Deficit Hyperactivity Disorder (ADHD)
ADHD is a chronic neurobehavioral mental-health disorder with functional
impairments as a result of concentration/attention or impulsivity/hyperactivity.1
The disorder affects one in every 20 Canadian children, and is thought
to be multifactorial, resulting from interactions of early childhood
learning, genetic expression, dietary intake, and neurotoxic pollutant
exposure during development. Diagnosis per the Diagnostic
and Statistical Manual of Mental Disorders 4th ed. (DSM-IV)
criteria requires the presence of six of nine characteristic behaviors
that significantly affect at least two areas of the patient's life
for a period greater than six months.2 DSM-IV criteria identify
three subtypes of ADHD: Primarily inattentive (ADHD/I), primarily
hyperactive-impulsive (ADHD/HI), and combined (ADHD/C). New developments
in the understanding of ADHD show the need not only to diagnose
but also to treat it based on the identification of these distinct
subtypes.3,4 While the etiology of ADHD is not clearly understood,
it is believed that environmental pollutants may be contributing
to a potentially increasing incidence of this debilitating disorder.5
Naturopathic treatment seeks to identify the root cause of disease,
and ADHD is no exception. Food sensitivities are addressed through
the elimination of common allergenic foods and additives ubiquitous
in processed foods. Genetic methylation deficits can be addressed
by administration of methylcobalamin and folic acid. Identification
and treatment of increased heavy-metal burden is clinically more
challenging, due in part to the lack of standardized diagnostic
testing and well-defined reference ranges. However, given that an
increasing volume of evidence implicates heavy metals and environmental
pollutants as a contributing factor in ADHD, it is important that
NDs consider this in their assessment and treatment plans.
Diagnosis of ADHD is often first made in school-aged children (age
six through nine years), with prevalence rates ranging from 4% to
12% of all school-aged children in North America.6 In the US, 4.2%
of children of ages four to fifteen (equivalent to 1.8 million children)
have ADHD and are treated with stimulant medications.7 Among schoolchildren,
males show predominance, with a diagnostic prevalence ratio of between
2:1 and 4:1 over females.8
Studies on the etiology of ADHD reveal an inheritable component
related to neurobiological deficits in the prefrontal cortex and
related subcortical regions, resulting in the dysregulation of dopaminergic,
serotonergic, and noradrenaline neurotransmitter systems.9-11 There
are a number of pharmacological treatment options based on the effects
of the release/inhibition of neurotransmitters, including stimulants
(methylphenidate, amphetamine, modafinil, pemoline), selective norepinephrine/serotonin
reuptake inhibitors (atomoxetine), antidepressants (bupropion, desipramine),
nicotinic agents (nicotine analogs), and antihypertensives (clonidine,
guanfacine).3 An estimated 30% to 50% of children with ADHD either
do not respond to or do not tolerate treatment with these stimulants.12
In addition, recent pharmaco-epidemiologic studies demonstrate that
compliance with stimulants is poor, with less than 10% of patients
still taking prescribed medications after one year.13-15 Both the
medical community and the public have expressed concern about the
severalfold increase in prescriptions of stimulant medications for
children over the past decade16,17 and the potentially serious physical
and social side effects of these medications.18-21 Unquestionably,
ADHD is a common disorder in Canada; and its negative burden on
individuals, their families, and society as a whole is profound.
There is a great need for exploration of the elements that contribute
to ADHD and into related strategies to prevent and mitigate this
Environmental Pollutants and ADHD
An expert committee from the US National Research Council found
that 3% of developmental disabilities are a direct result from exposures
to environmental pollutants, and a further 25% extend from genetic
susceptibilities to environmental factors.22 Currently, there is
no comprehensive analysis on the role of environmental pollutants
and ADHD. There is a wide base of evidence linking environmental
toxins with ADHD, and we believe that there are associations between
certain pollutants and the development, prognosis, and treatment
of ADHD. The following discussion on two heavy metals and exposure
to tobacco smoke serves to provide preliminary evidence signifying
the importance of these associations and to highlight specific exposures
to consider in the assessment and treatment of ADHD.
Heavy Metals and
In chemistry, the term heavy metal is currently used to describe
metals (and by extension, metalloids) commonly associated with contamination
and potential toxicity or ecotoxicity. Lead, mercury, arsenic, cadmium,
and manganese are examples of highly toxic heavy metals.23 Two neurotoxic
metals, lead and manganese, are associated with ADHD and are discussed
below to elucidate some of the evidence regarding the risk that
heavy metals pose to children and their neurological development.
Lead: Evidence is building that links exposure to lead with the
development of ADHD. In a recent cross-sectional study of 150 children
from Michigan aged 8 to 17, blood lead levels were found to be significantly
higher in ADHD/C than in non-ADHD control children.24 Of note is
that this was demonstrated amongst a subject population with lead
levels still defined as "low" by the Centers for Disease
Control (<5 µg/dL). This is the first study to correlate
ADHD with "low" blood lead levels (<5 µg/dL)
comparable to levels found in the general population (1-2µg/dL).
The study also supports previous findings that have confirmed a
linear association between higher blood lead levels >10 µg/dL
and symptoms of ADHD.24 While higher lead levels have been shown
to correlate with lower IQ, the apparent link to ADHD and lead appeared
independent of this effect on IQ. This study also found that there
was no correlation of maternal blood lead levels and child ADHD
diagnosis or symptoms, indicating that critical exposure was likely
to have occurred postnatally.24 Potential sources of lead include
paint from toys, enameled or ceramic pots, dishware that may be
improperly glazed, drinking water from pipes of old houses, as well
as paint from old houses, fertilizers, fungicides, and herbicides
(in the form of lead arsenate). Renovation work, especially where
floors, walls, and ceilings are torn up, may provide a source of
lead exposure in older homes.
Konofal and Cortese have hypothesized that iron supplementation
may be beneficial in cases of lead toxicity due to a neuroprotective
role of iron.25 When researchers gave 80 mg/d ferrous sulfate to
23 nonanemic children (ferritin levels >30 ng/mL) who met DSM-IV
criteria for ADHD, there was a progressive and significant decrease
in symptoms of ADHD as measured by the ADHD Rating Scale.26 The
iron hypothesis is supported by the fact that lead in the central
nervous system contributes to a dopaminergic dysfunction, which
may also disrupt the structure of the blood-brain barrier. However,
as iron supplementation may protect the integrity of the blood-brain
barrier against lead insult, it is suggested that iron deficiency
could potentiate the toxic effects of lead.27 Alternately, it is
hypothesized that lead may also contribute to iron deficiency by
reducing iron's bioavailability. Lead also affects neurotransmitter
pathways via decreased heme synthesis and consequent increased levels
of the precursor, d-aminolevulinic acid (ALA), which in turn suppresses
GABA-mediated neurotransmission.28 Regardless of the mechanism,
given the potential impact of iron status on ADHD, these children
ought to be screened for iron deficiency.
Manganese: In trace amounts, manganese is an element required for
proper physiological function via its role as an enzymatic cofactor.
At higher doses, however, manganese can become highly toxic. Although
the evidence for lead is much stronger, it is important to consider
the potential for this lower-profile element to be a contributing
factor in a child's diagnosis of ADHD. Current knowledge of manganese
neurotoxicity is based on occupational inhalation exposure, resulting
in an extrapyramidal syndrome, characterized by symptoms of gait
dysfunction with a propensity to fall backward, postural instability,
bradykinesia, rigidity, micrographia, masked facies, speech disturbances,
and muscle tremors. Clinical and subclinical effects of intoxication
have also been implicated and involve the striatal dopaminergic
system through GABA and serotonin imbalances. In a Quebec community,
a pilot study of 46 children ranging from 6 to 15 years old found
that higher exposure to manganese in well-water, reflected by higher
manganese levels in hair, was positively correlated with hyperactive
behaviors.29 It is interesting to note that girls had significantly
higher levels than boys (mean 6.3 ± 4.4 µg/g vs. 4.0
± 4.0 µg/g).
Manganese also exerts a strong inhibitory effect on iron absorption.
As iron deficiency is correlated with ADHD symptoms, the possible
confounding effect by iron also deserves examination for investigating
the impact of manganese in children with ADHD. As with lead, toxic-metal
induced decreases in iron absorption may also represent an indirect
mechanism by which manganese exerts its deleterious effects.
Assessment of Heavy
In addition to direct blood testing of lead levels, lead may be
assessed through provocative urine testing with DMSA and EDTA, and
potentially hair mineral analysis.30 Reference ranges for hair lead
in adults is 0-7.2 nmol/g; however, no ranges are given for children,
since no lead level is considered safe in children.31 There are
currently no established reference ranges for provocative urine
testing; ranges depend on the laboratory used and appear based on
normal (that is, unchallenged urine levels). Blood tests are recommended
for lead in children, with alert levels being >0.12 µmol/L
for whole blood samples in children under 16 years. Alert level
for erythrocyte lead concentration is >0.27 µmol/L. Urine
is not recommended for manganese testing; however, there are no
current reference ranges for manganese blood or hair measures.31
Tobacco Smoke and
In a cross-sectional analysis, the National Health and Nutrition
Examination Survey found that exposure to prenatal tobacco, as well
as environmental lead, was a clear risk factor for ADHD.7 In this
study, a representative sample, 4.2% of 4704 children (ages 4 through
15) were reported to have ADHD. While the highest levels of lead
were shown to be linked to ADHD incidence, prenatal exposure to
tobacco smoke was also significantly associated with ADHD.
The heritability of genetic factors contributing to the ADHD phenotype
is considered to be 65 to 90%, and interactions between the genotype
and the environment can be decisive.32 In a prospective longitudinal
study of 305 subjects from birth to age 15, it was confirmed that
children homozygous for the 10-repeat allele of the common dopamine
transporter (DAT1) polymorphism, who were also exposed to prenatal
tobacco smoke, had much higher hyperactivity-impulsivity than children
without this combination of environmental and genetic risk factors.32
Maternal prenatal smoking was assessed during a standardized interview
when infants were three months old, and postnatal smoking was assessed
periodically during child development via interview. At 15 years
of age, subjects were genotyped for the DAT1 40bp polymorphism variable,
and assessed for inattention, hyperactivity-impulsivity, and oppositional
defiant/conduct disorder symptoms. There was a significant interaction
between the DAT1 genotype and prenatal smoke exposure as well as
an association in males with prenatal smoke exposure who were homozygous
for the DAT1 10r allele and with higher hyperactivity-impulsivity
levels (p = 0.012).32 This supports the hypothesis of environmentally
moderated risk for ADHD, and that effects can depend on genetic
susceptibility operating through gene-environment interactions.
to Environmental Pollutants
Children at all stages of growth, and especially during fetal development,
are uniquely vulnerable to toxins in the environment.5 Not only
are they more physiologically susceptible to the effects of pollutants,
but the rate of uptake of these agents can be greatly increased
as well. More important than increased exposure levels, however,
is the developmental heterogeneity that exists in children, and
their potential vulnerability at critical junctures in neurological
development.26,27 Rapid and profound physiological changes are experienced
by the growing child, and this is greatly magnified in utero. The
potential for environmental pollutants or other xenobiotics to cause
irreversible damage upstream in a child's neurological development
is a risk much greater than that for a fully grown adult. The effects
of exposure to toxins on early embryological development from well-established
examples like alcohol and thalidomide are well known and acknowledged.
However, our understanding of the health impacts from the myriad
chemicals synthetically produced and in the environment is still
Although the role of the environment on health has recently been
receiving more attention, awareness and continued efforts need to
be directed towards prevention and decreased exposure to environmental
pollutants. While screening and assessment of exposure to these
harmful chemicals is a basic first step towards better patient care,
little formal research has been conducted on successful means of
decreasing the levels or effects of these toxins in children.
One small noncontrolled study demonstrated a decrease in serum (162%)
and urine (132%) levels of lead in non-ADHD children with the use
of 15g of modified citrus pectin (MCP) split into three 5-mg doses/day
over 28 days.28 No adverse effects were reported in participants
in this study, although allergy to MCP, changes to electrolyte levels,
and potential for constipation or fluid loss have been identified
as possible side effects.29
As mentioned above, treatment of children with ADHD using 80 mg/day
of ferrous sulphate may also help decrease the impact of lead or
other heavy metals on the severity of symptoms in ADHD.30
Representing a somewhat more "naturopathic" approach,
a small uncontrolled prepilot study of ten children previously diagnosed
with both ADHD and autistic spectrum disorder investigated the effect
of a comprehensive treatment protocol, consisting of nutritional,
environmental, and chelation interventions, on decreasing symptoms
associated with these conditions.31 Specifically, the protocol used
in the study included a mix of therapeutic interventions. First
of all, environmental control was advised, by which avoidance of
mold, tobacco smoke, pesticides, cosmetics, and cleaners was to
be maintained during the study. Other suggestions included an organic
rotation diet free from food additives and salicylates, and low
in refined sugar; a gluten-free, casein-free diet in patients with
sensitivity to these proteins (8/10 tested positive to food allergens
on IgG testing); gastrointestinal support including probiotics and
digestive enzymes; injections 1 to 3 times per week with methylcobalamin
and glutathione; and chelation therapy with IV EDTA, DMPS, and glutathione,
administered 1 to 2 times per week for a total of 10 to 20 treatments.
Antigen injection therapy and nutritional supplementation were also
part of the program. This comprehensive protocol was followed for
3 to 6 months. Provocative urinary metal testing was performed at
baseline and upon completion of the study. None of the children
took psychotropic medications during the study, but other behavioral
and special education interventions were continued. The results
of the trial indicate that the treatment protocol was associated
with significant reductions in urinary lead levels (high at baseline
for all participants) and significant clinical improvements in all
ten of the children. In addition to reduction in urinary lead levels,
patients had a large though not statistically significant drop in
urinary levels of mercury, cadmium, and aluminum. Comparison of
motor, behavioral, and education capacity by parents, teachers,
and the treating physician(s) from baseline to completion of the
study found improvement in all ten children. Four were able to return
to regular classroom education, and eight showed dramatic improvements
in verbal skills by study end.31
Although small and uncontrolled, this study is important in that
it represents the combined effect of an integrated intervention
protocol, rather than a single-agent intervention. While not standard
practice, the interventions utilized in the study are reflective
in many ways of the eclectic treatment approach commonly employed
by naturopathic doctors and integrative medical practitioners who
treat ADHD. Certainly, larger controlled studies are needed to further
investigate these interventions; however, this study begins to provide
compelling evidence on a holistic approach to treating children
With respect to heavy metal reduction, chelation as a treatment
approach for ADHD is still very much unestablished. Chelating agents
have a proven use for treating heavy-metal toxicities, yet their
immediate impact on cognition or behavior in ADHD children is limited,32
with no statistically significant improvements being observed more
than 4 years posttreatment.33
A number of studies have noted relative deficiencies in detoxification
enzymes (superoxide dismutase, paronaxase34, glutathione peroxidase35,
and sulphation enzymes36) and nutrients pertaining to liver detoxification
pathways37 (methionine, s-adenosyl methionine, cysteine, glutathione)
in children with autistic or autistic-spectrum disorders; these
studies may not be applicable to children who have ADHD with heavy
metal toxicities. It does seem reasonable that an increased ability
to process or remove environmental toxins may benefit children with
ADHD who have demonstrated an elevated burden, although there is
a paucity of research on this topic.
Other treatments with historical or theoretical uses that may address
toxic exposure to heavy metals include adrenal extract, algin, arrowroot
(Maranta arundinacea), blue flag (Iris versicolor), calamus (Acorus
calamus), colloidal silver, copper, Essiac, ground ivy (Glechoma
hederacea), liver extract, hydrotherapy, kudzu (Pueraria lobata),
marshmallow (Althaea officinalis), melatonin, organic food, ozone
therapy, reflexology, SAMe, spirulina, urine therapy, and vitamin
C.38 As yet, these interventions are not well supported by the evidence,
and they should be undertaken with caution, or avoided in lieu of
treatments with greater evidence to support their use.
Faced with a child with ADHD, if an etiology of heavy metal toxicity
is suspected, it is essential to balance potential benefit with
risk before engaging a process of therapeutic elimination. Chelation
with synthetic chemicals, nutritional supplements, or herbal agents
is not without risk, especially in the pediatric population. Issues
to consider include the fact that a child's organs of elimination
(most relevantly the kidneys and liver) are still developing and
may be adversely affected. In addition, the possibility of mobilizing
heavy metals resulting in redistribution to more sensitive tissues
(such as the brain) without adequate clearance is also a real concern.
Finally, the toxicity of the chelating agents, herbal or synthetic,
must also be carefully considered and weighed against possible benefits.
In general, the increased understanding of epigenetics and ontogeny
is clarifying the ways in which our chemical environment might influence
early development through gene-environment interactions. The role
of such factors as heavy metals and environmental tobacco smoke
in this interaction and subsequent disease evolution deserves much
further consideration, particularly with respect to ADHD. The role
of NDs is to identify and address the root cause of disease. Whether
root cause is dietary, genetic, environmental, or a combination
thereof, naturopathic doctors' ability to assess and influence contributing
factors will translate into more effective preventative and holistic
Dugald Seely ND, MSc
Director, Research & Clinical Epidemiology
The Canadian College of Naturopathic Medicine
1255 Sheppard Ave East
Toronto, Ontario M2K 1E2
416-498-1255, ext. 387
Seely ND, MSc, is a naturopathic doctor and director of research
at the Canadian College of Naturopathic Medicine (CCNM). Dr. Seely
is developing research suited to assess environmental impacts on
health as well as therapies used by NDs and the system of naturopathic
medicine as a whole. Dr. Seely is the principal investigator for
a number of clinical trials and is actively pursuing relevant synthesis
and clinical research in the area of environmental influences on
health with a focus on cancer prevention. Author of over 25 peer-reviewed
publications, Dugald is the editor-in-chief for the International
Journal of Naturopathic Medicine and is dedicated to helping
build the research capacity within the naturopathic profession.
Cooley, ND, MSc (Cand.), is an assistant professor and research
fellow at CCNM. Dr. Cooley is committed to fostering an evidence-based
approach to naturopathic medicine as well as fostering a culture
of inquiry and innovation through research. He has co-conducted
several clinical trials on naturopathic care for chronic low back
pain, stress and anxiety, and chronic shoulder pain, as well as
collaborating with various institutions to evaluate natural health
products. Currently he is investigating the effect of a natural
health product in children with attention deficit hyperactivity
disorder, and is receiving cross-training at the Center for Addiction
and Mental Health in Toronto in the diagnosis and management of
ADHD in children. He also has contributed to systematic reviews
and cost-effectiveness studies on complementary and alternative
medicines. As assistant professor, he mentors students and assists
in student research endeavors. Dr. Cooley's research interests include
whole systems research, evidence-based naturopathic medicine, clinical
trials, and mental health disorders in children.
Heidi Fritz, ND, MA
(Cand.), is a graduate of CCNM and a research associate with its
Department of Research and Clinical Epidemiology. Dr. Fritz completed
her undergraduate studies in physiology and English at the University
of Toronto, where she is also pursuing her master's degree in English.
Dr. Fritz is developing her skills in synthesis research at CCNM
and is practicing at the Bronte Naturopathic Clinic in Milton, Ontario.
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