsessive compulsive tendencies. They may have extreme inner anxiety that is hidden behind a calm exterior.

David – 22 (Undermethylation):

• After a breakup he was diagnosed with schizoaffective disorder (thought Russian agents were out to get him), hospitalized for 10 days, and medicated with Zyprexa, Depakote, and Zoloft. Despite significant improvement, David was unable to resume his studies or hold a job. He reported a 50-pound weight gain and had isolated himself from his friends.
• A biochemical evaluation revealed symptoms of undermethylation, including a history of seasonal allergies, perfectionism, competitiveness in sports, and sparse chest hair.
• His blood histamine level was extremely elevated at 170 ng/ml, and he was treated with SAMe, methionine, calcium, magnesium, zinc, serine, and vitamins A, B-6, C, D, and E. His family reported no change for six weeks, followed by slow improvement. After a year of nutrient therapy, David reported a nearly complete recovery, and his psychiatrist weaned him from Depakote and Zoloft and reduced the dosage of Zyprexa.

George – 21 (Undermethylation):

• George was diagnosed with paranoid schizophrenia, the same condition that had afflicted his mother. He was evaluated by a psychiatrist but refused to comply with medication.
• His evaluation revealed several undermethylation symptoms including hayfever, high libido, excessive saliva and tears, sparse chest hair, and chain smoking.
• His blood histamine and absolute basophil levels were both elevated, and he was treated with methionine, calcium, magnesium, zinc, chromium, and vitamins A, B-6, C, D, and E. In addition, he was given the nutrient inositol to help with sleep. George had chronic problems with compliance, but he reported significant improvement after six months.
• At a follow-up visit, he no longer was weighted down with metal and agreed to see a psychiatrist and receive low-dose medication support. After several years of wellness, he stopped compliance with his medication and nutrients, and his delusions returned within a few months.

Pyrrole Disorder Biotype of Schizophrenia

This phenotype involves a severe overload of oxidative stress that impairs brain function. This condition usually results in very elevated levels of pyrroles in urine along with severe deficiencies of zinc and vitamin B-6.

Most persons with elevated pyrroles have mild symptoms that do not interfere with daily living. However, about 20% of schizophrenics exhibit a severe version of this imbalance and report improvement following aggressive therapy with zinc and vitamin B-6. This condition involves free-radical oxidative stress and depleted levels of glutathione, metallothionein, and other protective proteins causing inhibition of glutamate activity at NMDA receptors.

Primary symptoms of pyrrole disorder generally include the following:

• Extreme mood swings
• Sensitivity to light and noise
• Poor stress control
• Severe anxiety
• Little or no dream recall
• Preference for spicy foods
• Abnormal fat distribution

A study of 67 schizophrenics found that pyrolurics were very deficient in arachidonic acid. This may explain the symptoms of dry skin and abnormal fat distribution associated with this disorder. Many pyroluric schizophrenics report benefits from supplements of primrose oil, a source of omega-6. Non-pyrrole schizophrenia phenotypes generally exhibit low omega-3 levels and omega-6 overload. A recent study reported biotin deficiency in pyrrole patients.

Most pyroluric schizophrenics report symptoms of zinc and vitamin B6 deficiency from early childhood. Physical symptoms include delayed growth, poor wound healing, dry skin, white spots on fingernails, delayed puberty, acne, and inability to tan. Most pyrolurics have a history of academic underachievement that has been attributed to severe vitamin B6 deficiency that can impair short-term memory. Mood swings may occur many times daily, and a common diagnosis is rapid-cycling bipolar disorder. The onset usually occurs during a period of extreme stress. Schizophrenics with this imbalance may have a combination of delusions and auditory hallucinations. They live in a world of fear and do not attempt to hide their anxieties.

Mary – 29 (Pyrrole):

• She suffered a severe mental breakdown when her mother was killed in a car accident. After many unsuccessful medication trials, she became suicidal with daily episodes of hysteria.
• A biochemical evaluation revealed several classic symptoms of pyrrole disorder, including morning nausea, aversion to sunlight, absence of dream recall, history of severe sunburn, preference for spicy Mexican and Indian foods, and abnormal menstrual cycles. She also exhibited the classic pyroluric fat distribution, with a slender neck and thin wrists and ankles along with huge amounts of fat at her midsection and upper thighs.
• Lab testing showed a single abnormality: a urine pyrrole level exceeding 150 μg/ml, more than 10 times the normal level. Her nutrient therapy involved very high doses of zinc and vitamin B-6 together with augmenting nutrients. She responded quickly, and the family reported great improvement after 30 days. She returned for a follow-up evaluation in three months and appeared to be completely recovered, despite the absence of psychiatric medication.

Overmethylation and Copper Overload

A common aggravating factor in overmethylated schizophrenia that results in more-extreme norepinephrine elevations. The usual result is greatly heightened anxiety, paranoia, and increased auditory hallucinations. Moreover, copper elevations are associated with zinc depletion, and zinc is an important factor in maintaining GABA levels. The combination of high norepinephrine and low GABA levels is a recipe for extreme anxiety. Female patients with this combination of imbalances tend to experience early mental breakdowns, frequently during puberty. Treatment of this condition must be gradual since rapid removal of excess copper from the body could cause temporary worsening of psychiatric symptoms.

Undermethylation and Pyrrole Disorder

Unlike most pyrrole patients, these persons usually have a history of high accomplishment in academics and career prior to their mental breakdown. After onset of the illness, many are plagued by severe mood swings, extraordinary delusional beliefs, and episodes of rage. Successful treatment of this hybrid condition often results in early improvement in behavior control followed by a four-to-six-month period before the delusions begin to fade away.

Low-Incidence Biotypes

Gluten intolerance appears to be responsible for an additional 4% of persons diagnosed with schizophrenia. The remaining 6% involve a collection of relatively rare mental illness biotypes, including thyroid deficiency, polydipsia, homocysteinuria, drug-induced psychosis, and porphyria.

Gluten Intolerance:

• Many cases of childhood schizophrenia can be traced to celiac disease.
• This disorder can also occur in young adults, most commonly in the third decade of life. This condition is associated with incomplete breakdown of gluten proteins in the GI tract, resulting in small proteins called gluteomorphins that can pass into the bloodstream and access the brain. The net result can be brain inflammation and disturbed function of brain receptors. Early symptoms include bloating, excessive gas, and explosive bowel movements.

Thyroid Deficiency:

• Dr. Pfeiffer reported that about 1 case of schizophrenia in 200 resulted from severe thyroid deficiency and that standard treatment with either Synthroid or Armour thyroid often resulted in complete recovery.

Polydipsia:

• Very low serum sodium and potassium levels, and urine with a water-like specific gravity of 1.000 with very low creatinine levels.

Homocysteinuria:

• The usual cause is a genetic lack of an enzyme needed to control levels of the amino acid homocysteine. Most cases can be traced to deficiency of the cystathionine β-synthase (CBS) enzyme (converts homocysteine and serine to cytathionine) or the methylenetetrahydrofolate reductase (MTHFR) enzyme (converts homocysteine to methionine).
• Dysfunction in these enzymes causes impairment to the methylation cycle and reduced production of glutathione and other antioxidants. This condition can be treated with supplements of vitamins B-6 and B-12 in conjunction with folic acid, serine, and trimethylglycine (TMG).

Drug-induced schizophrenia:

• Most patients with drug-induced schizophrenia that persists after abstinence exhibit the undermethyation biotype.

The Porphyrias:

• A group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway. Typical symptoms include abdominal pain, hallucinations, depression, paranoia, and anxiety.
• Coproporphyria is the most common type of porphyria inappropriately diagnosed as schizophrenia. Porphyrin molecules contain rings of pyrrole groups, and severe elevations of urine pyrroles and toxic metals are usually present along with a pronounced lack of zinc and vitamin B-6.
• Despite the presence of these correctable chemical imbalances, nutrient therapy has generally resulted in disappointingly minor improvements in these patients.

The Walsh Theory of Schizophrenia

They believe a proper theory of schizophrenia must include the following elements:

• Separate causation for the major phenotypes
• Explanation for the mental breakdown event that usually occurs in late adolescence or young adulthood
• Explanation for the lifelong persistence of schizophrenia after the mental breakdown
• Explanation of why this familial (heritable) disorder violates classical laws of Mendelian genetics

Thesis 1: Predisposition to schizophrenia involves fetal programming errors that cause lifelong vulnerability to oxidative stresses. These programming errors can result from a variety of causes: (a) an abnormal in utero methylation environment, (b) exposure to environmental toxins, (c) genetic weakness in oxidative protection, and (d) medication side effects.

Thesis 2: The mental breakdown event is triggered by overwhelming oxidative stress that alters DNA and histone marks that regulate gene expression. Cancer research has provided examples of cumulative oxidative stresses that eventually alter gene marks, producing an enduring disease condition. The onset of schizophrenia occurs when oxidative stresses exceed the threshold level needed to alter chromatin marks that control gene expression.

Thesis 3: Epigenetic changes are responsible for continuing psychotic tendencies after the breakdown event. A psychotic breakdown is usually followed by a lifetime of mental illness and misery, despite intensive therapies. This often-permanent change in functioning results from altered DNA or histone marks that regulate gene expression. Since the deviant marks are maintained during future cell divisions, the condition doesn’t go away.

Thesis 4: The three major phenotypes of schizophrenia develop in individuals who exhibit overmethylation, undermethyation, or overwhelming oxidative stress:

• A. Overmethylation: About 42% of persons diagnosed with schizophrenia exhibit severe overmethylation together with oxidative overload. Mental breakdowns generally occur during severe physical or emotional traumatic events that sharply increase oxidative stress and produce deviant gene marks. This schizophrenia biotype is a sensory disorder that generally involves auditory, tactile, or visual hallucinations. This condition is associated with elevated activity of dopamine and norepinephrine and reduced glutamate activity at NMDA receptors. The most common DSM-IV-TR diagnosis is paranoid schizophrenia.
• B. Undermethylation: About 28% of persons diagnosed with schizophrenia exhibit undermethylation together with weak antioxidant protection. Mental breakdowns generally occur during severe physical or emotional traumatic events that produce a separate set of altered gene marks. This schizophrenia biotype essentially is a thought disorder with delusions and catatonic tendencies as the primary symptoms. This condition is associated with low activity at serotonin, dopamine, and NMDA receptors. The most common DSM-IV-TR diagnoses are schizoaffective disorder or delusional disorder.
• C. Severe oxidative overload: The third major schizophrenia phenotype develops in persons with an inborn severe deficit in antioxidant protection. This condition is arbitrarily termed pyrrole disorder due to the presence of excessive pyrrole levels in blood and urine. Mental breakdowns occur for these persons during periods of extreme physical or mental stress in which deviant epigenetic marks are established. This condition is characterized by extraordinary anxiety and rapid mood swings, and it often involves both auditory hallucinations and delusional beliefs. Brain chemistry abnormalities include (a) depressed glutamate activity at NMDA receptors and (b) very depressed GABA activity.

Thesis 5: Failure to follow classical laws of genetic inheritance results from the epigenetic nature of schizophrenia. Schizophrenia is strongly heritable (runs in families) but fails to obey Mendel’s classic laws of genetic inheritance. There are countless examples of identical twins where one sibling develops the disorder and the other does not. In addition, intensive research efforts to identify the schizophrenia gene (or genes) have met with little success. Epigenetics provides two explanations for the non-Mendelian nature of schizophrenia:

• (a) environmental insults are required to produce deviant epigenetic marks, and environmental conditions are highly variable for different individuals, and
• (b) transgenerational epigenetic inheritance contributes to schizophrenia heritability by transmitting deviant epigenetic marks to one’s children and grandchildren.

Chapter 6. Depression

Typical symptoms include chronic sadness, feelings of worthlessness or guilt, social withdrawal, agitation, problems with concentration, and difficulty sleeping. Depression is a broad term used to describe a variety of medical conditions, including dysthymia, bipolar disorder, cyclothymic disorder, substance-induced mood disorder, seasonal affective disorder, and postpartum depression.

Biochemical Classification of Depression

Most depressives in the undermethylation biotype exhibit classic symptoms of low serotonin and report improved moods after serotonin-enhancing SSRI medications. In contrast, the folate deficiency biotype is associated with elevated serotonin and dopamine activity and intolerance to SSRI medications. High copper depressives have a strong tendency for reduced dopamine and elevated norepinephrine activity. Persons in the pyrrole biotype experience a nasty double deficiency of serotonin and GABA, which is the chief inhibitory (calming) neurotransmitter in the central nervous system. A serious toxic metal overload can impair the blood-brain barrier, disable key antioxidant proteins in the brain, damage the myelin sheath, and alter the concentrations of certain neurotransmitters.

• Undermethylation: Reduced serotonin, dopamine
• Folate deficiency: Elevated serotonin, dopamine
• Copper overload: Elevated norepinephrine
• Pyrrole disorder: Reduced serotonin, GABA

Undermethylated Depression

Approximately 38% of individuals in his depression database exhibit undermethylation as their dominant chemical imbalance. These persons appear to be highly sensitive to the methyl/folate ratio in the brain. They thrive on SAMe, methionine, and other powerful methylating agents but are strikingly intolerant to folates that also promote methylation.

Important indicators of this syndrome include a whole blood histamine level above 70 ng/ml and a depressed SAMe/SAH ratio in combination with key symptoms and traits such as OCD tendencies, seasonal allergies, and a history of perfectionism.

Methylation therapy for low-serotonin depressives is unique because of the need to limit folate intake that would increase production of SERT and reduce serotonin activity. The nutrient factor with the greatest positive impact for treatment of this depression biotype is direct methylation, either in the form of SAMe or the amino acid methionine.

Folate, choline, DMAE, and pantothenic acid supplements must be avoided since they increase chromatin acetylation and SERT levels. A high percentage of these patients exhibit low stores of calcium, vitamin D, and magnesium and thrive on supplements of these nutrients. In addition, nutrients that enhance synthesis of serotonin can be helpful (e.g., tryptophan, vitamin B-6, 5-HTP). Augmenting nutrients include vitamins A, C, and E.

Symptoms and Traits – Undermethylated Depression

• Good response to SSRIs
• Good response to SAMe, methionine
• Adverse reaction to folic acid
• High inner tension
• Obsessive-compulsive tendencies
• History of perfectionism
• Self-motivated
• Seasonal inhalant allergies
• Good response to antihistamines
• High libido
• Low tolerance for pain
• High fluidity (tears, saliva, etc.)
• Very strong-willed
• Competitiveness in sports
• High suicidal tendency
• Addictiveness
• Sparse chest/leg/arm hair
• Calm demeanor
• Denial of depression
• Frequent headaches
• Family history of high accomplishment
• Noncompliance with therapies
• Rumination about past events
• Oppositional defiance as child

Most undermethylated depressives exhibit low levels of homocysteine, but others may exhibit elevated levels. Since methylation therapy tends to elevate this biochemical, some patients must have treatment to normalize homocysteine levels prior to use of SAMe or methionine. In most cases, supplementation with serine and vitamin B6 for a few weeks can bring homocysteine down to a safe level. Experience with hundreds of undermethylated depressives has confirmed that folates, choline, manganese, copper, and DMAE tend to worsen their depression and must be strictly avoided.

Charles – 52 (Undermethylation):

• Despite impressive career and financial successes, he had been depressed for more than 15 years with persistent thoughts of suicide. He reported that depression didn’t affect his work performance but was causing problems in his second marriage.
• Symptoms of undermethylation included hay fever, high libido, internal anxiety, frequent headaches, and sparse hair on his chest, arms, and legs. Charles reported that Prozac, Zoloft, and Paxil all lessened depression, but side effects including a loss of sex drive, nausea, and a worsening of the headaches caused him to stop these medications.
• His lab work revealed an extreme elevation of blood histamine (142 ng/ml), a mild elevation of urine pyrroles, and low-normal homocysteine.
• His treatment consisted of SAMe, methionine, zinc, serine, calcium, magnesium, and vitamins A, B-6, C, D, and E.
• Charles complained of a lack of progress after two months of treatment, but he reported improvement during month 3. After 12 months of treatment, he returned for testing and stated that his depression had been nearly gone for several months.

Julie – 42 (Undermethylation):

• At age 16, she was diagnosed with oppositional-defiant disorder. She reported intermittent depression since her first marriage at age 19. She said her school grades were excellent until high school when she became more interested in boys than academics.
• Episodes of chronic depression, especially in late spring and early fall. She had worked as a hair stylist and a waitress, and she was presently a sales clerk in a large department store. She reported several symptoms of undermethylated depression, including a shopping disorder, habitual cigarette smoking, sensitivity to ragweed and grasses, and a good response to antihistamines. Julie had tried three separate antidepressants but claimed none were effective.
• Elevated blood histamine level of 82 ng/ml. Julie had limited funds and decided she couldn’t afford to take SAMe, a relatively expensive supplement. Her treatment involved high dosages of methionine, calcium, and magnesium together with zinc, vitamins B-6, C, D, and E, and chromium.
• Julie returned for a follow-up evaluation after 6 months and reported that her depression was gone but that she still had problems with allergies and shopping binges.

A significant number of undermethylated depression patients exhibit some degree of pyrrole disorder. Many persons with this combination of imbalances exhibit high accomplishment throughout life, but report extreme internal anxiety and poor stress control along with depression. Since both undermethylation and pyrrole disorder are associated with low serotonin activity, depression is usually more severe in these cases and also more likely to report suicidal ideology.

Many persons suffering from undermethyated depression have two traits that make successful treatment difficult. First of all, they have an innate tendency for noncompliance with any medical treatment. Some admit they won’t take aspirin during a headache, even though they know it would help them. The second trait is a tendency to deny depression, even when the problem is severe.

Folate Deficiency Depression

Most report anxiety in addition to depression, and about 20% have a history of panic disorder or anxiety disorder. With very few exceptions, these persons report intolerance to SSRI antidepressants and antihistamines. A high percentage are noncompetitive persons who complain of chemical and food sensitivities but deny hay fever and other seasonal allergies. Despite their suffering, a surprising number are caring, generous persons with a history of volunteer work. The incidence of ADHD and academic underachievement is about three times higher than that observed for the undermethylated biotype.

Symptoms and Traits – Low-Folate Depression

• Improvement after folate therapy
• High anxiety and panic tendency
• Adverse reaction to SSRIs
• Improvement after benzodiazapines
• Food and chemical sensitivities
• Absence of seasonal allergies
• Dry eyes and mouth
• Low libido
• High artistic abilities and interest
• Hirsutism (males only)
• Nervous legs, pacing
• Sleep disorder
• Noncompetitive in sports, games
• Underachievement in school
• Hyperactivity
• High pain threshold
• Upper body/head/neck pain
• Adverse reaction to SAMe, methionine
• Estrogen intolerance
• Copper intolerance

Laboratory indications of low-folate depression include whole blood histamine below 40 ng/ml, an elevated SAMe/SAH ratio, low serum folate, and an absolute basophil count below 30.

Nutrient therapy for this biotype is focused on building up folate stores aimed at increasing acetylation of chromatin. Typical treatment formulations for low-folate depression include the following:

• Folic or folinic acid
• Vitamin B-12
• Niacinamide, choline, DMAE, and manganese that reduce dopamine synaptic activity
• Zinc, PLP, and vitamin B-6, which tend to increase GABA levels
• Augmenting nutrients, including vitamins C and E

It is also important to avoid supplements of tryptophan, 5-HTP, phenylalanine, tyrosine, copper, and inositol in treating these individuals. Originally, folic acid dosages exceeding two mg/day were routinely prescribed to combat low-folate depression. However, folinic acid more efficiently passes the blood-brain barrier, enabling lower folate dosages for this depression biotype.

Marilyn – 36 (Low folate):

• Poor academics through elementary and high school despite an IQ of 132 and motivation to succeed. She was diagnosed with ADD in the fourth grade and took Ritalin until eighth grade (caused appetite suppression and weight loss).
• Depression at 20 and failure to improve symptoms with Zoloft (gave a panic attack), several other SSRIs, until Klonapin (benzo) lessened anxiety.
• Chemical sensitivities, problems concentrating, dry eyes, low libido, and chronic neck pain. She reported taking Benedryl on one occasion and feeling “wired” and agitated.
• Marilyn’s histamine tested at 16 ng/ml, and she was treated with high doses of folic acid, vitamin B-12, and niacinamide. Other prescribed nutrients included zinc, DMAE, manganese, chromium, and vitamins B-6, C and E, and she was urged to continue her Klonapin medication for several months.
• Marilyn complained of heightened anxiety after two weeks of therapy but reported significant improvement in depression and anxiety (but not chemical sensitivities) at a 4-month follow-up visit. Continued for 6 years and says 95% better.

Karl – 28 (Low Folate):

• Successful businessman, below-average student, happily married. Karl said he had experienced brief episodes of depression as a teen, but severe anxiety, depression, and a sleep disorder developed at age 25.
• Prozac provided some benefit but had to be discontinued due to nausea and headaches. Treatment with Paxil, Zoloft, and Celexa (SSRI medications) resulted in heightened anxiety and depression.
• Karl exhibited several symptoms of the low-folate biotype, including low libido, eye dryness that prevented wearing contact lenses, proficiency in water color painting, and thick hair on his chest and back.
• Karl’s blood histamine level was 31 ng/ml, confirming his low folate status. His treatment centered on high doses of folic acid, vitamin B-12, and niacinamide. In addition, he received zinc, manganese, GABA, magnesium, DMAE, and vitamins B-6, C, and E. Karl has continued his nutrient therapy for several years and reports that he is quite well.

Low folate biotypes are at risk of suicidal thinking and behavior with SSRI antidepressants. School shootings have been associated with these drugs.

Hypercupremic Depression

About 17% of depression patients exhibit hypercupremia or elevated copper (Cu) as their dominant chemical imbalance. The vast majority (96%) of persons with this biotype are women, with the first episode of depression typically occurring during a hormonal event such as puberty, childbirth, or menopause. In addition to depression, characteristic symptoms include severe anxiety, sleep disorder, hormone imbalances, hyperactivity in childhood, skin sensitivity to metals and rough fabrics, ringing in the ears (tinnitus), and intolerance to estrogen, shellfish, and chocolate.

Norepinephrine elevations have been associated with anxiety/panic disorders, sleep problems, paranoia, and, in severe cases, psychosis. Copper-overloaded depressives usually report that serotonin-enhancing antidepressants provide improvement in moods, but they worsen anxiety. Benzodiazapines such as Klonapin and Xanax can be effective in reducing anxiety but are reported to have little effect on depression for this biotype. High-copper females are usually intolerant of birth control pills or hormone replacement therapy since these treatments increase copper levels in the blood.

A primary natural mechanism for removal of excess copper involves binding to metallothionein (MT) proteins in the liver, followed by excretion via the bile duct. The genetic expression (production) of MT proteins is dependent on zinc, and this trace metal is usually depleted in high-copper persons.

Increasing MT protein levels using supplements of zinc together with manganese, glutathione, vitamins B-6, C, and E, and other nutrients known to increase MT activity. This therapy must be introduced gradually to avoid sudden release of excess copper into blood that could cause a temporary worsening of depression and anxiety. Patients currently taking psychiatric medications should continue them during the initial two to three months of nutrient therapy. However, more than 85% of high-copper patients report that psychiatric medication can eventually be eliminated without the return of depression.

Elevated serum copper is exhibited by most women with a history of postpartum depression (PPD). Moreover, the classic symptoms of PPD are consistent with elevated norepinephrine and depleted dopamine that can result from copper overload.

• Characterized by depressed mood, lack of energy, disruptions of sleep, high anxiety, reduced interest in previously enjoyable activities, and, in severe cases, suicidal and homicidal ideation and behavior. Most women experience mild depressive symptoms soon after childbirth, and 10-20% will experience a full-blown depressive episode. Normal pregnancies involve greatly increased levels of estrogens and copper in blood. During the nine months of a normal pregnancy, serum copper typically doubles from about 110 mcg/dl to about 220 mcg/dl. This additional copper enables rapid development of blood vessels (angiogenesis) needed for normal growth of the fetus. Normally, copper and estrogen levels begin to drop within 24 hours of delivery. It appears that PPD women have a genetic or acquired inability to eliminate excess copper.

Kathleen – 34 (Hypercupremia):

• Symptoms of copper overload included history of childhood hyperactivity, ringing in the ears, skin sensitivity to cheap metals, inability to tan, and severe worsening of depression after hormone therapy.
• Her serum copper level was 212 mcg/dl, compared to the normal range of 85-115 mcg/dl, and plasma zinc was out of range low at 65 mcg/dl. Initial treatment involved 25 mg/day of zinc, with the dose gradually increased to 75 mg/day.
• Kathleen complained of heightened anxiety during this period. Her complete program included ample amounts of B-6 and PLP together with supplements of manganese, DMAE, and vitamins B-3, C, and E. At her 6-month follow-up evaluation, Kathleen’s metal levels had normalized and she reported that her depression was gone and that her marriage was solid again.

Carol – 31 (Hypercupremia):

• Free of depression until she started birth control pills at age 16. Despite chronic depression, she excelled in college and had begun a successful career by age 24.
• Depression had become very severe with persistent thoughts of killing herself by crashing her car into a concrete viaduct. She was too embarrassed to have counseling but tried Effexor, Paxil, and Zoloft in the recent past without improvement. She exhibited symptoms of copper overload including intolerance to chocolate, allergy to shellfish, extreme skin sensitivity, and occasional rages.
• Carol’s lab results revealed elevated serum copper and depressed plasma zinc, and she was diagnosed with a metal metabolism disorder. Her therapy consisted of nutrients known to promote MT protein activity including zinc, manganese, selenium, DMAE, glutathione, 15 protein constituents of MT, and vitamins B-6, C, E, and PLP.
• Susan called several times during the first two weeks of nutrient therapy concerned that her depression appeared to be worsening. However, she noticed clear improvement during month two, and after six months she stated that she was depression free for the first time in eight years.

Pyroluric Depression

Approximately 15% of the 2,800 persons in our depression database exhibited elevated pyrroles as their dominant chemical imbalance. This is a stress disorder with onset of depression often triggered by severe emotional or physical trauma.

Most pyrolurics experience about 50% of the following symptoms and traits: severe mood swings, inability to cope with stress, rages, absence of dream recall, sunburn tendency and inability to tan, morning nausea, and sensitivity to bright lights and loud noises.

Many persons with severe pyrrole disorder have slender wrists, ankles, and neck, while having great amounts of fat at their midsection and upper thighs. Female pyrolurics may report disturbed menstrual periods or amenorrhea.

• Persons with this depression biotype are prone to delayed puberty and significant growth after age 16. Other symptoms include great inner tension, reading disorders, and academic underachievement regardless of intelligence. They tend to be fearful and pessimistic persons and isolate themselves from others. Many persons with this biotype are diagnosed with rapid-cycling bipolar disorder because of extreme mood swings that may occur many times daily.

Persons with pyrrole disorder suffer from a double deficiency of zinc and vitamin B-6 that may be genetic in nature. This results in a tendency for low brain levels of serotonin, dopamine, and GABA, which is a recipe for depression and anxiety. Nutrient therapy for pyrrole disorder simply involves normalization of zinc and B-6 levels.

Pyrrole disorders indicate elevated oxidative stress: ample dosages of selenium, glutathione, vitamin C, vitamin E, and other antioxidants assist in treatment. Depressed persons with pyrrole disorder respond more quickly to nutrient therapy than the other depression biotypes. Clear improvement is usually noticed within a few days, with the therapy achieving full effect within four to six weeks.

Because of morning nausea, many persons with pyrrole disorder cannot tolerate nutrients until lunchtime. They tend to perform badly in morning and are at their best late at night.

Curt – 24 (Pyrrole):

• He disliked academics and took a job with the railroad after graduation. He was famous for his temper and had several arrests for assault. Curt complained of chronic depression and suicidal ideation since the age of 16. He was muscular with Hollywood good looks and had a very engaging personality. He was interested in girls but seldom dated because of embarrassing erectile dysfunction.
• He reported several symptoms consistent with pyrrole disorder, including internal tension, poor short-term memory, absence of dream recall, enjoyment of spicy foods, pale complexion, avoidance of breakfast, and sensitivity to sunlight.
• Urine pyrroles that were 10 times above the normal level. His nutrient therapy involved powerful doses of vitamin B-6 and zinc along with augmenting nutrients aimed at lessening oxidative stress (selenium, manganese, vitamins C, and E).
• After two weeks of nutrient therapy, Curt called to report that he felt “weird” and was concerned that the vitamins were changing his personality. He was experiencing internal calm for the first time in his life and was alarmed at the striking change. At a 3-month check-up visit, Curt reported his depression had disappeared along with his violent temper but that the erectile dysfunction problem remained.

Marianne – 32 (Pyrrole):

• She reported a troubled childhood that included special education and treatment for depression and intermittent explosive disorder. Her depression and emotional outbursts continued despite treatment by three psychiatrists who prescribed more than a dozen psychiatric medications in an attempt to help her.
• She exhibited several symptoms of pyrrole disorder, including abnormal menstrual cycles, inability to handle stress, wild mood swings, white spots on fingernails, and morning nausea. In addition, she wore dark sunglasses throughout daytime hours and stated that she had never experienced a dream. Her urine sample turned a reddish-purple mauve color during storage in the lab refrigerator, and her pyrrole level tested at 82 mcg/dl.
• Marianne was diagnosed with severe pyrrole disorder and was treated with strong doses of vitamin B-6, PLP, and zinc in conjunction with augmenting nutrients aimed at reducing oxidative stress.
• Marianne’s parents reported that she underwent a transformation over the next four months. They were especially pleased that she appeared much happier, and her emotional outbursts had ceased. Two years later, we learned that Marianne had a steady job and was living independently in an apartment.

Toxic Overload Depression

Approximately 5% of the 2,800 persons in their depression database exhibited toxic-metal poisoning as their primary chemical imbalance. Most of these cases involved overloads of lead, mercury, cadmium, or arsenic.

Common features of this depression biotype are the following:

• Depression that arises suddenly during a period of relative calm and wellness
• Abdominal pain and cramping
• Increased irritability
• Headaches and muscle weakness
• Low energy
• Failure to respond to counseling or psychiatric medications

Toxic metal overload can be difficult to diagnose due to low concentrations of toxic metals in blood. An example of metal toxicity that does not usually show up in a blood test applies to the case of mercury: after a very short number of days, elevated mercury will not be found in the blood, having moved to other body tissues such as fatty tissue. Since depression due to metal toxicity is relatively uncommon, a logical first step is to rule out the presence of undermethylation, folate deficiency, copper overload, pyrrole disorder, casein/gluten allergy, or a thyroid imbalance. A careful chemical analysis of toxic metals in scalp hair can serve as a screen, recognizing the possibility of a false positive resulting from external contamination.

Many doctors test for toxic metal overload by introducing a chelating chemical that drives toxins from the body and then measuring the increased amount of toxins being excreted in the stool and urine. Unfortunately, reliable reference ranges have not yet been established for these challenge tests.

Young children are especially sensitive to toxic metals since their blood-brain barriers are still immature, and the toxins can interfere with the development of brain cells and receptors.

Depression, irritability, abdominal discomfort, kidney damage, and liver damage are the primary results of serious metal poisoning for adults.

Toxic metals in the brain can cause:

• weakening of the blood-brain barrier
• altered neurotransmitter levels
• destruction or demyelination of the myelin sheath
• increased oxidative stress
• destruction of glutathione and other protective proteins

Nutrient therapy for lead poisoning involves supplements of calcium, promotion of metallothionein synthesis, and generous supplementation of antioxidants. Lead is a bone seeker with about 95% of old lead stored within the skeletal structure. In the absence of therapies to remove lead, the half-life of lead in humans is estimated at 22 years. Nutrient therapy and chelation techniques can effectively remove lead from blood and soft tissues but cannot rapidly remove lead from bone.

John – 54 (Toxic Overload):

• He reported that counseling and several antidepressants had absolutely no effect on his condition. He also complained of uncharacteristic anger, nausea, and abdominal cramping. John’s lab chemistries were unremarkable except for a blood lead level 80 times above the normal level. John said he had purchased an old house and had spent the past six months scraping paint from the interior walls. They concluded that he had poisoned himself with repeated exposure to lead-based paint.
• Since his depression was severe, he was hospitalized for several days and received EDTA chelation. Within a week, John reported that his depression was completely gone and that he decided to sell his house.
• They prescribed supplements of calcium, zinc, selenium, and vitamins C and E to protect against lead that would be slowly leaching from his bones.

The half-life of mercury in the periphery of the body (everything except the brain) is about 42 days. The half-life of mercury in the brain has been measured at 70 days. However, mercury half-lives may be much higher for persons with a genetic metal metabolism disorder or severe oxidative stress. Mercury has a remarkable affinity for glutathione and MT proteins, and nutrient therapy that increases amounts of these proteins can effectively remove mercury from the body. Chelation and other therapies have been under active development for removal of mercury from autistic children.

Cadmium is especially dangerous since it tends to accumulate at kidney tubules and cause permanent damage. Sources of cadmium include shellfish, shallow wells, fertilizers, metal welding, brazing, fireworks, artist’s paints, mining operations, and various industrial plants. Cadmium is present in cigarettes, and smoking one to two packs daily can double blood and tissue levels of the metal. Cadmium removal must be accomplished with caution to avoid kidney damage, and treatments that enhance MT proteins are safer than chelation therapies that divert the departing cadmium through the kidneys.

Arsenic overloads are relatively rare and difficult to diagnose. The symptoms include upper respiratory problems, anorexia, muscle weakness, and irritation of mucous membranes. A definitive test for arsenic poisoning is the presence of elevated levels in both urine and scalp hair. Unfortunately, reference ranges for these assays are poorly defined, and interpretation of the results involves a degree of speculation. The biological half-lives of arsenic compounds are brief, ranging from 10 to 30 hours. The principal sources of arsenic are seafoods, contaminated drinking water, and pesticides. It has also been found on treated wood and playground equipment and in poultry feed. Nutrient therapy involving calcium and enhancement of glutathione protein levels can hasten the exit of arsenic.

Chapter 7. Autism

Genetics, Epigenetics, and Environment

60-90% concordance in identical twins in contrast to less than 10% for fraternal twins. Since concordance is less than 100%, a very significant environmental component exists.

More than two-dozen theories have been suggested, including increased vaccinations, toxic metal exposures (also possible via vaccines), changes in the water supply, a compromised in utero environment, industrial food processing, and changes in family dynamics. There is little agreement among autism researchers and clinicians regarding the environmental triggers, but one thing has become very clear: the usual recipe for autism is a combination of an inherited predisposition and severe environmental insults prior to age three.

Autism Onset

In typical regression cases (which have increased to 80% of cases), children develop normally until age 16-24 months, when a fairly sudden decline in functioning occurs.

Most families reported loss of speech; a divergent gaze; odd, repetitive movements; disinterest in parents and siblings; gastrointestinal symptoms; and emotional meltdowns.

Symptoms and Traits

Some are hyperactive, and others are lethargic. Many are completely nonverbal, whereas others have significant speech. About 30% have abnormal EEG brain waves and a tendency for seizures. Some have explosive behavior, and others are quite calm. Despite these individual differences, there are classic symptoms and traits usually present in four key areas.

• Socialization: This includes very poor social skills, including lack of interest in others, resistance to cuddling and holding, and an apparent preference to retreat into their own world.
• Language: This includes either absence of speech or a major speech delay, inability to start a conversation or keep one going, a tendency to repeat the sounds of others (echolalia), an unusual tone or rhythm of speech, and a very limited expressive vocabulary.
• Behavior: This category includes repetitive movements, such as rocking, spinning or hand flapping; behavioral routines or rituals; little or no eye contact; an obsessive interest in certain objects, such as spinning toys, or using the parts of toys in an atypical way (e.g., perseverating on spinning the car wheels); an inability to make transitions; sensitivity to touch, light, and sounds; and impulsive actions, such as running into the street.
• Cognition: This involves slowness in acquiring new knowledge or skills and weakness in applying knowledge to everyday life.

A high percentage of children diagnosed with autism have significant physical problems, including poor immune function, severe constipation, food allergies, intestinal yeast overgrowth, and heightened sensitivity to toxic metals.

Differential Diagnosis

Autism spectrum disorders consist of three major types: (1) classical or Kanner’s autism, (2) pervasive developmental disorder—not otherwise specified (PDDNOS), and (3) Asperger’s disorder (aka Asperger’s syndrome). There are great differences in severity among the three groups.

• Asperger’s syndrome is often referred to as high-functioning autism and typically involves normal or above normal intelligence and competent speech. However, Asperger’s individuals exhibit very poor socialization, divergent gaze, atypical behaviors, and obsessive or ritualistic interests. Many are savants with extraordinary abilities in mathematics, memory, or music.
• Classical or Kanner’s autism is the most severe disorder in the autism spectrum, and its sufferers usually exhibit most of the above symptoms and traits by age three. Without effective treatment, these individuals are likely to experience a lifetime of frustration and unhappiness as well as severe deficits in cognition, socialization, and speech.
• Children diagnosed with PDD-NOS have symptoms that are intermediate in severity between classical autism and Asperger’s syndrome. The distinction between classical autism and PDD-NOS is not always clear, and many children receive both diagnoses after evaluation by separate professionals.

A large chemistry database study in 2001 reported very disordered blood and urine chemistries for all members of the autism spectrum, with no detectible difference between classical autism, PDD-NOS, and Asperger’s. This finding suggests that all members of the autism spectrum may have the same inherited predisposition but differ in the type, severity, or timing of environmental insults. For example, children who achieve a higher degree of brain development prior to the insults would be expected to be capable of higher functioning.

The Autistic Regression Event

Wilson’s disease, schizophrenia, and autism are similar in that all involve oxidative overload, with extreme depletions of protective proteins MT and GSH. In Wilson’s, gradual worsening of oxidative stress can progress until the MT and GSH antioxidant functions are overwhelmed, resulting in (a) sudden impairment of bile transport of copper from the liver and (b) dramatic worsening of symptoms.

The onset of schizophrenia usually occurs after age 16 during a period of severe emotional or physical stress that may increase oxidative overload and trigger the mental breakdown event. These similarities suggest that a study of the regressions in Wilson’s disease and schizophrenia could provide valuable clues to the origin of autism spectrum disorders.

After age six, therapies that effectively overcome oxidative stress, toxic overloads, food sensitivities, yeast overload, metal metabolism imbalance, and weak immune function can provide significant improvements, but the essential autistic condition of cognitive and/or social and/or speech impairment usually remains at some level. I have witnessed hundreds of cases of autism recovery, but nearly all involved aggressive intervention prior to age four. This strongly suggests that (a) the central problem in autism is early brain development that has gone awry, and (b) a full recovery is extremely unlikely unless treatment begins before completion of this critical stage of brain maturation.

Findings Concerning Brain Structure

German researchers have found anatomical abnormalities of the amygdala-fusiform system, indicating poor connectivity between these brain areas. Researchers at Harvard and elsewhere have reported that primitive areas of autistic brains are immature, having failed to complete development of brain cells and synaptic connections. This knowledge suggests that therapies aimed at completion of brain development may be a high priority. Casanova has reported abnormalities in the cortex of autistic brains, especially narrowing of minicolumn arrays of cells. McGinnis and colleagues have reported threadlike accumulations of damaged fats in autistic brains, indicating oxidative damage. Courchesne found that many children with autism experience a rapid acceleration in brain size during the first year of life. Approximately 25% of autistics develop unusually large heads during early development.

Brain development involves four basic phases:

1. Pruning of some brain cells to make space for growth of other cells
2. Growth of neurons, axons, dendrites, and other cell components
3. Growth inhibition once a brain cell is fully mature
4. Development of synaptic connections

Researchers have reported an excessive number of short, undeveloped brain cells in the cerebellum, pineal gland, hippocampus, and amygdala of individuals with autism. This brain immaturity is primarily in areas with little or no protection from the blood-brain barrier, suggesting that chemical insults or excessive oxidative stress may have stunted brain development. In addition, these children exhibit a poverty of dendrites and synaptic connections.

The brain area with the most pronounced immaturity in autism is the cerebellum, which is responsible for smooth, controlled movements. A majority of individuals with autism exhibit odd, repetitive movements, possibly due to an impaired cerebellum. Another affected brain area is the amygdala that enables a person to develop social skills. Deficits in socialization are a hallmark of autism, and an immature amygdala may be part of the problem. The hippocampus partners with Wernicke’s area and Broca’s area in the development of speech. Mutism and speech delay are common in autism, and a poorly functioning hippocampus may be responsible.

Brains of individuals with autism also appear to be afflicted with significant inflammation that may inhibit brain development and cause a myriad of symptoms, including irritability, speech delay, sleep disorders, cognitive delay, and increased head size.

High-Frequency Health Problems in Autism

Many are afflicted with severe GI tract problems, including malabsorption, food sensitivities, esophagitis, reflux, incomplete digestion of proteins, yeast overgrowth, constipation, parasite overloads, and an incompetent intestinal barrier. Other common problems include poor immune function, seizures, sleep disturbances, chemical sensitivities, poor appetite, sensitivity to touch and sound, and enuresis (involuntary urination). There are numerous reports of high anxiety, apparent pain, frustration, and emotional meltdowns.

Food Sensitivities:

• They tested for gluten and casein intolerance by measuring casomorphin and gluteomorphin levels in blood. These abnormal proteins result from incomplete breakdown of certain dairy and grain proteins in the digestive tract. There is considerable evidence that these deviant proteins can readily pass intestinal and brain barriers and cause a myriad of behavioral and cognitive problems.
• Of 500 cases, 85% of families adopting the special diet reported major benefits. Hundreds of parents told him of very rapid and striking improvements in their children. A study of the 15% nonresponders revealed that about half had a family history of Crohn’s disease or other inflammatory bowel disorder.

Abnormal Biochemistry:

Biochemical Features of Autism (partial list)

• Low levels of glutathione
• Undermethylation
• Elevated mercury, lead, and other toxins
• Copper overload and insufficient ceruloplasmin
• Zinc deficiency
• Vitamin A deficiency
• Elevated urine pyrroles
• Depressed metallothionein protein levels
• Elevated carboxyethylpyrroles
• Low levels of magnesium
• Deficiency of selenium and cysteine

Oxidative Stress:

• More than 99% exhibit evidence of excessive oxidative stress. Chemical biomarkers for this condition include pervasive zinc deficiency; elevated pyrroles; low Cu/Zn SOD; copper overload; low ceruloplasmin; undermethylation; low levels of glutathione, selenium, and MT proteins; and elevated levels of mercury, lead, and other toxic metals.
• The most commonly prescribed drug for autism patients is Risperdal, which has antioxidant properties. Therapies to overcome hypomethylation result in more robust levels of the natural antioxidants glutathione, MT proteins, and cysteine. The GF/CF diet results in reduced inflammation, which lowers antioxidant requirements.
• They found that parents who would give their children chelation therapy for possible mercury toxicity would get results for a few days but it would regress after a few weeks. Every time they would repeat it there would be the same response. Possibly indicating the antioxidant effect was more useful, since mercury would have been cleansed after a few tries. High-normal toxic metal levels can result from weak antioxidant capability, without unusual mercury exposures. They did encounter a few autistic children with severe mercury poisoning, and a few weeks of oral DMSA chelation were administered to correct this problem.

Popular Biomedical Therapies for Autism (partial list):

• Methyl-B12 and other methylation therapies
• Supplementation with vitamins/minerals found in deficiency
• Transdermal glutathione
• Casein-free, gluten-free diets
• Chelation (removal of toxic metals)
• Metallothionein-Promotion therapy
• N-Acetylcysteine and alpha lipoic acid
• Therapies to combat yeast overgrowth
• Antibacterials and antifungals
• Decoppering protocols
• Amino acid supplements
• Digestive enzymes
• Hormonal treatments
• Secretin
• Hyperbaric therapy

Those with weakened antioxidant properties may be more sensitive to things like mercury and anything else that may cause oxidative stress.

Seizures:

• Roughly one-third of children diagnosed with an autism spectrum disorder have a history of either seizures or abnormal electroencephalograms (EEGs). A careful study of 503 ASD children that excluded subjects with a history of seizure tendencies found about 99% to have copper and zinc imbalances. Several studies of ASD populations that include subjects with seizure tendencies reveal that a substantial number of ASD children do not exhibit these imbalances. This suggests that the combination of ASD and seizures may represent a phenotype that is distinctly different from other ASD children.

What Can a Family Do?

Most families are initially told that autism is incurable, and the most common recommendations are applied behavior analysis (ABA), Risperdal, and/or institutionalization. Most families who utilized ABA reported that this system helped their child, although the benefits were painstakingly slow, expensive, and quite limited.

Risperdal is an atypical antipsychotic medication developed for schizophrenia that many psychiatrists prescribe for autism spectrum children and adults.

I doubt if doctors would suggest institutionalization if they knew that recovery was possible using advanced biochemical therapies.

It seems clear that ABA is an excellent recommendation for families who can afford it or whose children can obtain this via the school system, and it is especially effective when used together with biochemical treatments.

Behavioral Therapies:

ABA involves a multitude of direct interactions with an affected child over a period of months or years. The protocols are aimed at elimination of inappropriate behaviors and development of positive behaviors to enable improvements in speech, socialization, and learning.

• It’s likely that ABA stimulates the development of new brain cells and synaptic connections that can result in a permanent improvement in functioning.
• Many children exhibit disruptive behaviors because they are in pain from GI issues like constipation, esophageal inflammation, and reflux. A behavior plan simply won’t suffice. When the underlying GI issues are addressed, such as with therapeutic diet and anti-inflammatory agents, children have less pain and exhibit behaviors more suitable to learning in a classroom.

Repairing the gut also can accomplish the following important goals:

• Prevents undigested proteins from reaching the brain and causing aberrant behavior
• Allows desired nutrients to reach the brain and nourish it for tasks like learning
• Allows foods to be digested so that harmful overgrowths of detrimental flora (e.g., clostridia) do not proliferate, thereby releasing toxic byproducts that travel to the brain and cause detrimental behavioral effects
• Precludes further inflammation of the gut, which would have initiated a cascade of events whereby gut inflammation increased proinflammatory immune messengers that also traveled to the brain causing immune activation

General Health and Wellness:

• In many ways, children with autism are quite sick and can benefit greatly from treatments that overcome malabsorption, food sensitivities, yeast overgrowth, parasites, constipation, enuresis, poor immune function, etc.

Brain Inflammation:

• Numerous families adopting a GF/CF diet report a rapid reduction in autism symptoms. Since brain development is a gradual process that occurs over several years, it is likely that the sudden improvements in behavior, bedwetting, speech, and socialization are due to lessening of brain inflammation.
• Hyperbaric therapy is known to reduce brain inflammation in patients suffering from head injuries or strokes. Hyperbaric therapy has become a popular autism treatment with many reports of impressive improvements. However, in many cases, these benefits are temporary and repeated hyperbaric sessions are required to maintain improvements.
• A general rule is that any autism therapy that results in sudden improvement has reduced brain inflammation but that therapy may not be the best technique for development of new brain cells, dendrites, and synaptic connections needed for advances in cognition, speech, and socialization.

Oxidative Stress and Damage:

If all we knew about a patient was the presence of severe oxidative stress, we would expect the following:

• Incompetent intestinal and blood-brain barriers
• Weakened immune function
• Reduced levels of digestive enzymes that break down proteins
• Tendency for yeast overload
• Depressed levels of glutathione, cysteine, and metallothionein protective proteins
• Copper overload and deficiencies of zinc and selenium
• Disruption of the one-carbon cycle resulting in undermethylation
• Reduced ability to overcome inflammation
• Hypersensitivity to mercury, lead, and other toxic metals

Elevated oxidative stress in the womb could modify epigenetic imprinting of gene expression, alter brain development, and weaken development of lymphoid and thymic tissues needed for immune function. Continuing oxidative stress in early childhood could alter development of brain cell minicolumns needed for learning, memory, and other cognitive functions; could inhibit brain maturation; could impair connectivity of adjacent brain regions; could increase vulnerability to toxic metals; and could alter brain neurotransmitter levels. In addition, elevated oxidative stress is associated with neurodegenerative destruction of brain cells. It appears that autism may be slowly neurodegenerative, with gradual loss of brain cells and IQ, especially after puberty.

There are a number of antioxidant therapies including:

• Supplementation of glutathione, selenium, alpha lipoic acid, zinc, and vitamins C and E
• Methylation therapies
• Chelation
• MT-Promotion therapy

Risperdal and Brain Shrinkage: A Warning for Autism Families

This medication can effectively reduce irritability and emotional meltdowns in autistics. However, the safety of Risperdal has never been established for young children, and its impact on early brain development is unknown. Recent MRI studies have heightened these concerns due to strong evidence that atypical antipsychotic medications reduce brain cortex volumes.

Findings do not prove that Risperdal causes brain shrinkage in children with autism since similar experiments have never been performed for this population. However, the risk of Risperdal use in young children appears very real, especially for those who have not yet completed the brain development process. Risperdal’s benefits for autism patients are very real but are limited to behavioral improvements.

The Final Battleground—the Brain

Treatment initiatives may be divided into two general categories:

• Enhanced development of immature brain cells
• Therapies that promote formation of new dendrites, receptors, and synaptic connections.

Elevated copper and depressed zinc occurred throughout the autism spectrum, suggesting low activity of MT proteins that regulate these metals. Pervasive deficiency of cerulloplasmin (copper-binding protein) in ASD indicated that this copper elevation could not be attributed to inflammation. MT proteins are intimately involved in all phases of early brain cell development, including pruning, growth, and growth inhibition. Suspicion that low MT activity was involved in brain immaturity was supported by the fact that MT levels are highest in brain areas known to be immature in autism (e.g., amygdala, hippocampus, pineal gland, and cerebellum).

Other promising research areas that could lead to therapies for promoting brain plasticity include parvalbumin, GABAergic signaling, and Reelin (a protein that helps regulate processes of neuronal migration and positioning).

Bringing It All Together: An Epigenetic Model of Autism

Evidence of autism’s epigenetic nature includes:

• Abnormal methylation, the most decisive factor in epigenetic disorders
• Severe oxidative overload, a condition that can produce deviant gene marks
• Vulnerability to toxic metals and other environmental insults
• Many cases of sudden onset after a period of relative wellness
• Persistence of autism after onset, indicating that a life-changing event has occurred
• Violation of classic laws of genetics in autism, a condition with a strong heritable component

It appears the combination of undermethylation, oxidative overload, and epigenetics. In essence, autism appears to be a gene programming disorder that develops in undermethyated persons who experience environmental insults that produce overwhelming oxidative stress.

Walsh Model of Autism:

1. Predisposition to autism results from in utero hypomethylation that that causes over-expression of several genes, weakened protection against oxidative stresses, and increased vulnerability to environmental insults.
2. Sometime between conception and age three, environmental insults reach a threshold in which oxidative stresses overwhelm oxidative protectors (a tipping point). This triggers an epigenetic event in which DNA and histone marks are altered, producing the syndrome with the diagnostic label of autism. Since the deviant marks are maintained during future cell divisions, the condition doesn’t go away and can result in a lifetime of disability.
3. Autism onset may occur in utero or after birth, depending on the timing and severity of the environmental insults.
4. The altered marks result in abnormal brain development, a tendency for serious brain inflammation and oxidative stress, and significant biochemical imbalances.
5. Many genes are adversely affected, producing a myriad of physical problems, such as weakened immunity, food sensitivities, seizure tendencies, heightened sensitivity to toxins, and poor behavioral control.

The Aftermath of Autism and Treatment Opportunities

Since autism involves deviant gene marks that survive many cell divisions, the condition can persist throughout life. The severity of autism may depend on the relative progress in brain development prior to inundation by oxidative stress and the number and type of deviant gene marks. With these insights, he believes the following three approaches have the highest promise for achieving major improvements in cognition, speech, and behavior:

1. Antioxidant therapies: Many symptoms of autism are directly related to elevated oxidative stress. The following are examples of benefits that may be achieved by effective antioxidant therapy:

• Reduction of brain inflammation may reduce irritability and enhance development of speech, cognition, and socialization.
• Improved glutathione and metallothionein levels can enhance memory by increasing glutamate activity at NMDA receptors.
• Reductions in the number of oxidative free radicals would enhance immune response, protein digestion, and eliminate the tendency for yeast overload.
• The filtering action of intestinal and blood-brain barriers can be improved by eliminating oxidative overload.
• Increased activity of metallothionein proteins could promote development of new brain cells and synaptic connections.
• Elimination of oxidative overloads would protect against brain cell death (apoptosis) and cognitive impairments.

It cannot be stressed enough that continuous, strong antioxidant therapy should be employed as appropriate under medical oversight in order to prevent progressive and severe cognitive deterioration as the individual with autism ages; this can be accomplished with fairly routine and inexpensive supplementation.

2. Normalization of chromatin methyl/acetyl levels: Undermethylation is a distinctive feature of autism that results in altered kinetics of gene expression. Epigenetic therapies aimed at increasing methyl levels at CpG islands and histone tails have great promise. In many cases, this requires removal of acetyl groups and substitution with methyl at these locations. The dominant factors that control the methyl/acetyl competition are four families of enzymes: acetylases, deacetylases, methylases, and demethylases. Standard methylation protocols may be inappropriate due to the impact of specific nutrients on these enzymes. For example, folic acid supplements can reduce chromatin methylation due to folate’s powerful role in enzymatic demethylation of histones. Development of nutrient therapies to normalize methyl/acetyl levels at CpG islands and histone tails is a very fertile area for research.

3. Reversal of deviant gene marks: Cancer researchers are actively investigating epigenetic therapies aimed at reversing abnormal gene marks believed responsible for many types of cancer. If autism truly is an epigenetic disorder, this approach could eventually lead to effective autism prevention. For example, early infant genomic testing could determine if autism-predisposing marks are present, and it’s likely that future research will identify clinical methods for normalizing the marks with natural, biochemical therapy. This line of research may represent the ultimate solution for this devastating disorder, and it should be a high national priority.

Chapter 8. Behavioral Disorders and ADHD

Sibling Experiment

Most violent subjects exhibited abnormal levels, especially with respect to copper, zinc, lead, and cadmium. In general, the violent children exhibited higher lead and cadmium levels than did the controls. However, this test group was about evenly split between children with elevated Cu/Zn ratios and others with depressed Cu/Zn ratios. None of the well-behaved children exhibited a Cu/Zn imbalance.

Most parents of high Cu/Zn children reported periods of good behavior interrupted by violent episodes. Most reported genuine remorse after the meltdowns. The children with low Cu/Zn ratios were described as oppositional, defiant, assaultive, cruel to animals, with several families reporting fascination with fire. This latter group clearly fit the psychiatric definition of antisocial personality disorder. In contrast, the high Cu/Zn group had symptoms associated with intermittent explosive disorder.

Biochemistry of Behavioral Disorders and ADHD

Data reveal a high incidence of chemical abnormalities for both groups, especially disorders of metal metabolism, methylation, pyrroles, toxic metals, glucose, and absorption.

Copper is an important factor in the conversion of dopamine to norepinephrine; zinc is needed for efficient regulation of GABA; vitamin B-6 is a cofactor in the synthesis of several neurotransmitters; methionine and folic acid have powerful impacts on synaptic activity; and toxic overloads can impair brain function.

Significant chemical imbalances were found in 94% of the 10,000 persons in my behavior database. Many of the remaining 6% had a history of a serious head injury, epilepsy, or oxygen deprivation during birth. The incidence of chemical imbalances for the ADHD population was about 86%. Males outnumbered females by a three-to-one ratio in both groups. The vast database revealed strong correlations between chemical abnormalities and specific behavioral disorders and ADHD:

Intermittant explosive disorder (IED):

• About 90% of IED children exhibit a very elevated Cu/Zn ratio in blood, often coincident with elevated urine pyrroles. Most families report somewhat improved behavior during the first week of nutrient therapy, with about 60 days needed for the full effect.

Oppositional-defiant disorder (ODD):

• The classic chemical signature of ODD is undermethylation, which can be identified using blood tests for SAMe/SAH ratio, histamine, absolute basophils, etc. This imbalance is associated with low activity of dopamine and serotonin neurotransmitters. Psychiatric drugs for ODD usually involve stimulants (Ritalin, etc.) or antidepressants aimed at increasing activity of these neurotransmitters.
• Methionine and SAMe, while avoiding folates and choline.
• Increasing serotonin and dopamine levels in the brain
• Suppressing formation of transporters at synapses
• A high percentage of successfully treated patients have been able to eliminate psychiatric medications without a return of the bad behavior. A major barrier to success is the innate tendency of undermethylated patients to be noncompliant with any treatment.

Conduct disorder (CD):

• Children with conduct disorder act out aggressively and express anger inappropriately. They engage in a variety of antisocial and destructive acts, including violence toward people and animals, destruction of property, lying, stealing, truancy, and running away from home.
• They are prone to abusing drugs and alcohol and having sex at an early age. Irritability, temper tantrums, and low self-esteem are common personality traits of children with CD, and many are also oppositional and defiant.
• The classic chemical signature of CD is a combination of severe pyrrole disorder and undermethylation.

Antisocial personality disorder (ASPD):

Persons with this condition are sometimes referred to as sociopaths or psychopaths. Early warning signs include bedwetting, cruelty to animals, and fascination with fire. In most cases, they are oppositional and defiant by age 4 and exhibit a conduct disorder by age 10.

• Extreme narcissism – total absence of care and concern for others
• Engaging personality and good verbal skills
• Hypersexuality
• Easily enraged, especially after consuming alcohol
• High pain threshold
• Disregard for laws and social norms
• Fearless use of illegal drugs
• Low opinion of normal people, who they believe are cowards
• Impulsive actions without regard for consequences

The chemical signature of ASPD is an odd combination of undermethylation, pyrrole disorder, elevated toxic metals, severe zinc deficiency, and low-normal copper levels. Nutrient therapy to correct these imbalances generally results in reports of great improvement in ASPD children, but there is little sustainable benefit for teens or adults actively abusing alcohol or illegal drugs.

Nonviolent behavioral disorders:

Most cases involved poor academics and work performance along with a tendency for lying, stealing, and deceptive practices.

Chemical studies indicate that most patients with a nonviolent behavioral disorder fit into one of the following biochemical classifications:

• Malabsorbers who exhibit low levels of most vitamins, minerals and amino acids
• Persons with severe glucose dyscontrol
• Nonviolent, undermethylated persons with ODD

Biochemistry of ADHD

There are three major subtypes of ADHD, and each has a different chemical signature:

1. Predominantly inattentive: These persons may have normal or high intelligence but exhibit poor focus and concentration. In school, they may sit quietly, but they have little interest in the subject matter and are prone to daydreaming. Many of these children have excellent behavioral control and socialization but very poor academics. More than half of these persons are deficient in folic acid, vitamin B12, zinc, and choline, and they develop better focus after supplements of these nutrients. Another cause of inattention can be extreme boredom, especially in children of very high intelligence, and these children need to be intellectually challenged.
2. Predominantly impulsive and hyperactive: These persons tend to be in constant motion, are highly distractible, and have a short attention span. As a result, they underachieve academically, regardless of their intelligence level. The classic chemical signature for this group is a metal metabolism disorder involving copper overload and zinc deficiency. This metal imbalance is associated with low dopamine and elevated norepinephrine and adrenalin activity. Ritalin, Adderall, and other stimulant medications can effectively elevate dopamine activity and improve academics. However, nutrient therapy to balance copper and zinc levels can often achieve the same result without the unpleasant side effects associated with stimulant medications, including appetite suppression, delayed growth, tic disorders, and personality change. It is interesting to note that Ritalin and cocaine share the same mechanism of action—dopamine reuptake inhibition by impairing the action of DAT transport proteins. Cocaine provides a sudden high due to rapid elevation of dopamine activity and is highly addictive. Ritalin taken orally causes a much slower dopamine activity rise and is generally not addictive.
3. Combined hyperactive/impulsive and inattentive: This largest subtype of ADHD generally involves more severe academic underachievement than subtypes 1 and 2. This population includes persons with more than one chemical imbalance, and lab testing is essential to successful diagnosis and treatment. About 68% exhibit a seriously elevated Cu/Zn ratio in blood and tissues, and normalization of these trace metals can greatly reduce hyperactivity and improve attention span. Others in this classification may have a methylation disorder, toxic overload, pyrrole disorder, or other imbalance, and blood and urine testing are necessary for accurate diagnosis.

Nutrient Therapy Outcomes

Early Behavior Findings: 1978-1988

• About 65% of families reported improved behavior, with better results for young children.
• About 80% of children under age 14 exhibited improved behavior, with more than half ceasing physical violence altogether.
• A gradual decline in efficacy was observed after age 14.
• Higher efficacy was reported for severe cases involving a history of frequent assaultive behavior.
• Most persons diagnosed with oppositional-defiant disorder were undermethylated.
• Most persons diagnosed with conduct disorder had elevated urine pyrroles.
• About two-thirds of ADHD children exhibited an elevated Cu/Zn ratio in blood.
• Many families reported compliance problems, with more than 10% failing to initiate treatment.
• About 15% reported occasional nausea or stomach pain if nutrients were taken on an empty stomach.

Elevated copper/zinc ratio: A total of 75.4% of test subjects exhibited elevated serum copper and depressed plasma zinc. Behavioral disorders associated with this imbalance include episodic rage disorder, attention-deficit disorder, and hyperactivity. Treatment involved MT promotion therapy using zinc, glutathione, selenium, and cysteine together with augmenting nutrients such as pyridoxine, ascorbic acid, and vitamin E.

Overmethylation:

About 29.5% of the BD subjects exhibited depressed blood histamine, which is a biomarker for overmethylation, an elevated methyl/folate ratio, and elevated levels of dopamine and norepinephrine. This imbalance is associated with anxiety, paranoia, and depression and was treated using folic acid, vitamins B3 and B12, and augmenting nutrients.

Undermethylation:

A total of 37.7% of the patients exhibited elevated blood histamine, a biomarker for undermethylation and a depressed methyl/folate ratio. This imbalance is associated with depression, seasonal allergies, obsessive-compulsive tendencies, high libido, and low levels of serotonin. Treatment involved supplements of methionine, calcium, magnesium, and vitamins B6, C, and D.

Pyrrole disorder:

This imbalance was exhibited by 32.9% of the patients. Elevated pyrroles have been associated with an inborn error of pyrrole chemistry, but this also can result from porphyria or exposure to heavy metals, toxic chemicals, and other conditions enhancing oxidative stress. This imbalance results in severe deficiencies of pyridoxine and zinc and is associated with poor stress control and explosive anger. Treatment for this disorder involved supplements of pyridoxine, pyridoxal-5-phosphate, zinc, and vitamins C and E.

Heavy metal overload:

Elevated levels of lead, cadmium, or other toxic metals were exhibited by 17.9% of the BD persons. Toxic metal overloads have been associated with behavioral disorders and academic underachievement. Treatment involved supplementation with calcium, zinc, manganese, pyridoxine, selenium, and other antioxidants to promote the excretion of toxic metals.

Glucose dyscontrol:

Among the test population, 30.4% exhibited a tendency for unusually low blood glucose levels. This imbalance appears to represent an aggravating factor rather than a cause of behavioral disorders. Treatment involved supplements of chromium picolinate and manganese along with dietary modifications.

Malabsorption:

A total of 15.5% exhibited a malabsorption syndrome involving generalized low levels of amino acids, vitamins, and minerals. This chemical imbalance has been associated with irritability, impulsivity, and underachievement. Treatment varied, depending on the type of malabsorption (for example, low stomach acid, gastric insufficiency, yeast overgrowth, or a brush border disorder). The treatments included the use of nutrients for regulating stomach acid levels, digestive enzymes, biotin, and probiotics.

Treatment effectiveness results:

Compliance is a major barrier to treatment success in behavioral disorders. For example, it is very difficult to get an oppositional-defiant teenager to do anything, including swallowing a number of capsules daily. In this study of 207 subjects, a total of 76% remained compliant at the time of the follow-up interview. The families reported that about 50% of the noncompliant persons never began treatment.

Nutrient Therapy Timeframes

The time required for academic improvement is generally longer than that for behavioral improvements. Correction of chemical imbalances does not inject new knowledge into a child’s brain, but it can greatly increase the rate of learning.

The most rapid progress is achieved by pyrrole disorder patients who may become calmer after a few days of therapy. The slowest imbalance to resolve is undermethylation, with 30-60 days typically required before improvements are observed.

Three factors can delay progress:

• Type A blood
• Malabsorption
• Hypoglycemia

Some have all three factors and require six months of treatment before success is achieved. Nutrient therapy for ADHD children usually requires three months to achieve full effect. ADHD adults respond more slowly, with more than six months often required before progress begins. BD patients usually respond to nutrient therapy within two weeks, with full effect achieved after two months.

Recommendation: Doctors should perform blood tests prior to prescribing SSRI antidepressants for young males. Inexpensive blood testing for histamine, serum folate, and/or SAMe/SAH ratio can efficiently identify persons at risk for suicidal or homicidal ideation following use of SSRI antidepressants.

Chapter 9. Alzheimer’s Disease

Stages of Alzheimer’s Disease

1. Early warning signs: Many patients exhibit subtle symptoms of AD several years prior to diagnosis. The most common indications are loss of interest in events and activities along with a decline in mental sharpness. Mild cognitive impairment.
2. Mild Alzheimer’s disease: A formal diagnosis of AD usually is made when there is a striking loss of recent memories, while older memories are still retained. Another diagnostic symptom is a shrinking vocabulary and loss of communication skills. In this stage of the disease, most persons still enjoy life and can accomplish basic tasks but require supervision for activities requiring complex thought or logic.
3. Moderate Alzheimer’s disease: The deterioration of neurons eventually spreads throughout the brain and the patient loses the ability to perform many common activities of daily living. Memory continues to deteriorate, and the patient may no longer recognize his own grandchildren or recent friends. Reading and writing skills gradually disappear, and irritability, wandering, falling, and physical aggression symptoms can be very challenging for the family. About one-third of AD victims develop delusions and urinary incontinence. Most families are forced to move their loved one to a long-term care facility when they can no longer cope with the worsening symptoms. This step frequently does not seem to bother the patient.
4. Advanced Alzheimer’s disease: During this final stage, the patient becomes completely dependent on caregivers. As the disease progresses, many develop a wooden expression, lose the ability to speak, and fail to respond to visitors. In the final stages, they become bedridden, totally incontinent, and unable to feed themselves. Death usually results from an infection, respiratory problems, etc. and not directly from AD itself.

Role of Genetics

Familial AD typically develops between the ages of 40 and 55 and represents about 5% of cases. This condition is caused by mutations to genes that produce presenilin 1, presenilin 2, or amyloid precursor protein (APP). The late-onset form of AD represents about 95% of cases, usually developing after age 70. In 1993, researchers at Duke University reported that an apolipoprotein E (ApoE) abnormality represents a powerful risk factor in late-onset AD. ApoE is a protein containing 299 amino acids that can exist in three isoforms: E2, E3, and E4. Isoform E3 is identical to that of E2 except that a cysteine in the amino acid chain is replaced by arginine. In isoform E4, two cysteines are replaced by arginine. The risk of developing AD is lowest in ApoE2, intermediate in ApoE3, and highest in ApoE4. Persons born with an E4 allele from both parents are between 10 and 30 times more likely to develop AD by age 75 when compared with persons without an E4 allele. However, many persons with both E4 alleles live to a ripe old age without developing memory loss or other symptoms of dementia. Moreover, 40% of AD victims do not have the E4 gene.

Risk Factors

• Age: The likelihood of this disease increases sharply with age, and about one-third of persons reaching age 85 are in some stage of the disorder. Surprisingly, there is evidence that the risk of AD declines after age 90.
• Head Injury: Boxers have an increased risk for AD, and some acquire the disorder before age 40.
• Education Level: Higher education delays the onset of AD but that the disease progresses more rapidly once AD has begun in these persons.
• Mental Activity: Mentally stimulating activities such as playing bridge, doing puzzles, or learning a new language reduce the risk of AD.
• Physical Activity: Persons engaging in regular physical activity were found to have reduced AD risk. However, it’s possible this is due to better cardiovascular health or reduced obesity rather that a direct result of physical exercise.
• Vascular Factors: The first brain areas damaged are close to blood vessels. A variety of cardiovascular problems increase AD risk. Examples include strokes, hypertension, hypotension, atrial fibrillation, atherosclerosis, and elevated serum homocysteine.
• Alcohol Use: Mentions drinking red wine. Not likely.
• Physical Illness: Persons with a history of diabetes or other autoimmune diseases appear to have a higher risk of AD. The strongest data are for type 2 diabetes and insulin resistance.
• Toxic Metals: Mercury exposure causes increased oxidative stress and this factor is elevated in AD.
• Poor Nutrition: Inadequate nutrition is a common problem in elderly populations, and low levels of zinc and vitamins A, C, and E result in increased oxidative stress. Several studies indicate that oxidative stress plays an important role in the development of AD. In addition, elevated serum homocysteine is a known AD risk factor that can result from deficiencies of folic acid and vitamin B12. A high-quality diet may represent an important protective factor against AD.

Alzheimer’s Disease Theories

Cholinergic Theory:

This theory states that AD begins with the depletion of acetylcholine activity in the brain. Acetylcholine is a major neurotransmitter important for memory processes and is seriously depleted in AD brains. This has been attributed to a shortage of enzymes (choline acetyltransferase and acetylcholine esterase) necessary for production and regulation of acetylcholine. However, these low enzyme levels only tend to appear in the late stages.

Amyloid Plaque Hypothesis:

Aβ is formed when APP is cut into small sections by enzymes called secretases. The factors that cause the disintegration of APP into Aβ fragments are a subject of active research. The Aβ plaques tend to clump together and form a mass outside brain cells. Advocates of the amyloid theory believe production and aggregation of Aβ to be the key event in the brain cell destruction process. Aβ plaques may be a result and not a cause of AD.

The Tau Hypothesis:

Tau and other proteins assist in keeping the delicate tubules intact and in the proper place. However, in AD patients, tau proteins become chemically modified and clump together, resulting in microtubule disintegration and disabling tangles. The net result is loss of nutrient transport and death of the brain cell.

Inflammation Theory:

The Scripps theory suggests that amyloid proteins are modified during inflammation, causing them to misfold and accumulate into the characteristic plaques found in AD brains.

Oxidative Stress Theories:

Oxidative free radicals perform several useful functions in the body, such as killing bacteria and burning glucose to produce energy. However, a chronic excess of free radicals can lead to death of brain cells. Sources of free radicals include physical injury, bacteria, viruses, inflammation, heavy metals, and nuclear radiation. The body has a supply of antioxidant molecules that have the job of keeping free radicals from reaching concentrations lethal to brain cells. A healthy brain requires (a) a competent blood-brain barrier to reduce influx of toxics, and (b) enough antioxidant protection within the brain to cope with the number of free radicals present. 

Metal Metabolism Theories:

Bush, MD, and colleagues reported that copper overloads cause increased Aβ in the brain. Copper and iron are major sources of free radicals in the human brain, and elevated copper levels have been found in Aβ. Metallothionein and Cu/Zn SOD protect against copper free radicals, but both are depleted in AD brains. This theory suggests that excess copper prevents the natural removal of Aβ from AD brains. Interestingly, two 2009 studies have reported a protective role for copper in AD. It’s possible that either deficiency or excess of copper can be harmful to the brain and that homeostatic regulation of copper levels is essential.

Advanced Photon Source Measurements

Large calcium-rich circular areas were observed in the AD samples and very small calcium-rich zones in the controls. In both cases, the calcium concentrations were 15 times higher in the calcium-rich areas when compared with adjacent tissues. Another interesting finding was the presence of very elevated Cu/Zn ratios in parts of the AD samples but not in the controls.

The Case for Metallothionein

Two separate autopsy studies have reported severe deficiency of MT protein levels in deceased AD patients. MT proteins have several protective functions in the brain including the following:

• Preventing toxic metals from passing the blood-brain barrier
• Regulation of copper levels
• Powerful antioxidant action against free radicals

The protective properties of MT depend on ample amounts of glutathione and selenium. Gene expression of MT is zinc dependent, and most AD patients are depleted in zinc. MT proteins are far more powerful than selenium, coenzyme Q10, vitamins C and E, and other antioxidants that have been used in experimental AD therapies.

Chapter 10. The Clinical Process

Advanced nutrient therapy involves a five-step process:

1. Medical history and review of symptoms
2. Lab testing of blood and urine
3. Diagnosis of chemical imbalance(s)
4. Treatment design
5. Aftercare

Medical History and Review of Symptoms

Successful nutrient therapy requires in-depth knowledge of the patient, and an extensive medical history is essential. Lab chemistries provide only 50% of the information needed for accurate diagnosis.

Medical History Factors:

• Problems during pregnancy
• Problems during birth
• Early health issues
• Food sensitivities
• Developmental milestones
• Growth history
• Seasonal allergies
• Chemical sensitivities
• Illnesses Injuries
• Academic strengths and weaknesses
• Academic level
• Family unit
• Occupation
• Medical diagnoses and treatments
• Response to medications
• Immune function
• Behavior control
• OCD tendencies
• Sleep issues
• Substance abuse issues
• Pain threshold
• Family history of illnesses
• Socialization issues
• Competitiveness Diet

Telltale Clues of a Chemical Imbalance

Zinc Deficiency:

Poor growth through puberty with significant growth after age 16, white spots on fingernails, frequent infections, tendency for sunburn, preference for spicy foods, irritability, poor stress control, anger, poor wound healing, poor muscle development, premature graying of hair, abnormal or absent menstrual periods, stretch marks on skin.

Copper Overload:

Hyperactivity, academic underachievement, skin sensitivity to metals and rough fabrics, estrogen intolerance, emotional meltdowns, ringing in ears, sensitivity to food dyes, high anxiety, sleep problems, adverse reaction to nutritional supplements containing copper, abnormal menstrual periods.

Undermethylation:

Obsessive-compulsive tendencies, seasonal allergies, strong-willed, competitive in games and sports, ritualistic behaviors, high libido, poor pain tolerance, addictive tendencies, sparse arm/leg/chest hair, history of perfectionism, chronic depression, high fluidity (tears, saliva), phobias.

Overmethylation:

High anxiety; dry eyes and mouth; hirsutism; noncompetitive; low libido; talkative; low motivation in early school years; obsessions without compulsive actions; sleep disorder; food and chemical sensitivities; estrogen intolerance; absence of seasonal allergies; postpartum depression; antihistamine intolerance; adverse reaction to SSRI antidepressants, methionine, and SAMe.

Pyrrole Disorder:

Poor stress control, poor short-term memory, reading disorder, sensitivity to noise and bright lights, little or no dream recall, spleen area pain, poor growth, many fears, dry skin, underachievement, tendency to skip breakfast, frequent infections, extreme mood swings, severe inner tension, abnormal fat distribution, affinity for spicy or salty foods, high anxiety, delayed puberty, abnormal EEG.

Toxic Metal Overload:

Abdominal discomfort, poor appetite, increased irritability and temper, decline in academics, metallic taste in mouth, bad breath, change in personality.

Laboratory Testing

Whole Blood Histamine:

This is a useful test for evaluating methylation status. Histamine and methyl groups are present in measurable levels throughout the body, and an inverse relationship exists between them. Histamine is metabolized (destroyed) by methylation, and this is a primary mechanism for regulating histamine concentrations. Elevated blood histamine indicates undermethylation, and low histamine is evidence of overmethylation. Antihistamine treatments can artificially lower blood histamine and should be avoided for several days prior to sampling. Laboratory assays for SAMe/SAH ratio are more decisive, but they are not widely available in commercial laboratories.

Plasma Zinc:

There are about 10 different approaches for measuring zinc status, and plasma testing has consistently been regarded by zinc experts as the best way to obtain reliable and meaningful results. The zinc concentration in blood serum is nearly identical, but this approach involves a greater likelihood of contamination during sampling. Some doctors prefer to assay packed cells, which gives an indication of the zinc level within blood cells rather than in blood fluids. Testing of both plasma and blood cells provides additional information that is sometimes useful in diagnosis.

Serum Copper:

This is a routine and highly reliable assay that is available in many parts of the world. Copper has special significance in mental health due to its role in metabolism of dopamine and synthesis of norepinephrine. Elevated serum copper can alter the synaptic activity of these important neurotransmitters.

Urine Pyrroles:

This chemical assay is available in laboratories in the USA, Europe, and Australia and is gaining in popularity. This test serves two purposes:

• Identification of pyrrole disorder, a medical condition associated with extreme deficiencies of B6 and zinc
• Assessment of oxidative stress in an individual
• Pyrrole disorder typically involves high anxiety, poor behavioral control, a reading disorder, impaired immune function, and other troubling symptoms. Severe pyrrole levels have been observed in persons diagnosed with violent behaviors, depression, schizophrenia, and other serious mental disorders. Elevated pyrroles can also result from excessive oxidative stress levels in persons who do not have the classic symptoms and traits of pyrrole disorder.

Serum Ceruloplasmin:

In healthy individuals, about 80 to 95% of serum copper is bound to ceruloplasmin, with the remaining 5-20% present as loosely bound atoms or unbound free radicals. Patients with more than 25% of their copper not bound to ceruloplasmin have a metal metabolism disorder involving elevated oxidative stress. This condition is common in autism, postpartum depression, ADHD, and certain forms of psychosis.

Thyroid Panel:

A surprisingly high number of patients with chemical imbalances also exhibited hypothyroidism. Normalizing thyroid levels is essential to treatment success for these persons. In rare cases, hypothyroidism alone can cause clinical depression or psychosis.

Liver Enzymes:

The presence of elevated liver enzymes suggests this organ is under significant stress, and nutrient therapy should be modified to avoid aggravating the condition. Liver enzyme elevations are a common side effect of psychiatric medications. In any case, high dosages of niacinamide and fat-soluble vitamins such as A, D, and E should be avoided for these patients.

Treatment Compliance

Typically, patients are asked to take some nutrients with breakfast and others with the evening meal. Vitamin B6 is a component of most treatments and can make sleep difficult if taken late in the day. For patients who are intolerant of morning nutrients, they recommend vitamin B6 be taken prior to 3:30 pm. About 25% of patients taking zinc in the morning (or without food) report nausea or stomach pain. For this reason, zinc is usually given with the evening meal. Absorption efficiency drops somewhat for certain nutrients if taken at mealtime. The doctor can adjust for this effect by prescribing small increases in dosage.

Many persons with pyrrole disorder report little or no appetite in the morning and avoid breakfast entirely. For these patients, they recommend the morning nutrients be taken with the first substantial meal.

Many patients are unable to make a major change in lifestyle before the major imbalance is corrected. A nutritional practitioner needs to grit his/her teeth and avoid major dietary changes until treatment progress is achieved. In an exception, ADHD children should limit sweets and restrict food dyes at the outset. Another exception involves children diagnosed with ASD who need special diets from the initial stages of treatment.

Patients Taking Concerta, Adderall, or Ritalin

Many ADHD and BD patients report ongoing treatment with an amphetamine medication during the initial evaluation. Outcome studies have shown best results are attained if the medication is continued during the first three to six months of nutrient therapy. After that time, they suggest the family ask the psychiatrist to gradually reduce doses until an optimum condition is reached.

Alcoholic patients who continue drinking during nutrient therapy rarely improve. Nearly all patients underestimate their alcohol intake, and a general rule is to multiply their reported intake by a factor of three. Complete abstinence for at least six weeks should precede nutrient therapy. Alcohol abuse is known to diminish glutamate activity at NMDA receptors, and nutrients that enhance NMDA function are an important part of therapy. These include vitamin B-6, zinc, sarcosine, D-serine, and D-cycloserine.

Nutrient Therapy Side Effects

Adverse reactions may be divided into three types: (a) side effects resulting from rapid biochemical transitions during early treatment, (b) symptoms associated with extreme nutrient sensitivities, and (c) adverse reactions associated with incorrect diagnosis or excessive nutrient dosages.

• a. Transitional side effects: Many patients exhibit an overload of copper or a toxic metal prior to treatment. These excess materials depart the body via the bloodstream during early nutrient therapy. If the exit from the body is too rapid, blood levels can escalate and cause unpleasant side effects. Other side effects can occur if excess histamine is released too rapidly from tissues. In all cases of transitional side effects, the solution is to take one’s foot off the accelerator and temporarily reduce treatment dosages.
• b. Nutrient sensitivities: There is great individuality with respect to nutrient sensitivities, and doctors should be alert for these rare side effects. Some patients are very sensitive to nutrients that are in deficiency. For example, many children with autism are deficient in cysteine, glutathione, and other sulfur-containing nutrients, but they exhibit extreme negative reactions during modest dosages. Human biochemistry is complex, and there are a multitude of genetic variations between different persons. Occasional unexpected results of nutrient therapy are inevitable.
• c. Incorrect therapy: Nutrient therapy should be supervised by a medical professional with experience in this medical approach. An example of improper treatment is excessive zinc dosage that can produce anemia due to reduction in iron stores. Manganese incorrectly given to an undermethylated patient can produce Parkinsonian-like symptoms. Patients with vitamin B6 sufficiency can develop temporary skin neuropathy and wild troubling dreams after doses of vitamin B6.

Undermethylated patients can develop worsened depression and psychotic symptoms if mistakenly given folic acid. Overmethylated patients may develop worsened anxiety and depression if given methionine or SAMe methylating agents. Treatment with copper can increase the risk of hormonal cancers in high-copper females. Individualized nutrient therapy should never be attempted by inexperienced lay persons.

Nutrient Therapy Response Times

• Pyrrole disorder: Nice improvement in behavior control and calming can be seen during week one, with full effectiveness after one month.
• Zinc deficiency: Little improvement is seen during the first two weeks, with gradual improvement thereafter and full effectiveness after 60 days.
• Copper overload: There are many reports of mild worsening during the first 10 days, followed by clear improvement during weeks three and four and full effectiveness after three to four months (except in the case of type A blood, which may require 6-12 months for full effectiveness).
• Overmethylation: There is increased anxiety during the first two to three weeks, followed by sharp improvement during weeks four to eight and full effectiveness after three to four months.
• Undermethylation: Little/no improvement is seen during the first three to four weeks, followed by steady improvement during months two to six.
• Toxic metal overload: There is mild worsening during the first 10 days, followed by steady improvement for four to six months. Removal of lead is especially slow (half-life of long-term lead in the body is 22 years). Other metal toxins can be removed relatively quickly.

Factors that often retard progress are malabsorption, type A blood, and hypoglycemia. For these persons, improvement usually begins after 3 to 6 weeks, with 12 months often needed for the full effect.

Nonresponders

1. Noncompliance: More than 50% of all treatment failures resulted from poor treatment compliance. About 10% of oppositional children and teens refused to comply, and some never took a single capsule. 
2. Growth spurt: Some zinc-deficient patients experience rapid growth during the first few months of treatment and fail to improve until the growth spurt has ended. We use and lose zinc when cells divide, and standard zinc doses are insufficient if rapid growth occurs.
3. Physical injury: Successfully treated patients may experience a temporary relapse after a broken leg or similar injury. If an injury occurs during early treatment, symptoms may worsen for weeks before progress is noted.
4. Illness: Infections and other illnesses can result in biochemical changes that may delay response to treatment.
5. Emotional stress: Several chemical imbalances are heightened during traumatic experiences. 
6. Type A blood: Outcome studies indicate that persons with type A blood respond very slowly to nutrient therapy. The combination of a metal metabolism disorder and type A blood can require great patience on the part of the family.
7. Malabsorption: Persons who process foods inefficiently usually have a slowed response to nutrient therapy.
8. Anoxia during birth: Patients with a history of oxygen deprivation during birth were found to have an increased probability of treatment failure.
9. Head injuries: Persons with a history of serious head injury have an increased incidence of treatment failure.
10. Substance abuse: Many nonresponding patients eventually were discovered to have been secretly abusing alcohol or illegal drugs during treatment. Serious substance abuse usually nullifies the benefits of nutrient therapy

Appendix A. Methylation

Methyl groups participate in dozens of chemical reactions in the body and brain that are essential to physical and mental health. In addition, methylation status is a major factor in a person’s personality and traits. Undermethylation is associated with perfectionism, strong will, high accomplishment, OCD tendencies, and seasonal allergies. Typical features of overmethylation include excellent socialization skills, many friendships, noncompetitiveness, artistic or musical interests, chemical and food sensitivities, and a tendency for high anxiety.

There are four primary types of methylation reactions that are essential to life:

• Methylation of Atoms: An important chemical reaction in humans is methylation of metals. For example, methylation of mercury or other toxic metals impacts the availability of the toxin to the brain and other organs, and influences the rate of excretion from the body.
• Methylation of Molecules: There are hundreds of important biochemical reactions in which a methyl group is donated to a molecule. In most cases, the reaction requires a methyltransferase enzyme. Methylation of amino acids is an important mechanism for producing a wide variety of proteins in the body.
• DNA Methylation: Gene expression (protein production) within cells is regulated by methylation at certain cytosine sites along the DNA double-helix molecule. This reaction primarily occurs at CpG sites where a guanine residue is adjacent to cytosine… connected only by a phosphorous atom. With few exceptions, CpG methylation inhibits gene expression. The relative degree of CpG methylation can determine the rate of protein synthesis in individual cells and tissues.
• Methylation of Histone Proteins: Another process for regulating gene expression involves methylation of acetylation of histones, the tiny protein aggregates that serve as structural supports for fragile DNA strands in the nucleus of every cell. Histone methylation usually occurs at lysine or arginine sites and results in compaction of the DNA, thereby restricting the access of transcription factor molecules necessary for gene expression. However, there are exceptions to this rule in which methylation at certain histone sites can promote gene expression.

Methylation Lab Testing

A person’s methyl status is affected by diet and environment but genetics is usually the dominant factor. Most methyl groups originate from dietary methionine that converts to s-adenosylmethionine, (SAMe), a relatively unstable molecule that donates methyl groups for dozens of essential methylation reactions. The production and regulation of SAMe is achieved by a complex “one-carbon cycle” or “methylation cycle” of biochemical reactions that depends on numerous enzymes that are prone to genetic mutations.

Enzymes are formed in the body by genetic expression and many of them are extremely large molecules. For example, the important MTHFR enzyme contains more than 500 amino acids and has a molecular weight exceeding 77,000. Genetic mutations usually take centuries to develop and statistically are most likely to occur in very large molecules.

The most common mutations are “single nucleotide polymorphisms” or SNPs which can cause one of the enzyme’s amino acids to be in the wrong place. For example, a cysteine may be where an arginine is supposed to reside. While many SNPs do not alter the enzyme’s function, others such as certain MTHFR mutations can markedly reduce the production of SAMe and result in an undermethylated condition. To complicate matters, overmethylation can result from inefficient utilization of SAMe, especially in the creatine pathway. Normally, more than 70% of SAMe produced in the one-carbon cycle is consumed in the production of creatine. SNP mutations in this process can result in an overabundance of unused SAMe throughout the body.

Since there are SNPs that tend to reduce methylation and others that tend to increase methylation, a patient’s overall methyl status depends on the overall combined impact of these SNPs. The popular genetic tests for MTHFR, MS, and other SNPs provide interesting information, but are qualitative in nature and limited in their ability to accurately determine overall methyl status. SNPs that reduce SAMe production are often counterbalanced by SNPs that tend toward overmethylation. Diagnosis of overall methyl status is very important in clinical treatment of mental disorders. Two lab assays that directly measure the net effect of the competing SNPs are SAMe/SAH ratio and whole-blood histamine.

The One-Carbon Cycle

A versatile methyl donor is SAMe, a molecule found in each of the trillions of cells in the human body. SAMe is produced from methionine, an amino acid present in dietary protein. A stable SAMe concentration is essential to normal embryonic development and a multitude of chemical processes throughout life. An important means for regulating SAMe levels is the one-carbon cycle, also known as the SAM cycle or the methylation cycle. This process consists of a series of chemical reactions that produce, consume, and regenerate SAMe.

• Step 1: Dietary methionine combines with adenosine triphosphate (ATP) to form SAMe. ATP is a high-energy molecule that drives the reaction with the assistance of magnesium. SAMe is a molecule that readily gives up its methyl group.
• Step 2: After giving its methyl group away, SAMe is transformed into SAH (Sadenosylhomocysteine), a molecule that can be recycled to form methionine. However, if SAH builds up to excessive levels, methylation by SAMe slows down. Therefore, it is necessary for SAH to be efficiently removed by chemical reaction to enable proper methylation capability. The gold standard test for methylation status is the ratio of SAMe to SAH.
• Step 3: In healthy persons, SAH is efficiently converted to homocysteine (Hcy) and proper methylation levels are maintained. The reaction involves removal of the adenosine group, assisted by an enzyme. Adenosine, in turn, is removed from the scene by adenosine deaminase (ADA), a zinc-containing enzyme. There is considerable evidence that the ADA enzyme reaction is abnormally weak in autism and other disorders.
• Step 4: Part of the homocysteine is recycled to methionine, with the remainder converted to cystathionine. Both of these pathways are essential to good health:
• (a) recycling to methionine assists in maintenance of SAMe levels, and (b) the cystathionine pathway is a primary source of cysteine, glutathione, and other valuable antioxidants.

The fraction of Hcy converted to methionine (or alternatively to cystathionine) depends on the level of oxidative stress present. It’s interesting to note that high oxidative stress can cause undermethylation and also that undermethylation can cause excessive oxidative stress. The presence of either imbalance can cause the other. Recycling of Hcy to methionine can be achieved by reactions with 5-methyltetrahydrofolate (5-MeTHF) and vitamin B-12. The 5-MeTHF supplies a methyl group to form methyl-B-12, which then reacts with Hcy to produce recycled methionine. This reaction is enabled by the methionine synthase enzyme. Hcy can also convert to methionine by direct reaction with trimethylglycine (TMG), a molecule that transfers a methyl group to Hcy to form methionine and dimethylglycine (DMG).

Appendix B. Oxidative Stress

Modest levels of oxidative stress are needed for several essential chemical processes, including immune function. For example, oxidative stress combats bacterial infections by surrounding bacteria with H2O2 (a powerful oxidizing agent) that kills the unwanted organisms. In another example, superoxide and nitric oxide are oxidizing agents that regulate important processes, such as controlling vascular tone.

Regulation of free radicals is accomplished by numerous antioxidant chemicals, such as glutathione, cysteine, zinc, selenium, catalase, metallothionein, and vitamins C and E. These natural biochemicals are essential to cope with environmental toxins, disease processes, and other sources of free radicals.

Conditions associated with oxidative stress include aging, heart disease, cancer, autism, Alzheimer’s, and most mental illnesses. Environmental sources of oxidative stress include toxic metals, smog, pesticides, cigarettes, nuclear radiation, and industrial waste products.

Most free radicals encountered in the body can be neutralized by glutathione, zinc, catalase, melatonin, vitamin C, etc. However, the highly aggressive superoxide free radical (O2-) requires a special deactivation mechanism.

Superoxide radicals leak from the mitochondria of all cells during natural processes and must be destroyed to avoid damage to DNA, proteins, membranes, etc. This is accomplished by a one-two punch in which a chemical known as a dismutase converts superoxide to H2O2 and O2 that can be neutralized by glutathione and other antioxidants. The primary dismutases are metalloenzymes containing copper, zinc, or manganese. Ceruloplasmin, the major copper-carrying protein in the blood, also functions as a dismutase.

Appendix C. Metallothionein

Metallothionein (MT) proteins play an important role in mental health. Poor MT function has been associated with ADHD, autism, schizophrenia, Alzheimer’s disease, and Parkinson’s disease. MT proteins perform a myriad of vital functions including the following processes:

• Early brain cell development
• Powerful antioxidant capability
• Detoxification of mercury and other toxic metals
• Reduction of inflammation after injury or illness
• Enhanced efficiency of the intestinal and blood-brain barriers
• Development and functioning of the immune system
• Delivery of zinc to cells throughout the body
• Homeostatic control of zinc and copper levels in blood
• Prevention of yeast overgrowth in the intestines
• Regulation of stomach acid pH
• Taste discrimination by the tongue
• Protection of enzymes that break down casein and gluten
• Zinc signaling in brain cells
• Regulation of tumor suppression genes
• Transcription factor regulation

The Metallothionein Family of Proteins

Metallothioneins are short, linear, cysteine-rich proteins composed of between 61 and 68 amino acids. All human MTs contain 20 cysteines and have an “S” configuration with extraordinary metal binding capability.

There are four varieties of metallothionein proteins. MT-I and MT-II are found throughout the body, and their functions include regulation of zinc and copper levels, development of neurons and synaptic connections, enhancement of immune function, and protection against toxic metals. MT-III is a necessary factor in the pruning and growth-inhibitory phases of brain cell development. MT-IV regulates stomach acid pH and enables taste discrimination by the tongue.

Synthesis of MT proteins involves genetic expression of thionein (induction) followed by loading of thionein with metal atoms. MT-I and MT-II take on seven zinc atoms, while MT-III typically contains four copper atoms and 3 zinc atoms.

MT proteins are generated in response to injury, illness, emotional stress, or exposure to toxic metals. They represent a major antioxidant system in the body.

MT proteins are found at high levels in four brain areas: hippocampus, amygdala, pineal gland, and cerebellum. The hippocampus is essential to cognition, speech, learning, memory, and behavioral control. The amygdala has a role in emotional memory and socialization. The pineal gland produces melatonin that assists sleep. The cerebellum enables smooth physical movements.

Brain Development

MT-III plays an important role in pruning of brain neurons during early development, which enables the remaining brain cells to grow and develop synaptic connections. In addition, MT-III is the primary inhibitory factor that stops the growth process when brain cells reach optimal size.

An early MT-III dysfunction would be expected to result in the following:

• Incomplete pruning
• Areas of densely packed undeveloped neurons
• Increased brain volume and head diameter

All of these phenomena have been reported in autism spectrum disorders. This understanding has led to MT-Promotion therapies aimed at completion of brain development in children. These therapies are also under development for Alzheimer’s disease since extremely low MT levels have been observed in this disorder.

Detoxification of Heavy Metals

Metallothioneins are heavy metal magnets. They bind mercury, lead, cadmium, and other toxic metals tightly and render them relatively harmless.

MT proteins work in tandem with GSH and selenium. Metal atoms are transferred into thionein by reduced GSH to form Zn7MT. However, glutathione disulfide (GSSG) enables the release of zinc in exchange for another atom, for example, mercury, cadmium, lead, or copper. The cellular redox state of GSH determines the direction of zinc transfer.

When more than 10% of reduced GSH has been converted to GSSG (oxidized GSH), the GSSG activates MT to enable its participation in sequestering toxic metals. In essence, GSH is the first defense against mercury and other heavy metals, and MT joins the fray after GSH levels have been significantly depleted.

Selenium increases the kinetics of mercury transfer into MT by about 50%. Optimal protection against toxic metals requires proper amounts of GSH, MT, and selenium.

Intestinal and Blood-Brain Barriers

MT-I and MT-II are present in very high concentrations in intestinal mucosa, forming a barrier to penetration of mercury, lead, and other toxins into the portal blood stream. With respect to toxic metals, the expression leaky gut often means a failure of MT to function normally. In healthy persons, toxic metals in the diet are sequestered in mucosal MT, which is sloughed off every 5 to 10 days to be left harmlessly in the stool.

MT proteins are in high concentration at the blood-brain barrier (BBB) and represent the primary protection against toxic metals from entering the brain. In addition, MT proteins within the brain assist in sequestering any toxins that penetrate the BBB. It has been estimated that in healthy adults, 90% of mercury in the diet is prevented from entering the portal blood stream that flows to the liver. In the liver, MT, GSH, and other antioxidants bind to about 90% of the mercury that has penetrated the intestinal barrier. The MT in the BBB is believed to be about 90% efficient in stopping mercury’s access to the brain.

However, if MT function is weak or disabled, toxic metals can wreak havoc in the brain by altering neurotransmitter synthesis, destroying myelin, producing inflammation, increasing oxidative stress, and, in some cases, killing brain cells. Two studies have indicated MT levels are less than one-third of the normal concentration in Alzheimer’s patients, and this may be a factor in the relentless death of brain cells in this disease.

Metallothionein and the GI Tract

The highest concentrations of MT proteins in the body are in the GI tract. An important role of MT in the intestines is the donation of zinc for synthesis of the enzymes carboxypepidase A and aminopepidase, which are needed to break down casein, gluten, and other proteins from food. Zinc is also required for proper functioning of dipeptidyl peptidase-IV, which breaks down gliadin, casomorphins, and other proline-containing proteins. A significant impairment in MT function could cause incomplete breakdown of casein, gluten, casomorphins, etc., which could result in severe food allergies.

MT is an important defense mechanism against intestinal inflammation and diarrhea. In addition, MT proteins kill Candida and tend to prevent yeast overgrowth. Stomach parietal cells are rich in MT-IV proteins that promote formation of hydrochloric acid (HCl). MT-IV on the surface of the tongue enables taste discrimination.

Metallothionein and Immune Function

MT proteins are the primary vehicle for delivery of zinc to cells, and zinc deficiency can severely impair the immune system.

Weak MT activity can result in a premature transition from cell-mediated immunity to humoral response and can result in a decreased amount of circulating T cells. MT also enhances immune function through its role as an efficient scavenger of free radicals. When the body is under attack by bacteria or viruses, macrophages and neutrophils work overtime to destroy the invaders. Once they have engulfed and killed an intruder, excess hydrogen peroxide is left behind, and MT is effective in mopping up this toxic oxidizing chemical.