Neurons and Exercise

Neurons and Exercise

Saturday, March 21, 2020

Aluminum, Mercury, and Genetics as Causal Factors of ADHD

Aluminum, Mercury, and Genetics as Causal Factors of ADHD
Dennis N. Crouse 2/24/2020 Draft from book I am currently writing
Research has made it clear that environmental factors modulate the symptomology of those with a genetic predisposition to attention deficit hyperactivity disorder (ADHD). Herein is a review of how this research has cast light on mechanisms that explain why both environmental aluminum and mercury are modulators and thereby causal factors of ADHD.
Sometimes anecdotal information forces us to ask: Why? The following anecdotal information was received shortly after publishing the book “Silica Water the Secret of Healthy Blue Zone Longevity in the Aluminum Age”18:
1.      “My son has been on Fiji water for about 5 months, and his ADHD is basically gone. We saw a change in him after one week on Fiji. He had ALL the symptoms of ADHD to the max. He had little control over his physical movements or his emotions. But that has really changed since the Fiji.” Nov. 2018

2.      “Personally, I have used Acilis silica water for my child who has ADHD and monitored any changes. As you may know silica rich water removes accumulated aluminium from the body. I can now say after several months of use my son who is 12 has gained better focus to the point where he is refusing to use ADHD medicating presently (which I am monitoring). He feels he can now focus without it, and so far, I have had no indication from school to negate that. He has improved in his self-regulation, his skin is less dry and minor eczema and dry scalp have gone. After some dietary research it has been noted he is no longer craving aluminium affected foods which he did previously. So, I believe he has been affected by aluminium toxicity” Aug. 2019
These two reports from the U.S. and U.K. indicate that by drinking one of two different silica waters, Fiji with 124ppm of orthosilicic acid (OSA) or Acilis with 88ppm of OSA, the symptoms of ADHD are significantly diminished. This review of the scientific literature answers the question: “Why can drinking silica water rich in OSA decrease the symptoms associated with ADHD?”   
Diagnosis of ADHD
A diagnosis of ADHD depends on meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition’s (DSM-V 2013) criteria for symptoms of ADHD1. Criteria for symptoms of ADHD have remained about the same since 1995 when the fourth edition was published. In DSM-V ADHD is defined as a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity that “interfere with or reduce the quality of performance in important life domains”1. Formerly in DSM-IV an ADHD diagnosis was characterized by the same symptoms but required “clinically significant impairment”. In 2009 ADHD was the most common psychiatric disorder among children with 3 – 4 fold increased prevalence in males2. Although usually diagnosed in childhood, 60% of these ADHD cases persist into adulthood3. Those diagnosed with ADHD are divided into three presentations:
·         Predominantly inattentive presentation
·         Hyperactive-impulsivity presentation
·         Combined presentation – at least 6 inattentive and 6 hyperactive-impulsive symptoms
Because of this variety of presentations among individuals diagnosed with ADHD, more than just one neurotransmitter/hormone system must be involved4. The primary factors in the development of ADHD are generally accepted to be the failed ability of several monoamine systems in the brain to produce sufficient serotonin, dopamine, norepinephrine, epinephrine and/or acetylcholine2,5.
Pharmacology of ADHD
Based upon the insufficient monoamine premise underlying ADHD, the pharmaceutical industry has demonstrated to the satisfaction of the US Food and Drug Administration (FDA) that certain manmade chemicals (i.e. drugs) that impact these monoamine systems can be used to treat the symptoms ADHD. These drugs do not increase the total number of monoamine neurotransmitter molecules in the brain, instead these drugs provide palliative relief by blocking transporters of monoamine neurotransmitter molecules in the brain and thereby inhibiting reuptake of monoamine transporters in certain locations. For example Ritalin, Adderall, and Strattera all potentiate norepinephrine by blocking its transporter and thereby inhibiting its reuptake. Unfortunately, most of these drugs have serious side effects and the process of reuptake inhibition may deplete monoamine neurotransmitters/hormone throughout the body5. These factors lower the efficacy of these drugs through the course of treatment.
Genetic Component of ADHD
Twin, adoption, and molecular genetic studies all have shown that ADHD is heritable and therefore has genetic components2,6-8. A genetic variant in the gene (SLC6A2) that encodes the norepinephrine transporter (NET) has been found. This genetic variant has an abnormal T allele at nucleotide 3081 that reduces gene expression of NET by 50% in individuals with this polymorphism. This genetic variation in expression of NET significantly increases the risk for ADHD6. A genetic variant in the gene (SLC5A7) that encodes the presynaptic choline transporter (CHT) is found in 6% of the human population. This genetic variant encodes a substitution of valine for isoleucine at position 89 resulting in a CHT polymorph that exhibits only 50-60% of the maximal rate of normal choline uptake7.  This genetic variation in CHT lowers acetylcholine production and significantly increases the risk for ADHD, particularly in children with the combined presentation2. 
Epidemiology of ADHD
Epidemiology studies indicate that the prevalence of an ADHD diagnosis in young children is increasing in the U.S. and worldwide. Using The National Survey of Children’s Health (2007-2008, 2011-2012, and 2016) it was found that 1% of U.S. children aged 2 to 5 had an ADHD diagnosis in 2007-2008, 1.5% had an ADHD diagnosis in 2011-2012, and 2.0% had an ADHD diagnosis in 20179,10. This data is consistent with a study of insurance claims for children 2 to 5 receiving clinical care for ADHD showing a similar increase from 2008 to 201411. All of these increases in the U.S. were seen during a period of time when there was no change in the criteria for symptoms of ADHD published in the DSM IV and DSM V. The worldwide pooled prevalence of ADHD is also rising with 5.29% of children in 2007, 5.9-7.1% in 2012, and 7.2% in 201412-14.     
Environmental Causal Factors of ADHD
Assuming this increase in ADHD as seen in epidemiology studies is real, then the cause of ADHD must have an environmental component as a genetic change due to one or more mutations does not move through  the population fast enough to account for the increased prevalence of ADHD. Identifying causal environmental factors of ADHD requires brain analysis and a mechanism accounting for how environmental factors cause the pathology seen in those with ADHD.  Clues would include the identification of one or more environmental factors that lower the biosynthetic production of the four monoamine neurotransmitters in the brain: serotonin, dopamine, norepinephrine, and acetylcholine, in addition to the monoamine hormone epinephrine (a.k.a. adrenaline). All of these monoamines are biosynthesized in the body from three amino acids: L-tryptophan (TRP), L-phenylalanine (PHE), and L-serine (SER). These three amino acids are among the 20 amino acids that are made into proteins by our body. The biosynthesis from TRP, PHE, and SER of monoamine neurotransmitters/hormone in the body is shown in figures 1-3.
Aluminum Causes THB Deficiency
Without sufficient THB as a cofactor for either the enzymatic conversion of TRP to 5-HTP (figure 1) or PHE to L-DOPA (figure 2), the production of serotonin, dopamine, norepinephrine, and epinephrine will decrease. In addition, without sufficient THB the level of PHE in the blood will increase (figure 2).  An elevated level of PHE in the blood is in some cases associated with ADHD symptomology15.and in other cases with phenylketonuria (PKU) symptomology16. PKU is an inherited genetic condition involving lower levels of the enzyme phenylalanine hydroxylase. This results in impaired breakdown of PHE to L-tyrosine (TYR) in the liver that also leads to detrimental PHE accumulation in the brain16.  It was found that 57% of those diagnosed with PKU responded to THB treatment lowering their PHE levels by at least 20%. Of those who responded to THB treatment, 32% had ADHD symptoms prior to treatment and 85% of these were not on medication for ADHD. After 13 weeks of THB treatment there was a significant improvement in the attentiveness score of the 32% with ADHD symptoms as compared to the group given a placebo15.   
When THB is used as a cofactor in the conversions diagrammed in figures 1 and 2 it is oxidized to DHB (dihydrobiopterin).  In order to maintain levels of THB, the body regenerates THB from DHB with either of two enzymes: dihydrobiopteridine reductase (DHPR) and dihydrofolate reductase (DHFR)17. An enzyme is a protein that facilitates the conversion of chemicals and in this case two enzymes can facilitate the regeneration of THB from DHB. Both of these enzymes have active sites where DHB can bind and be more easily reduced to THB. This process of regenerating THB from DHB is diagrammed in figure 4. 
Aluminum is an environmental pollutant whose production is increasing exponentially worldwide18. Because of this, worldwide aluminum exposure is also increasing exponentially18 and could be a causal factor of ADHD accounting for the increasing rate of ADHD in the U.S. and worldwide. Aluminum inhibits regeneration of THB by reducing the activity of DHPR by 40%19,20. What inhibits DHPR also likely inhibits DHFR as both of these enzymes have similar amino acid sequences at their active sites. Both of these amino acid sequences involve the amino acids tyrosine (TYR) and lysine (LYS) separated by three amino acids21. Aluminum is known to bind tightly with both TYR and LYS22. Therefore aluminum likely inhibits DHFR as well as DHPR.
When aluminum inhibits the regeneration of THB from DHB there is a less THB. Less THB results in less production of both 5-hydroxytrypthophan (5-HTP) and L-DOPA (see figures 1 and 2). Since 5-HTP and L-DOPA are the precursors of serotonin, dopamine, norepinephrine, and epinephrine, the question is: does administration of 5-HTP and L-DOPA reverse the symptoms of ADHD? Just such a protocol was tested with 85 patients, aged 4-18 years, diagnosed with ADHD. The results published in 2011 demonstrated that the efficacy of this protocol appears superior to some ADHD prescription drugs5.  This work supports the contention that environmental pollutants, such as aluminum, that reduce the activity of DHPR and DHFR and thereby lower DHB to THB regeneration, may be a casual factor of ADHD.
Lower than normal THB levels in the cerebrospinal fluid is a characteristic of several neurodevelopmental disorders, including autism (ASD)23-25. Children diagnosed with ASD compared with normal children have 42% lower than normal THB levels in the cerebrospinal fluid25. ASD is symptomatically a clinically heterogeneous neurodevelopmental disorder. Some children with ASD have a high rate of executive function problems, inattention, and hyperactivity and these ADHD-like symptoms suggest dopamine and norepinephrine deficits26-28. The DSM-V diagnostic criteria permit ADHD to be diagnosed in conjunction with ASD1. In the past it was felt that ADHD symptoms were always better explained by the child’s autism.
By administering drugs that are designed to increase dopamine and norepinephrine levels, these ADHD like behaviors are mitigated in some children diagnosed with ADHD and ASD29,30.  Therefore it is not surprising that oral administration of THB as Kuvan has been shown to improve these behaviors of some children with ADHD and ASD15,31. Also administration of a chelator of aluminum (desferoxamine) reverses DHPR inhibition by aluminum in humans20. Since drinking silica rich water has been shown to lower aluminum in all major organs of the body, including the brain, it is not surprising that drinking silica rich water also improves these behaviors in some children with ASD18 and ADHD (see anecdotal information in the introduction). Recently much higher than normal levels of aluminum has been found in the brains of those diagnosed with ASD32. Currently levels of aluminum have not been tested in the brains of those diagnosed with ADHD.
Aluminum Causes SAM Deficiency
There is experimental evidence that acetylcholine increases the response to major stimuli of cortical circuits in the brain while suppressing minor background stimuli and enhancing encoding of memory for specific stimuli resulting in improved attention33. Therefore acetylcholine improves attention and an attention deficit will be observed when its biosynthesis is inhibited.  The biosynthesis of acetylcholine requires three molecules of SAM (S-adenosyl-methionine, SAMe) to trimethylate each molecule of 2-aminoethanol to choline (figure 3). Also the biosynthesis of epinephrine from norepinephrine requires SAM (figure 2) and the enzyme phenylethanolamine N-methyltransferase (PNMT).
Aluminum inhibits the activation of methionine synthase, an enzyme involved in SAM biosynthesis, thereby lowering availability of SAM and decreasing production of acetylcholine and epinephrine34,35. SAM also increases the half-life of PNMT by protecting it from degradation36. Aluminum inhibition of SAM biosynthesis results in less PNMT and less epinephrine. This inhibition by aluminum may be reversed by drinking silica rich water18. 
Aluminum Inhalation Increases the Prevalence of ADHD
A study of 65 aluminum welders revealed above normal levels of aluminum in their urine and serum when compared with 25 mild steel welders. Concentration and memory difficulties were the two most prevalent symptoms among the aluminum welders. The severity of these symptoms correlated with urine and serum aluminum levels (P-values 0.005 and <0.001 respectively) 37. These attentional deficits seen in adult welders due to the inhalation of aluminum vapor is also seen in children of mothers who smoked during pregnancy. Tobacco and cannabis contain aluminum, as much as 3.7mg per gram, and it is vaporized, inhaled, and absorbed by the lungs during smoking38. A study of 209 preschool children in New York found that maternal smoking during pregnancy was associated with an increased risk of ADHD39.  In a second case-control study of 222 children it was found that maternal smoking during pregnancy increased the odds of ADHD40.    
Mercury Inhibits Acetylcholine Biosynthesis  
Inorganic mercury ions (Hg2+) inhibit the biosynthesis of acetylcholine at concentrations of 1 micromolar by inhibiting the enzyme, choline acetyltransferase (ChAT)41. Organic methylmercury chloride (MMC) at concentrations of 20 micromolar has also been shown to inhibit ChAT and lower both choline uptake and the production of acetylcholine in vitro42.  Both organic and inorganic mercury had no effect on cholinesterase activity. This result proves that lower levels of acetylcholine are due to ChAT inhibition by mercury and not increased acetylcholine metabolism. Chronic in vivo treatment of rats with MMC lowers acetylcholine levels in their brains43. In vivo mercury inhibition of ChAT is reversed with mercury chelators, such as 2,3-dimercapto-propanol (BAL)39. This inhibition by organic and inorganic mercury can also be reversed by taking a daily selenomethionine supplement44.
Mercury Inhibits AADC and Serotonin Biosynthesis
Inorganic mercury ions (Hg2+) from mercuric acetate and organic methylmercury chloride (MMC) at a level of 100 micromolar have both been shown to inhibit AADC (aromatic amino acid decarboxylase) an enzyme required for biosynthesis of three monoamine neurotransmitters and serotonin45. Because of this it is not surprising that chronic treatment of rats with MMC lowers serotonin levels in their brains43. 
Mercury Exposure Increased the Prevalence of ADHD
A meta-analysis of epidemiology studies looking at the association between ADHD and environmental mercury exposure during embryo and early infancy found the odds of ADHD being 1.6 fold greater among those exposed to organic (methylmercury chloride) and inorganic (Hg2+) environmental mercury46.  
This meta-analysis also found exposure to Thiomersal (a.k.a. mercury((o-carboxyphenyl)thio)ethyl sodium salt) used clinically to protect vaccines from biological contamination had no associated risk of ASD or ADHD65. This finding is supported by fact that the rate of ASD in the U.S. continues to climb exponentially despite elimination of Thiomersal from routine childhood vaccines in the summer of 200118.
Aluminum, used as an adjuvant in vaccines, is a much more likely candidate for being a causal factor of the recent dramatic rise in the rates of ASD18 and possibly ADHD.  Aluminum (inhaled, ingested, and injected), environmental organic (e.g. methylmercury chloride), and environmental inorganic (e.g. Hg2+) mercury exposures are casual factors of ADHD as described herein. 
Although a casual factor of ADHD is genetics, this does not explain a two fold increase in ADHD prevalence seen in the decade between 2007 and 2017 using diagnostic criteria published in 2013 with no change in ADHD symptoms from diagnostic criteria published in 1995. This increased prevalence of ADHD suggests that environmental factors are modulating the severity of ADHD symptoms, resulting in the doubling of diagnosed cases of ADHD. The two environmental factors that have been implicated by scientific research as causal factors of ADHD are aluminum and mercury. The data linking these environmental factors to ADHD and a mechanism showing how these factors modulate monoamine systems in the brain is presented in this review of the recent scientific literature. There are two recommended ways to reverse the effects of these two environmental factors:
·         Silicic (e.g. OSA) rich drinking water for aluminum detox and facilitated aluminum elimination in the urine and sweat36
·         Selenomethionine supplementation for mercury detox and facilitated mercury elimination in the urine44          
These treatments are proven safe by multiyear daily use and involve only supplementing substances normally found in our bodies18,47. These treatments remove the environmental causes of ADHD and offer hope that ADHD can be treated in some cases without drugs. Palliative relief of ADHD symptoms with THB as Kuvan, 5-HTP, L-DOPA, and SAM supplementation is possible, but taking these supplements does not remove causal factors and these supplements have numerous undesirable side effects48-52.   

11.   American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder V, Fifth Edition. Text Revised. Washington, DC: American Psychiatric Association; (2013)
2.   English, B.A., et al.; Choline transporter gene variation is associated with attention-deficit hyperactivity disorder; J. Neurodevelopment Disord.; 1:252-63 (2009)
3.   Spencer, T., et al.; Nonstimulant treatment of adult attention-deficity / hyperactivity disorder; Psychiatr. Clin. North Am.; 27:373-83 (2004)
4.   Pliszka, S.R., et al.; Catecholamines in attention-deficit hyperactivity disorder: current perspectives; J. Am. Acad. Child Adolesc. Psychiatry; Mar.; 35(3):264-72 (1996)
5.   Hinz, M., et al.; Treatment of attention deficit hyperactivity disorder with monoamine amino acid precursors and organic cation transporter assay interpretation; Neuropsych. Dis. Treatment; 7:31-8 (2011)
6.   Kim, C-H, et al.; A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder; PNAS; Dec.; 103(50):19164-9 (2006)
7.   Okuda, T., et al.; Single nucleotide polymorphism of the human high affinity choline transporter alters transport rate; J. Biol. Chem. 277:45315-22 (2002)
8.   Langer, I., et al.; Twin and sibling studies using health insurance data: The example of attention deficit / hyperactivity disorder (ADHD); PLOS One; Apr.; 8(4):1-8 e62177 (2013)
9.   Danielson, M.L., et al.; A national profile of attention-deficit hyperactivity disorder diagnosis and treatment among US children aged 2 to 5 years; J. Dev. Dehav. Pediatr.; Sept.; 38(7):455-464 (2017)
10. Danielson, M.L.; et al.; Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. children and adolescents, 2016; J. Clin. Child Adolesc. Psychol.; 47(20:119-212 (2018)
11. Vissar, S.N., et al.; Cital signs: National and state-specific patterns of attention deficit / hyperactivity disorder treatment among insured children aged 2-5 years – United States, 2008-2014;  Morbidity and Mortality Weekly Report; 65(17):442-50 (2016)     
12. Polanczyk, G., et al.; The worldwide prevalence of ADHD: A systematic review and metaregression analysis; Am. J. Psychiatry; 164:942-948 (2007)
13. Willcutt, E.G.; The prevalence of DSM-IV attention-deficit hyperactivity disorder: A meta-analytic review; Neurotherapeutics; 9:490-9 (2012)
14. Thomas, R., et al.; Prevalence of attention-deficit / hyperactivity disorder: A systematic review and meta-analysis; Pediatrics; 135(4):e994-e1001 (2015)
15. Burton, B., et al.; A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with apropterin-responsive phenylketonuria; Mol. Genetics Metab.; 114:415-24 (2015)
16. Scriver, C., et al.; The hyperphenylalaninemias; The metabolic and molecular bases of inherited disease; McGraw-Hill, New York, pp. 1015-75 (1995)   
17. Crabtree, M.L.; Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling; J. Biol. Chem.; Oct.; 284(41):28128-36 (2009)
18. Crouse, D.N.; Silica water for healthy blue zone longevity in the aluminum age; Etiological Publishing (2018)
19. Leeming, R.J. and Blair, J.A.; Dialysis dementia, aluminum, and tetrahydrobiopterin metabolite; Lancet; 1:556 (1979)
20. Altmann, P., et al.; Serum aluminum levels and erythrocyte dihydropteridine reductase activity in patients on hemodialysis; N. Engl. J. Med.; Jul.; 9:317(2):80-4 (1987)
21. Fischer, M., et al.; The biosynthesis of folate and pterins and their enzymology; 7.15 Comprehensive Natural Products II; (ii) Dihydropteridine reductase; Chem. Biol.; 7:599-648 (2010)
22. Bohrer, D., et al.; Interaction of aluminium ions with some amino acids present in blood; Amino Acids; Aug.; 27(1):75-83 (2004)
23. Blair J.A., Leeming R.J.; Tetrahydrobiopterin metabolism, neurological disease and mental retardation. In: Dobbing J., Clarke A.D.B., Corbett J.A., Hogg J., Robinson R.O. (eds) Scientific Studies in Mental Retardation. Palgrave Macmillan, London (1984)
24. Williams, A.C., et al.; CFS hydroxylase cofactor levels in some neurological diseases; J. Neurology Neurosurgery Psychiatry; 43:735-38 (1980)
25. Tani, Y., et al.; Decrease in 6R-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients; Neurosci. Lett.; 181:169-72 (1994)
26. Bramham, J., et al.; Executive functioning differences between adults with attention deficit hyperactivity disorder and autistic spectrum disorder in initiation, planning and strategy formation; Autism; 13:245-64 (2009)
27. Corbett, B.A., et al.; Examining executive functioning in children with autism spectrum disorder, attention deficit hyperactivity disorder and typical development; Psychiatry Res.; 166:210-22 (2009)
28. Jahromi, I.B., et al.; Positive effects of methylphenidate on social communication and self-regulation in children with pervasive development disorders and hyperactivity; J. Autism Dev. Disord.; 39:395-404 (2009)
29. Troost, P.W., et al.; Atomoxetine for attention-deficit / hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study; J. Child Adolesc. Psychopharmacol.; 16:599-610 (2006)
30. Posey, D.J., et al.; Open-label atomoxetine for attention-deficit / hyperactivity disorder symptoms associated with high-functioning pervasive developmental disorders; J. Child Adolesc. Psychopharmacol.; 16:599-610 (2006)
31. Frye, R.E., et al.; Tetrahydrobiopterin as a novel therapeutic intervention for autism; J. Am. Soc. Exp. NeuroTherapeutics; 7:241-49 (2010)
32. Mold, M., et al; Aluminum in brain tissue in autism; J. Trace Elements in Med. Biol.; March; 46:76-82 (2018)
33. Hasselmo, M.E. and McGaughy, J.; High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation; Prog. Brain Res.- Chapter 15; 145:207-30 (2004)
34. Waly, M., et al.; Activation of methionine synthase by insulin-like growth factor-1 and dopamine: at target for neurodevelopmental toxins and thimerosal; Mol. Psychiatry; 9:358-70 (2004)
35. Waly, M. I-A., and Deth, R.; Neurodevelopmental toxins deplete glutathione and inhibit folate and vitamin B12-dependent methionine synthase activity – a link between oxidative stress and autism; FASB J.; 22:894 1 (2008)
36. Ciaranello, R.D.; Regulation of phenylethanolamine N-methyltransferse; Biochem. Pharm.; 27(15):1895-7 (1978)
37. Riihimaki, V., et al.; Body burden of aluminum in relation to central nervous system function among metal inert-gas welders; Apr.; Scand. J. Work Environ. Health; 26(2):118-30 (2000)
38. Exley, C., et al.; Aluminum in tobacco and cannabis and smoking related disease; Am. J. Med.; 118:276 (2006)
39. Nomura, Y., et al.; Prenatal exposure to maternal and paternal smoking on attention deficit hyperactivity disorders symptoms and diagnosis in offspring; J. Nerv. Ment. Dis.; 198:672-8 (2010)
40. Motlagh, M.G., et al.; Severe psychosocial stress and heavy cigarette smoking during pregnancy: an examination of the pre- and perinatal risk factors associated with ADHD and Tourette syndrome; Eur. Child Adolesc. Psychiatry; 19:755-64 (2010)  
41. Nunes-Tavares, N., et al.; Toxicity induced by Hg2+ on choline acetytransferase activity from E. electricus electocytes: the protective effect of 2,3-dimercapto-propanol (BAL); Med. Sci. Monit.; Apr.; 11(4):BR100-5 (2005)
42. Kobayashi, H., et al.; Effects of methylmercury chloride on various cholinergic parameters in vitro; J. Tox. Sci.; 4:351-62 (1979)
43. Hrdina, P.D., et al.; Effects of chronic exposure to cadmium, lead, and mercury on brain biogenic amines in the rat; Res. Comm. Chem. Path. Pharmacol.; 15:483-93 (1976)
44.  Li, Y-F, et al.; Organic selenium supplementation increases mercury excretion and decreases oxidative damage in long-term mercury exposed residents from Wanshan, China; Environ. Sci. Technol.; 46:11313-18 (2012)
45. Tunnicliff, G., and Wood, J.D.; The inhibition of mouse brain neurotransmitter enzymes by mercury compounds and a comparison with the effects of hyperbaric oxygen; Comp. Gen. Pharmacol.; 4(13):101-5 (1973)
46. Yoshimasu, K., et al.; A meta-analysis of the evidence on the impact of prenatal and early infancy exposures to mercury on autism and attention deficit/hyperactivity disorder in the childhood; Neurotoxicology; Sep.; 44:121-31 (2014)
47. Duffield-Lillico, A.J., et al.; Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial; J. National Cancer Inst.; Oct.; 95(19):1477-81 (2003)
48. Gleich, G.J.; Eosinophilia Myalgia Syndrome; NORD National Organization for Rare Disorders; Rare Disease Data Base
49. Foster, H.D., and Hoffer, A.; The two faces of L-DOPA: benefits and adverse side effects in the treatment of encephalitis lethargica, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis; Med. Hypothesis; 62(2):177-81 (2004)
50. Berigan, T.R.; A case report of a manic episode triggered by S-adenosylmethionine (SAMe); Primary Care Companion; J. Clin. Psychiatry 4(4):159 (2002)
51. Kagan, B.L., et al.; Oral S-adenosylmethionine in depression: A randomized, double-blind, placebo-controlled trial; Am. J. Psychiatry; 147(5):591-5 (1990)
52. Da Vanna, and Rigamonti, R.; Oral S-adenosyl-L-methionine in depression; Current Therapeutic Res.; 52(3):478-85m (1992)