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Attention Deficit/Hyperactivity Disorder (ADHD) in children: Rationale for its integrative management

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Attention Deficit/Hyperactivity Disorder (ADHD) is the most common behavioral disorder in children. ADHD is characterized by attention deficit, impulsivity, and sometimes overactivity ("hyperactivity"). The diagnosis is empirical, with no objective confirmation available to date from laboratory measures. ADHD begins in childhood and often persists into adulthood. The exact etiology is unknown; genetics plays a role, but major etiologic contributors also include adverse responses to food additives, intolerances to foods, sensitivities to environmental chemicals, molds, and fungi, and exposures to neurodevelopmental toxins such as heavy metals and organohalide pollutants. Thyroid hypofunction may be a common denominator linking toxic insults with ADHD symptomatologies. Abnormalities in the frontostriatal brain circuitry and possible hypofunctioning of dopaminergic pathways are apparent in ADHD, and are consistent with the benefits obtained in some instances by the use of methylphenidate (Ritalin) and other potent psychostimulants. Mounting controversy over the widespread use of methylphenidate and possible life-threatening effects from its long-term use make it imperative that alternative modalities be implemented for ADHD management. Nutrient deficiencies are common in ADHD; supplementation with minerals, the B vitamins (added in singly), omega-3 and omega-6 essential fatty acids, flavonoids, and the essential phospholipid phosphatidylserine (PS) can ameliorate ADHD symptoms. When individually managed with supplementation, dietary modification, detoxification, correction of intestinal dysbiosis, and other features of a wholistic/integrative program of management, the ADHD subject can lead a normal and productive life.
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Page 402 Alternative Medicine Review
Volume 5 Number 5 2000
Parris Kidd, PhD (Cell biology, University of California at Berkeley) – Contributing Editor, Alternative Medicine Review;
Health educator and biomedical consultant to the supplement industry. Correspondence address: 847 Elm St, El Cerrito,
CA 94530
Attention Deficit/Hyperactivity Disorder
(ADHD) in Children: Rationale for Its
Integrative Management
Attention Deficit/Hyperactivity Disorder (ADHD) is a loosely defined assemblage of
neuropsychiatric symptom clusters that emerge in childhood and often persist into adulthood.
Though the means to its diagnosis is only empirical, ADHD increasingly is being employed as
a diagnostic label for individuals who display a wide range of symptoms, such as restlessness,
inability to stay focused, mood swings, temper tantrums, problems completing tasks,
disorganization, inability to cope with stress, and impulsivity.
The etiology of ADHD is not
understood, yet potent drugs are being employed for its medical management while safe and
Parris M. Kidd, PhD
Attention Deficit/Hyperactivity Disorder (ADHD) is the most common behavioral disorder
in children. ADHD is characterized by attention deficit, impulsivity, and sometimes
overactivity (“hyperactivity”). The diagnosis is empirical, with no objective confirmation
available to date from laboratory measures. ADHD begins in childhood and often persists
into adulthood. The exact etiology is unknown; genetics plays a role, but major etiologic
contributors also include adverse responses to food additives, intolerances to foods,
sensitivities to environmental chemicals, molds, and fungi, and exposures to
neurodevelopmental toxins such as heavy metals and organohalide pollutants. Thyroid
hypofunction may be a common denominator linking toxic insults with ADHD
symptomatologies. Abnormalities in the frontostriatal brain circuitry and possible
hypofunctioning of dopaminergic pathways are apparent in ADHD, and are consistent
with the benefits obtained in some instances by the use of methylphenidate (Ritalin
and other potent psychostimulants. Mounting controversy over the widespread use of
methylphenidate and possible life-threatening effects from its long-term use make it
imperative that alternative modalities be implemented for ADHD management. Nutrient
deficiencies are common in ADHD; supplementation with minerals, the B vitamins (added
in singly), omega-3 and omega-6 essential fatty acids, flavonoids, and the essential
phospholipid phosphatidylserine (PS) can ameliorate ADHD symptoms. When
individually managed with supplementation, dietary modification, detoxification,
correction of intestinal dysbiosis, and other features of a wholistic/integrative program
of management, the ADHD subject can lead a normal and productive life.
Altern Med Rev
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 403
effective alternatives are being neglected.
ADHD is the most prevalent behavioral
disorder in children,
and frequently its
symptoms are commingled with learning
problems, oppositional conduct, and
depression, which altogether compound the
family’s emotional burden. Particularly since
the dominant mode of treatment to date has
involved the drug methylphenidate (Ritalin
which acts on the CNS much like cocaine and
has marked potential for severe side-effects
and addictive abuse, ADHD has become a
lightning rod for controversy. The scientific
literature on ADHD is voluminous, with more
than 4,000 peer-reviewed articles published
since 1966.
An intense debate has developed
around the diagnosis, etiology, and medical
management of ADHD. Parent groups, con-
sumer advocacy organizations, and progres-
sive physicians are calling for alternatives to
methylphenidate and the many other potent
stimulants used to treat ADHD, while phar-
maceutical interests and physicians particu-
larly oriented to prescribing pharmaceuticals
attempt to defend the status quo (currently in
the United States, between 1.5 million and 3
million ADHD children are likely taking me-
thylphenidate). This review is intended to bring
the medical and scientific issues surrounding
ADHD into sharper focus, to better define a
wholistic/integrative strategy for its medical
Background and Scope of the
ADHD Problem
A condition in children somewhat re-
sembling ADHD was first described by Still
in 1902.
He discussed 43 cases of children
with aggression, defiance, emotionality, lim-
ited sustained attention, and deficient rule-gov-
erned behavior. Although his population pos-
sessed normal intellectual capacity, he com-
mented, “...the control of activity in confor-
mity with moral consciousness is markedly
defective.” He suggested, “inhibitory volition,”
that is, the capacity to exercise good judgment,
might be imperfectly developed in these sub-
jects. From 1940 through 1960, the condition
was identified with “minimal brain damage or
dysfunction,” and its etiology was speculated
to be insults to the brain such as head injury,
infection, and toxic damage.
In the 1960s it
became “hyperactivity” or “poor impulse con-
trol,” reflecting that no underlying organic
damage had been identified.
By the 1970s-1980s, the “hyperactiv-
ity” symptomatology had taken on more di-
agnostic significance in comparison with the
other symptoms. In 1980, the American Psy-
chiatric Association’s Diagnostic and Statisti-
cal Manual of Mental Disorders, Third Edi-
tion (DSM-III) listed the term “hyperkinetic
reaction of childhood,” which then evolved
through “hyperkinetic syndrome” and “hyper-
active child syndrome,” to “attention deficit
disorder” (ADD), either “with hyperactivity”
or “without hyperactivity.” By 1987, in the
revised DSM-III (DSM-III-R), the earlier fo-
cus on hyperactivity had shifted toward inat-
tention and impulsivity.
As the research on ADHD progressed,
the balance between the three major diagnos-
tic symptom clusters was subsequently further
refined, so that in the 1994 DSM-IV the offi-
cial term was Attention Deficit/Hyperactivity
Disorder, or ADHD, with three subtypes.
attention and impulse control are now regarded
more as the cardinal defects than is hyperac-
Some professionals continue to reserve
the term ADD for children who are only inat-
tentive and ADHD for children who are also
hyperactive, but all official reports or other
records are required to use ADHD.
ADHD is usually diagnosed in school-
age children, and is conservatively estimated
to occur in 3-6 percent of this population from
diverse cultures and geographical regions.
In some U.S. cities the percentage may reach
10-15 percent.
As of 1993, more than two
million U.S. children were diagnosed ADHD,
Page 404 Alternative Medicine Review
Volume 5, Number 5 2000
the number having increased steadily from
902,000 in 1990. Currently, as many as four
million carry this diagnosis, which is respon-
sible for 30-50 percent of the referrals to men-
tal health services for children.
ADHD estimated prevalence ranges from 1.7-
10.0 percent in Canada, Puerto Rico, the
United Kingdom, Norway, the Netherlands,
Germany, and New Zealand.
ADHD rou-
tinely continues into adolescence, and also can
persist into adulthood in as many as half of
those individuals who manifest the disorder
in adolescence.
The adverse social, familial, and per-
sonal consequences of ADHD cannot be over-
stated. Most ADHD subjects develop emo-
tional, social, and family problems as a con-
sequence of their primary difficulties. ADHD
is a major problem both for society and for
the child, as it causes friction in school or at
the workplace, depresses the academic perfor-
mance of the student’s entire class, interferes
with peer relationships, and increases intra-
family stress. For the individual afflicted, un-
til ADHD symptomatologies can be recog-
nized and brought under medical management,
daily existence is likely to be severely com-
promised along with the lives of those around
him (or her, although ADHD is more preva-
lent in boys by a 3:1 margin).
Parents and
children express desperation for interventions
that will work, but without the adverse effects
inflicted by the pharmaceutical management
The first report of stimulant use to treat
ADHD was in 1937.
The current overwhelm-
ing reliance on methylphenidate and other
stimulants for ADHD treatment belies the
ample evidence that ADHD symptomatologies
can be ameliorated without the use of drugs.
This degree of reliance on methylphenidate is
unfortunate because its action is virtually iden-
tical with cocaine, to such an extent that in the
United States it is a Schedule II controlled
The frequent practice of maintaining
ADHD subjects on methylphenidate over
many years increases the potential for its abuse.
In fact, it is fast becoming a “street drug”
among teenagers.
The controversies over
methylphenidate use and the ever-increasing
frequency of ADHD diagnosis are now so po-
liticized that they are interfering with society’s
urgent need to better serve the children (and
adults) involved. Fortunately, a balanced ex-
amination of the available scientific and clini-
cal evidence reveals an improved prognosis for
The Diagnosis and Progression of
No matter how well trained the physi-
cian may be in this area, making the diagnosis
of ADHD is anything but straightforward. No
“hard” clinical tests—physical, laboratory, or
neurological—are available with which to
unequivocally correlate the symptoms. Rather,
the definitive diagnosis must be deduced from
a highly detailed clinical history, as synthe-
sized from information provided by parents,
teachers, and (last but hopefully not least), the
afflicted individual.
The conscientious cli-
nician will do an in-depth parent and patient
interview along with a physical examination,
solicit corroborative information from adults
in other settings (especially teachers), and ob-
tain an assessment of academic functioning.
Many clinicians use standardized rating scales
in order to assess the age- and sex-matched
relative symptom severity.
For U.S. practitioners official ADHD
diagnostic guidelines are found in the DSM-
IV, which is related to the World Health
Organization ICD-9 and ICD-10 categories.
In North America, ADHD is viewed as a
common but heterogeneous developmental
disorder linked with diverse co-morbidities. By
contrast, in Europe the diagnosis (i.e., of
hyperkinetic syndrome) is reserved for ADHD
uncomplicated by co-morbid
psychopathology. With this relatively narrow
definition the condition becomes relatively
rare, but the European perspective appears to
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 405
be gradually shifting toward that of North
The symptoms of ADHD are most of-
ten first recognized by the child’s teacher.
ADHD children have difficulty sitting still,
maintaining their attention on the task at hand,
and thinking through their answers before they
respond to questions. Although ADHD is dis-
tinctly different from learning disability per
se, the behavioral features that define this dis-
order—short attention span, distractibility,
impulsivity, overactivity—occur on a con-
tinuum across the population, thus the ADHD
diagnosis requires thorough consideration of
the severity of the symptoms and the relative
degree of functional impairment.
ADHD per DSM-IV is diagnosed in
five major steps, each with specific criteria.
The symptoms must appear before age seven,
persist for at least six months, and appear in
the school environment as well as the home.
The first step is to establish EITHER (a) ab-
normal and persistent inattention, from at least
six symptoms continuing over a minimum six
months, OR (b) abnormal and persistent hy-
peractivity-impulsivity, also from at least six
symptoms over six months. The second step
is to establish that these symptoms were
present before seven years of age. Third, these
symptoms must be present in two settings,
usually at school (or work, if an adult) and at
home. Fourth, there must be clear evidence of
“clinically significant impairment in social,
academic, or occupational functioning.” The
fifth criterion is exclusionary—that the symp-
toms not be secondary to some other disorder.
Whereas some of the ADHD symptomatolo-
gies can be linked to family changes (e.g., di-
vorce) or other life events (e.g., head trauma),
ADHD typically begins early in life, is chronic,
and is pervasive.
Once the basic ADHD diagnosis is es-
tablished per the above-described criteria,
three subtypes can be differentiated.
These are
(1) ADHD, combined type, applied where both
inattention and hyperactivity-impulsivity—(a)
and (b) above—are extant for at least 6 months;
(2) ADHD, predominantly inattentive type, if
only the inattention criteria are met; and (3)
ADHD, predominantly hyperactive-impulsive
type, if only the hyperactivity-impulsivity cri-
teria are met. There is also a DSM-IV crite-
rion of ADHD In Partial Remission, for indi-
viduals (usually adolescents or adults) who
exhibit only some of the required symptoms
but are otherwise experiencing significant
functional impairment. Then come the assess-
ments for the learning disabilities and other
neurologically based disorders with which
ADHD is often associated.
Between 30-40 percent of ADHD sub-
jects have learning disabilities,
but the
ADHD child is not mentally retarded and can
be realigned toward a productive life path. To
help make this possible the physician and the
other professionals involved must work closely
with parents and teachers to assess the child
as a total individual. They must objectively
discern the entire range of difficulties the child
is experiencing, and make the degree of com-
mitment necessary to treat the child
wholistically with all the resources available.
Unfortunately, the current norm for ADHD
management is to do a minimal psychological
assessment, then prescribe methylpheni-
Other neurobiological difficulties en-
countered in the ADHD population are motor
tic disorder or Tourette’s disorder, anxiety dis-
order, anger control problems, and depres-
Some children will have two, three,
or more of these difficulties without having
ADHD, but Biederman studied a large popu-
lation of ADHD children and found that more
than half also had depression, anxiety, and
conduct disorder.
The clinician must there-
fore verify, document, and prioritize these vari-
ous symptom clusters, both to assess their rela-
tive contributions to the child’s apparent
ADHD patterns and to develop means for their
medical management concurrently with
Page 406 Alternative Medicine Review
Volume 5, Number 5 2000
ADHD Medical Management—
Current Status
The conventional management of
ADHD formally involves a multimodal ap-
Currently, this approach in-
cludes individual and family education, coun-
seling, behavioral therapy, school remediation,
and medication.
Close coordination between
the subject, the family, the practitioner and the
school system ought to be integral to this ap-
but in mainstream pediatric practice
medication with pharmaceuticals is practically
the sole component of medical management.
Typically, it falls on the family of the afflicted
child to implement additional modes of man-
agement that have proven effectiveness, such
as clearing allergies, regulating the diet, and
supplementing with nutrients.
Psychostimulant medications are gen-
erally the first choice in medication of ADHD.
Approximately 70 percent of the children
treated show improvement in the primary
ADHD symptoms and in co-morbidity such
as conduct disorder,
although the benefits
may not hold beyond two years. Currently,
methylphenidate is the drug of choice; other
first-line stimulants include dextroamphet-
amine (Dexedrine
) or a mixture of four salts
of dextroamphetamine (Adderall
second-line stimulants include methamphet-
amine (Desoxyn
or the longer-lasting
Desoxyn Gradumet
), or pemoline (Cylert
which causes hepatotoxicity in about three
percent of subjects treated and can cause death,
so must be closely monitored. In practice, the
use of any of these stimulants is so fraught
with uncertainties and potential complications
that only the most intrepid practitioners pre-
scribe them with comfort.
The psychostimulants ought to be se-
verely limited in their applicability, due to their
marked and sometimes severe adverse ef-
Decreased appetite secondary to anor-
exia or nausea may occur, leading to weight
loss. Insomnia may also occur, as can head-
ache. Lowering the dose and changing the tim-
ing may eliminate these side-effects. Rarely,
psychostimulants may cause tics to develop,
and cases of leukopenia and psychosis have
been reported.
Methylphenidate (Ritalin),
dextroamphetamine (Dexedrine), and Adderall
are all classified as Schedule II agents in the
U.S., consonant with their significant abuse
As blood levels of the stimulant
decrease over time, irritability may manifest
as a “rebound” type of withdrawal symptom.
Some subjects are very prone to abus-
ing stimulants and must be placed on non-
stimulant, alternative medications. A subgroup
with more depression and anxiety may respond
better to tricyclic antidepressants (imipramine,
desipramine) than to stimulants,
both can have major adverse effects, with de-
sipramine linked to sudden death.
The anti-
depressant bupropion (Wellbutrin“) can, like
the stimulants, exacerbate an underlying tic
disorder. This drug is also contraindicated in
children with anorexia nervosa, bulimia, or
epilepsy. ADHD subjects have a higher risk
of moving into drug abuse,
and there is now
a trend toward placing ADHD children on
, withdrawal from which has been
linked to violence and other possibly disas-
trous outcomes.
Certain non-stimulant medications can
serve as allopathic alternatives in ADHD when
stimulants have failed. Among these are the
alpha-adrenergics clonidine (Catapres
) and
guanfacine (Tenex
). Both are less well vali-
dated than the stimulants and not as effica-
cious. Clonidine can cause sedation and dys-
phoria, and both of these drugs require blood
pressure monitoring because they are also
The psychological disorders that often
coexist with ADHD also require management.
The more serious of these include tics or
Tourette’s syndrome; depression, including the
bipolar type which is quite prevalent; anxiety;
and obsessive-compulsive disorder. For chil-
dren who have tic disorders, extreme
overactivity, oppositional or conduct disorder,
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 407
or hyperarousal, clonidine may prove useful.
ADHD also can be associated with impulse
control problems more extreme than the usual
ADHD spectrum; sometimes antipsychotics
are prescribed, although their risks outweigh
their advantages.
In summary, pharmacologic
management of ADHD and the coexisting con-
ditions can challenge even the most experi-
enced practitioner, and safer modes of man-
agement are urgently indicated for this unfor-
tunate patient population.
Ritalin—Its Benefits and Risks
The continuing status of methylpheni-
date, or Ritalin, as the single-most common
intervention for the symptomatic management
of ADHD is the basis for considerable,
oftentimes bitter disagreement and contro-
versy. The author considers methylphenidate
to be a highly cerebroactive pharmaceutical
that offers symptomatic benefit in ADHD but
carries high potential for abuse and possible
life-threatening effects over the long term.
Ritalin and Ritalin-SR
preparations of methyl-alpha-phenyl-2-
piperidineacetate hydrochloride.
Methylphenidate acts on the central nervous
system with a dopamine-agonistic effect that
is slower in onset but mechanistically almost
identical to cocaine and amphetamines.
Advocates of methylphenidate attest that it
works more effectively than any other single
intervention to enhance attention span and
impulse control.
Yet methylphenidate does
not consistently benefit academic
performance. Opponents of the drug (along
with some of its advocates) point to its many
serious adverse effects,
and many critics
argue that children should not be put at risk
for the known major adverse effects of a
drug that is virtually banned for use by
adults. Methylphenidate also has potential
for abuse, and the abuse pattern is very
similar to cocaine and amphetamines.
A majority of ADHD children—up
to 70 percent of those treated—do seem to de-
rive a degree of benefit from methylpheni-
but its benefits have been overstated
and there are compelling reasons to believe
this drug is being overprescribed. Citing cred-
ible survey data, Swanson and collaborators
documented a dramatic increase in outpatient
visits for ADHD in the early 1990s, accompa-
nied by a near-tripling in Ritalin production—
in 1993, more than 2.5 million Ritalin prescrip-
tions were written for ADHD. They attributed
the markedly increased frequency of ADHD
diagnosis to heightened public awareness and
to policy changes that have forced public
schools to identify students with ADHD. But
as so many of the “mainstream” practitioners
tend to do, they dismissed the increase in me-
thylphenidate prescribing as merely “required
to meet the demand for stimulant medication.”
This intensifying confrontation is fu-
eled by the realization that methylphenidate
can (and does) exert serious adverse effects.
listed the most severe effects re-
ported in the professional literature: psychic
(hypomania, mania, delusions, paranoid delu-
sions, paranoid psychosis, toxic psychosis);
Figure 1: Methylphenidate hydrochloride
Page 408 Alternative Medicine Review
Volume 5, Number 5 2000
hallucinations, auditory and visual; exacerba-
tion of schizophrenia and autism; muteness,
extreme withdrawal, partial dissociation;
boundary loss, disorganization; nervousness,
agitation, terrifying affect, aggressiveness,
assaultiveness, anxiety, panic; drug abuse—
rebound depression, psychic dependence, in-
creased euphoria, and cocaine-like activity.
The Indiana Prevention Resource Center
culated information on the major street abuse
of methylphenidate currently occurring in In-
diana and the potential for life-threatening
When methylphenidate is used with
antidepressants (such as the tricyclics and
Prozac), seizures, hypertension, hypothermia,
and convulsions can ensue.
Over the long
term, weight loss can occur, as can scalp hair
loss, vasculitis, leukopenia, visual distur-
bances, and anemia. A no less recognized au-
thority than the Physicians’ Desk Reference
carries a long list of potential adverse reac-
tions in children and also has this to say about
“In children, loss of appetite, abdomi-
nal pain, weight loss during prolonged therapy,
insomnia and tachycardia, may
occur...Periodic CBC, differential, and plate-
let counts are advised during prolonged
therapy...Ritalin should be periodically discon-
tinued to assess the child’s condition...Drug
treatment should not and need not be
indefinite...Patients with an element of agita-
tion may react adversely; discontinue therapy
if necessary.”—Physicians’ Desk Reference,
53rd Edition, 1999, pgs. 2078-9.
The PDR section on methylphenidate
also starkly states, “Sufficient data on safety
and efficacy of long-term use of methylpheni-
date in children are not yet available...”
In 1994, U.S. Government researchers
reported that Ritalin caused liver cancer in
male mice.
The carcinogenic doses were
equivalent to just 2.5 times higher than the
highest human prescribed dose. The U.S. Na-
tional Toxicology Program has concluded that
methylphenidate is a “possible human carcino-
gen.” This revelation about methylphenidate,
taken together with the major adverse effects
of the other psychostimulants, makes it im-
perative that alternative modalities be imple-
mented for the management of ADHD.
ADHD Etiology and Contributory
ADHD is highly inhomogeneous in the
biological sense, and although classed as a
disorder it amounts to hardly more than an
assemblage of symptom clusters. Its etiology
also is far from homogeneous, with many
likely contributory factors. Certainly some of
these etiological factors generate symptoma-
tologies that closely resemble ADHD. Among
these are sensitivities to food additives, intol-
erances to foods, nutrient deficiencies and
imbalances, heavy metal intoxication, and
toxic pollutant burden. Also, evidence is
mounting that abnormal thyroid responsive-
ness, perhaps engendered perinatally by envi-
ronmental pollutants, is on the rise and pre-
disposes to ADHD.
ADHD has been linked to inherited
susceptibilities; for a critical review refer to
Findings from twin studies and
adoption studies support some degree of heri-
tability for the disorder,
though co-morbid
conditions complicate the analyses. Numerous
familial-genetic studies have documented a
higher prevalence of psychopathology, particu-
larly ADHD, in the parents and other relatives
of children with ADHD, and there is a statisti-
cally and clinically significant risk for ADHD
to occur in children where either biological
parent had onset in childhood.
cated studies confirm a higher incidence of
ADHD in the closest relative of ADHD males.
The actual degree to which genetic
heritability may predispose to childhood on-
set of ADHD is still an open question. Popu-
lation studies indicate attentional problems,
conduct problems, and emotional problems
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 409
tend to cluster within families.
Genetics and
environment are notoriously difficult to sepa-
rate within the family unit, and Fisher sug-
gested the genetic predisposition to ADHD
might fuel a negative family atmosphere that
exacerbates latent ADHD in the child.
Twin and adoption studies are gener-
ally the most precise means for estimating rela-
tive heritability of a trait. Such studies in
ADHD suggest a relatively high degree of heri-
They also suggest that rather than
being a discrete disorder, ADHD may be
viewed as the extreme end of a behavior con-
tinuum that varies genetically throughout the
Both inattention and impulsiv-
ity/hyperactivity appear to be heritable and
share a genetic component,
but no one gene
is likely to be the culprit.
Important advances have been made in
the pursuit of genes for ADHD.
To date, the
evidence for single-gene inheritance is uncon-
vincing; rather, a polygenic mode of inherit-
ance is more likely—either several strong
genes or many genes with weak effect. Genes
within the dopamine transmitter system are the
most likely to be most involved, given: (1) the
effective reduction of symptoms by dopam-
ine agonists such as methylphenidate; (2) re-
sults from brain imaging studies that impli-
cate brain structures with rich dopaminergic
innervation, such as the frontostriatal cir-
(3) early results from gene isola-
tion studies.
The heritability of the associations
between ADHD and its various co-morbid
conditions may span the entire spectrum of
possibilities. Biederman and his colleagues
suggest ADHD and major depressive disorders
may have common familial vulnerabilities.
ADHD with co-morbid conduct disorder also
may be preferentially associated, whereas the
anxiety and learning disorders may segregate
separately. ADHD relatives of patients with
ADHD do have markedly higher risk for major
depressive disorder, antisocial disorders, and
substance abuse. To date there is insufficient
data to quantify any relative degree of co-
heritability of ADHD with a trait for any of
these co-morbid conditions.
Food Additives and Food
Intolerances in ADHD
In the mid-1970s, Feingold broke new
ground with his claim that up to 50 percent of
all hyperactive children were sensitive to food
additives (artificial food colors, flavorings, and
preservatives) as well as to salicylates that
occur naturally in some foods.
basic finding of the connection between food
additives and ADHD symptomatology was not
new. As early as 1922, Shannon had published
on the successful treatment of children with
hyperactivity and learning disorders using an
elimination diet.
On this regimen 30-50 per-
cent of children improved. Most recently,
Schardt reviewed 23 double-blind studies that
examined whether food dyes or ordinary foods
worsened behavior in children with ADHD or
other behavioral problems.
In eight of the
nine studies conducted with ADHD children,
the behavior of some children worsened after
consumption of food dyes or improved on an
additive-free diet. The symptomatology of
these adverse responses mimicked ADHD.
The other 14 studies reviewed by
Schardt looked at children with ADHD plus
asthma, eczema, or food allergies, irritability
or sleep disturbances, or more severe behav-
ioral or neurological disorders. In 10 of the 14
studies, some children improved when they ate
diets free of additives or certain foods. Some
deteriorated when they ate food dyes or foods
like corn, wheat, milk, soy, oranges, eggs, or
chocolate. Schardt concluded his critique with
suggestions from experts that dietary modifi-
cation be systematically attempted before the
decision is made to place an ADHD child on a
pharmaceutical regimen.
Feingold’s original case histories
covered 1,200 pediatric cases in which food
Page 410 Alternative Medicine Review
Volume 5, Number 5 2000
additives were linked to behavioral and
learning disorders, and pointed the finger at
some 3,000 different additives, yet subsequent
research to “verify” his work focused on less
than a dozen additives. The majority of the
double-blind studies designed to test
Feingold’s hypothesis reported their outcomes
as negative, yet a careful review of the data
from these studies by Murray and Pizzorno
concluded that a full half of the children placed
on the Feingold diet in these studies actually
showed a decrease in hyperactivity.
A pattern
is evident, as discerned by
Boris: single-agent
elimination studies tended
to show limited
improvement or no
improvement at all, while
multi-agent elimination
studies were almost
universally successful.
Rippere has criti-
cized in depth
the meth-
odologies of the “double-
blind” studies conducted
by Conners and other crit-
ics of Feingold.
points out: (a) the con-
scious design of active,
potentially allergenic pla-
cebos (such as chocolate
cookies); (b) the decisions
to use dosages of test ad-
ditives lower than known
to be consumed in foods;
(c) the use of highly unre-
liable laboratory tests for
allergy determination; and
(d) formulation of impre-
cise rating scales as out-
come measures. Perhaps
the most serious criticism
by Rippere is that of inves-
tigator bias; i.e., the re-
searchers ignored study
outcome data that sup-
ported the Feingold interpretation while over-
emphasizing contrary data. Boris,
and others have con-
ducted their own studies and trials, reviewed
the cumulative data, and come out in support
of the Feingold hypothesis. It is interesting to
note that studies conducted in non-U.S. coun-
tries produced results markedly more favor-
able to the Feingold interpretation,
and that
most of the U.S. investigations were sponsored
by a corporate food lobby group, the Nutri-
tion Foundation.
Figure 2: Changes in a child’s drawing and handwriting
during the four phases of acute reaction to offending
food. Note the hostility expressed in the drawing.
From Rapp, 1996.
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 411
Food additives are big business, espe-
cially in the United States (see Murray and
Pizzorno for an overview).
There are some
5,000 additives in widespread use, including
but not limited to: anticaking agents such as
aluminosilicates; synthetic antioxidants such
as BHA and BHT; bleaching agents such as
hydrogen peroxide; colorants such as artificial
azo dye derivatives; preservatives such as ben-
zoates, nitrates, and sulfites; and many others.
Per capita daily consumption of food additives
in the U.S. is 13-15 grams, and the population’s
total annual consumption of food colors alone
is approximately 100 million pounds. Other
countries have significantly restricted artificial
food additives whereas the United States has
never done so.
The removal of artificial food color-
ings and preservatives from the diet is an in-
dispensable and practicable clinical interven-
tion in ADHD, but rarely is sufficient to elimi-
nate symptomatology. Up to 88 percent of
ADHD children react to these substances in
sublingual challenge testing,
but in blinded
studies no child reacted to these alone. Aller-
gies to the foods themselves must also be iden-
tified and eliminated. Doris Rapp, MD, a pe-
diatrician with considerable experience in this
area, has claimed that two-thirds of children
diagnosed ADHD have unrecognized food al-
lergies that generate most, if not all, of their
symptoms (see Fig. 2). These can usually be
detected and the symptoms cleared using a
simple one-week elimination diet. She has
thoroughly documented her findings in books,
professional articles, and videotapes.
Data from two double-blind studies
indicated 73-76 percent of ADHD children
responded favorably to food elimination
Maintenance on even more-restricted,
low-antigen (oligoantigenic) diets raised the
success rate to as high as 82 percent.
Invariably in these studies, reintroduction of
the offending foods led to reappearance of
Sugar intake makes a marked contri-
bution to hyperactive, aggressive, and destruc-
tive behavior.
A large study by Langseth
and Dowd found 74 percent of 261 hyperac-
tive children manifested abnormal glucose tol-
erance in response to a sucrose meal.
studies have been conducted, but industry in-
terests may have influenced their outcomes in
a manner inconsistent with good scientific re-
Wolraich and collaborators conducted
a trial on sugar and hyperactivity that was pub-
lished in the New England Journal of Medi-
cine in 1994.
The findings were portrayed by
the study investigators and the media as prov-
ing that sugar did not significantly contribute
to hyperactivity. Yet the control, “low-sugar”
diet averaged 5.3 teaspoons of refined sugar
per day, fed to children aged 6-10 years. This
“baseline” level of sugar intake is arguably so
high that the investigators should not have been
surprised the “test” group on a higher sugar
diet did not show significantly more symptoms
than the “controls.” No attempt was made to
eliminate dietary allergens such as milk, wheat,
and egg, which trigger behavioral problems
in some hyperactive children, and all the chil-
dren were allowed to consume soda drinks
during the study. At the end of their report, the
authors acknowledged their gratitude to Gen-
eral Mills, Coca-Cola, PepsiCo, and Royal
Metal Pollutants in ADHD
An amazing variety of toxins extant in
the modern environment have deleterious ef-
fects on the central nervous system that range
from severe organic destruction to subtle brain
Toxic metals are ubiquitous
in the modern environment, as are
organohalide pesticides, herbicides, and fumi-
gants, and a wide range of aromatic and ali-
phatic solvents.
All these categories of envi-
ronmental pollutants have been linked to ab-
normalities in behavior, perception, cognition,
Page 412 Alternative Medicine Review
Volume 5, Number 5 2000
and motor ability that can be subtle during
early childhood but disabling over the long
Children exposed acutely or chroni-
cally to lead, arsenic, aluminum, mercury, or
cadmium are often left with permanent neu-
rological sequelae that include attentional defi-
cits, emotional lability, and behavioral reac-
Lead is damaging to cognition and
behavior in children, and can cause develop-
mental delay and mental retardation as well.
The many studies conducted on the neurotox-
icity of lead serve rather as a model for stud-
ies with the other toxic metals. Perhaps their
most significant consensus finding is that lead
toxicity observes no threshold for causing
A meta-analysis of cognitive damage
from lead exposure concluded there was no
threshold for damage down to blood lead lev-
els of 7µg/dl,
and levels as low as 10µg/dl
have been linked to psychobehavioral deficits.
In the U.S., more than three million children
are estimated to have blood lead levels of 10µg/
dl or higher.
In addition, increased tooth den-
tine-lead and hair-lead levels have been linked
to increased distractibility and attentional defi-
cit. Tuthill’s group sampled hair lead levels
from 277 first-grade children in Massachusetts
who were diagnosed ADHD.
Hair levels
ranged from 1µg/g to 11.3µg/g, and a striking
dose-response relationship was found between
hair lead level and the likelihood of being di-
agnosed ADHD by a physician and the rated
severity of attention deficit.
Some deleterious effects ascribed to
lead may include contributions from other
metals. In ADHD subjects found to be loaded
with more than one toxic metal, whether at
high or threshold levels, the metals may be
acting in combination to increase the totality
of the toxic effect.
Thus, combinations of lead
with aluminum, lead with arsenic, lead with
cadmium, and aluminum with arsenic all have
the potential for synergistic toxicity.
documented by Marlowe and collaborators,
learning disabilities follow a pattern similar
to ADHD, with lead, cadmium, and aluminum
being the main culprits.
Lead and aluminum
seem especially synergistic, and mercury has
great potential for synergy with lead.
This growing body of pessimistic data
strongly indicate that children with ADHD
should be screened for heavy metal load, ei-
ther where prior exposure is established and/
or where other ADHD risk factors have been
ruled out. Moon and collaborators
called for
teachers to have parents complete a Metal
Exposure Questionnaire in order to assist with
this process. Where levels are found to be high,
children can be detoxified via lead chelation
therapy. David et al reported that chelation
therapy significantly improved hyperactivity,
impulsivity, conduct problems, and learning
problems in children diagnosed ADHD with
no apparent risk factors.
Environmental Illness Affects
Doris Rapp, MD, is a foremost author-
ity on environmental illness (EI) and ADHD.
For over a quarter of a century in her pediatric
practice she has documented the myriad re-
sponse patterns children can display in re-
sponse to dust, mold, or chemicals present in
their environment. Symptomatologies of hy-
peractivity and impulsivity/loss of self-control
are common. Rapp, together with a growing
number of physicians and environmentalist
scientists, believes that more and more indi-
viduals are falling prey to EI because of the
continued widespread pollution of food, wa-
ter, air, homes, workplaces, and schools.
The school environment is a major of-
fending source of EI, for adults as well as chil-
dren. Rapp
cited data that indicate 25,000,
or one-third of all U.S. schools, need exten-
sive repair or replacement due to significant
contamination with lead, asbestos, radon, or
sewage; leaking underground storage tanks;
poor plumbing or ventilation; termites; or
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 413
structural inadequacies. There are also the ad-
ditional, and at times more significant, roles
of dust, molds, indoor chemicals, foods, and
microorganisms. Placed in a contaminated
classroom environment, a child can quickly
become tired and irritable and suddenly seem
incapable of learning. According to Rapp, the
child (as well as the teacher) “can feel con-
fused, perplexed, bewildered, and depressed,
when for no apparent reason they become ir-
ritable, moody, angry, sad, aggressive, vulgar,
or can’t think clearly.”
Ironically, the adverse
effects of daytime exposure to a contaminated
school environment may not manifest fully
until the end of the day, after the child is home.
This can foster confusion between teachers and
parents about the source(s) of the offending
Nor is the home a necessarily safe,
clean, and protected environment.
cals in carpets and wall materials, dust, molds,
microorganisms, lead in paint, radon contami-
nation, and pollutants in air, water, and food
can be as offensive and toxic in some home
environments as in the worst schools. The
modern parent must be vigilant for environ-
mental insults and observant of their child,
never abdicating this responsibility to the
teacher or pediatrician, especially since most
physicians are not skilled at diagnosis of EI.
Rapp has a “Big Five” list of symptoms that,
when used before and after an adverse expo-
sure, are surprisingly effective at pinpointing
an EI response.
These are:
1. How does the child feel, behave, and
2. How does the child’s appearance change?
3. Is there any handwriting or drawing
change? (for a typical example, refer to
4. Does asthma or other breathing problem
5. Is there a change in the pulse rate or
rhythm? (especially a sudden 20-point
increase in the rate)
Rapp maintains that in many children
the signs of EI can be traced all the way back
to infancy, even as far back as in utero, where
they are hyperactive and hiccup frequently in
response to foods their mothers ate, beverages
she drank, or odors she smelled. As a child
grows the symptoms of EI may change (e.g.,
the responses to milk and other dairy products
differ between fetus, infant, toddler, child, ado-
lescent, and adult).
But these are merely
different manifestations of adverse responses
to the same food or other offending agent.
The environment surrounding the
home, school, or community may not be any
friendlier to the susceptible child. Indeed, the
entire planetary environment is now suffused
with organochlorines and other persistent or-
ganic pollutants.
Children are especially
vulnerable to these substances, as they have
higher cell-level turnover and relatively im-
mature detoxification capacities.
Children are
more susceptible to loss of brain function if
exposed to neurotoxins during critical devel-
opment periods, however low the exposure
level, as is evident from studies on irradiation,
drug, alcohol, and lead toxicities.
Pesticides capable of injuring the cen-
tral nervous system include metals, chlorinated
hydrocarbons, organophosphates, and carbam-
The so-called “inert” pesticide in-
gredients include benzene, formaldehyde, and
petroleum distillates, but all these are far from
being inert to children. Crinnion recently re-
viewed the extent to which these toxic pollut-
ants are ubiquitous in the air, water, soil, foods,
and human indoor and outdoor environments.
Children may be exposed prior to birth, and/
or after birth by ingestion, inhalation, transfer
through mothers milk or baby food, and
through skin contact.
Literally all residents of the industri-
alized countries can be shown to carry “back-
ground” levels—parts per billion to parts per
trillion—of organochlorine pollutants in their
Several studies of infants prenatally
exposed to background environmental levels
Page 414 Alternative Medicine Review
Volume 5, Number 5 2000
of organochlorine compounds demonstrated
subtle damage to the thyroid system, associ-
ated with measurable changes in
neurodevelopmental parameters.
Thyrotoxins and
Neurodevelopmental Damage
Thyroid hormones help regulate neuro-
transmitter systems—dopaminergic, noradren-
ergic, serotonergic—in the brain, and are piv-
otal to the very process of fetal matura-
Regarding the possible contributory
factors in ADHD, suspicion is growing around
a possible role for thyroid hypofunction dur-
ing early childhood development. A link be-
tween hypothyroidism during pregnancy and
diminished mental function in the offspring has
been recognized for more than 100 years,
in 1969 came the first solid indication that mild
maternal hypothyroidism could lower IQ val-
ues in the offspring.
The condition of generalized resistance
to thyroid hormone, or GRTH, features re-
duced tissue responsiveness to thyroid hor-
In children with GRTH attentional
function is abnormal,
and among this popu-
lation ADHD is very common, occurring in
46-61 percent.
Studies with animals estab-
lished that adequate thyroid system integra-
tion is required for the development of the
same brain zones found to have subtle anoma-
lies in ADHD, such as the caudate, cerebel-
lum, corpus callosum, cortex, and hippocam-
Children with ADHD have a higher fre-
quency of occurrence of GRTH (estimated at
5.4%, versus <1% for non-ADHD chil-
In 1999, Haddow and a large collabo-
rative group reported in the New England Jour-
nal of Medicine on a multi-center study that
first screened blood samples from 25,216
mothers to assess thyroid adequacy, then tested
their seven- to nine-year-old children for IQ,
attention, language, reading ability, school
performance, and visual-motor performance.
When the children from hypothyroid mothers
(untreated during pregnancy) were compared
with those of euthyroid (control) mothers, sta-
tistically significant impairments were docu-
mented for attention (WISC-III freedom from
distractibility score, Continuous Performance
Test of Conners) and school difficulties and
learning problems, along with several mea-
sures of IQ and visual-motor performance.
The emerging evidence for involve-
ment of thyroid damage in ADHD begs the
question of what factors might be responsible
for thyroid damage. Synthetic chemicals re-
leased into the environment (pesticides and
herbicides) are the main suspects, along with
industrial chemicals.
In a major review
of thyrotoxicity from chemicals, Brucker-
listed 77 chemicals proven to damage
the mammalian thyroid. Her list includes the
most ubiquitous and persistent environmental
pollutants, among them PCBs (polychlorinated
biphenyls), dioxins, furans, chlorophenols,
chlorobenzenes, phenols, and related sub-
stances, which are widespread in human tis-
sues and routinely detectable in mothers
The degrees of thyroid toxicity from
these various chemical categories can be se-
vere to mild, depending on the specifics of
exposure. Severe thyroid damage does not
appear necessary to effect developmental brain
damage; in the landmark Haddow study, mild
and asymptomatic thyroid hypofunction sig-
nificantly correlated with attentional and other
cognitive impairment in children in the U.S.
PCBs remain ubiquitous in the envi-
ronment. In 1996, Jacobson and Jacobson re-
ported in the New England Journal of Medi-
cine on their study of 212 children born to
women who had eaten Lake Michigan (USA)
fish contaminated with PCBs.
The children
were tested at 11 years of age. Prenatal PCB
exposure was significantly associated with
lower cognitive performance scores; the stron-
gest deficits were related to attention and
memory. Incidentally, this same pediatric
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 415
population evidenced reduced weight and head
circumference at the time of birth.
The Neurobiology of ADHD
Modern brain monitoring techniques
have established that ADHD can be organi-
cally expressed in the brain. Neuropsychologi-
cal assessments were the first techniques to
successfully measure alterations in frontal cor-
tical and frontal-basal ganglia information pro-
cessing in the disorder.
Ever more precise
neurochemistry, neuroimaging, and functional
neuroimaging techniques implicate these brain
regions as well.
Neurochemical studies suggest alter-
ations in catecholaminergic—mainly dopam-
inergic and noradrenergic—transmitter func-
tions markedly contribute to the symptoms of
ADHD (see Tannock
and Glanzmann
reviews). The symptoms of ADHD are signifi-
cantly ameliorated by agents that specifically
influence these neurotransmitter systems, and
animal studies implicate areas of the brain in
which these neurotransmitters are most domi-
Studies of these catecholamines and
their metabolites in the blood, urine, and spi-
nal fluid did not initially provide definitive
but with better study design there is
promise for positive results in this area.
Magnetic Resonance Imaging (MRI)
scanning can be used to reliably measure the
size of a specific brain region. Fourteen stud-
ies using volumetric analysis by MRI were
conducted on ADHD subjects and controls;
they suggest localized abnormalities in the
prefrontal cortex, basal ganglia, and corpus
callosum of children with ADHD.
Smaller frontal lobe or right prefrontal cortex
was found for the ADHD groups in all studies
that examined this measure. Five of six stud-
ies found a smaller anterior or posterior cor-
pus callosum. Four of six found loss of the
normal caudate asymmetry (left side greater
than right, see Fig. 3), and these four also found
a smaller left or right globus pallidus.
In two
more recent studies, smaller volumes of right
prefrontal cortex and of other structures in-
volved in impulse control—the caudate and
globus pallidus—correlated with deficient per-
formance on response inhibition tasks in boys
with ADHD.
Figure 3: Possible subtle brain differences in ADHD.
Asymmetry (left minus right) of glucose metabolic rate, measured using PET. The
anterior putamen (subcortical, involved with motor activity) and sylvian region (parietal,
involved with visual attention) differed significantly between girls with ADHD and
normal girls. From Ernst et al, 1997.
Page 416 Alternative Medicine Review
Volume 5, Number 5 2000
Functional/dynamic neuroimaging is a
field undergoing particularly rapid develop-
ment. The techniques include positron emis-
sion tomography (PET), single-photon PET
(SPECT), quantitative electroencephalography
(QEEG), and functional MRI (fMRI). These
help quantify brain metabolic activity and cor-
relate it with anatomical differences in the
brain, on a real-time basis. Certain QEEG
measures do consistently differ between
ADHD and normals, but their functional mean-
ing is not yet evident. Measures of event-re-
lated potentials document P300 wave differ-
ences consistent with ADHD children being
deficient in response selection and organiza-
With PET, abnormal regional blood per-
fusion is evident in the striatal region of ADHD
Zametkin obtained similar findings
in adults
but fell short of statistical replica-
tion in children.
Meanwhile, the first SPECT
study in children revealed the ADHD group
had greater overall metabolic asymmetry, with
less activity in the left frontal and left parietal
From the neurobiological studies a
consensus is emerging that motor and
attentional functions associated with the fron-
tal cortex are adversely affected in
Taken altogether, the volumet-
ric and correlational functional analyses
roughly point to the frontostriatal circuitry, and
possibly intracortical connections via the cor-
pus callosum, in the neuropsychological defi-
cits associated with ADHD. These zones are
predominantly dopaminergic, and hypofunc-
tion of dopamine pathways is a consistent fea-
ture of the disorder. The diagnostic potential
of this information is becoming evident. The
cerebellum is functionally linked with the pre-
frontal cortex, and three anatomical measures,
namely the right globus pallidus volume, cau-
date asymmetry, and left cerebellum volume,
correlate highly with ADHD in children.
overall, with the differences running as small as
five percent less than normal,
definitive con-
clusions on brain region differences in ADHD
must await further quantitative and qualitative
analyses. The rapidly increasing understanding
of the normal growth cycles of the brain should
enable better design of controlled normal vs
ADHD comparisons in this
Roles of Nutrient Deficiencies and
Nutrients are required by the brain, as
they are by every other organ, so virtually any
nutrient deficiency can impair brain function.
Assessment of ADHD children often reveals
nutrient deficiencies or imbalances which,
when corrected, result in considerable behav-
ioral and academic improvement. Little con-
trolled research has been conducted into di-
etary supplementation effects on ADHD, but
the sparse data available do indicate signifi-
cant potential for benefit in this realm. This
subject recently was reviewed by Galland.
Multiple vitamin-mineral
Dietary supplementation can improve
academic performance in healthy school-aged
children. In a series of studies that spanned 18
years and culminated in a double-blind trial,
Schoenthaler et al found that a vitamin-min-
eral supplement produced significantly less
antisocial behavior than did placebos in
healthy elementary school children and teen-
age delinquents.
Cognitive performance also
was significantly improved, but the research-
ers found no clinical improvement could be
expected unless at least one nutrient was ab-
normally low by blood test. Pyridoxine, folic
acid, thiamin, niacin, and vitamin C were the
nutrients most commonly found to be low in
children who responded to supplementation
with measurable improvement. Deficiencies of
vitamins A, E, B12, pantothenic acid, ribofla-
vin, and of minerals also were linked to bad
behavior. Improvement could not be expected
unless all deficiencies were corrected.
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 417
B Vitamins in Combination
Two early controlled trials utilized
combinations of B vitamins against ADHD and
reported no benefit.
Later, Brenner suc-
cessfully used B vitamin combinations to treat
hyperkinetic children who had not responded
favorably to Feingold’s diet.
They also found
that ADHD children responded variably to dif-
ferent B vitamins, with pyridoxine and thia-
mine antagonizing each others benefits. Treat-
ment with single B vitamins rather than com-
binations may sometimes be necessary in or-
der to normalize lowered blood levels and se-
lectively increase transmitters in ADHD; for
example, pyridoxine can be used to normalize
lowered blood serotonin.
Vitamin B6 (pyridoxine)
This vitamin might help ameliorate
hyperactivity, as indicated from widespread
physician experience and one small double-
blind trial conducted to date. Vitamin B6 is an
essential cofactor for a majority of the meta-
bolic pathways of amino acids, including de-
carboxylation pathways for dopamine, adrena-
line, and serotonin. In 1979, Coleman et al
reported that B vitamins improved the behav-
ior of some children with ADHD in a double-
blind crossover comparison with methylpheni-
Coleman’s group took note of physi-
cian observations that in some hyperactive
children blood serotonin levels are low, and
that high-dose B6 often benefited the symp-
toms while boosting serotonin into the normal
range. They investigated six children ages 8-
13, diagnosed with Hyperkinetic Reaction of
Childhood (DS-II) and known to be respon-
sive to methylphenidate. In a double-blinded,
multiple crossover trial, each child received
placebo, low and high doses of methylpheni-
date (averaging 10.8 mg/day and 20 mg/day,
respectively), and low and high doses of B6
as pyridoxine (averaging 12.5 mg/kg/day and
22.5 mg/kg/day) over 21 weeks. Blood sero-
tonin levels increased dramatically on B6, and
teacher ratings showed a 90 percent level of
statistical trend in favor of B6 being slightly
more effective than methylphenidate.
This is the most common of all nutri-
ent deficiencies in U.S. school-age children.
Iron deficiency is associated with markedly
decreased attentiveness, narrower attention
span, decreased persistence, and lowered ac-
tivity levels, which respond positively to
supplementation. An uncontrolled Israeli study
of boys with ADHD found a 30 percent im-
provement in Conners Rating Scale scores fol-
lowing iron supplementation.
According to Galland,
the magne-
sium deficiency status often observed in
ADHD is reminiscent of Latent Tetany Syn-
drome, which features lowered red cell levels
of the mineral. This disorder is believed re-
lated to three factors: inadequate dietary mag-
nesium (Mg) intake, genetic susceptibility, and
the Mg-depleting effects of catecholamines
and related stress hormones which are elevated
in the blood and urine of ADHD children. A
Polish team reported reduced Mg levels in 95
percent of a group of 116 children with
dietary supplementation with Mg
significantly decreased their hyperactivity.
Several studies conducted in different
countries have found this mineral to be low in
ADHD (for references see Galland).
zinc can be markedly below normal,
and also
urinary zinc clearance can be lower; both find-
ings suggestive of poor zinc intake and/or ab-
sorption. Findings from one placebo-con-
trolled trial suggest poor zinc status also may
predict poor response to amphetamine treat-
ment of the disorder.
Page 418 Alternative Medicine Review
Volume 5, Number 5 2000
Essential fatty acids (EFA)
These oily, vitamin-like nutrients have
shown promise in the non-pharmaceutical
management of ADHD. The two main
classes—omega-3 and omega-6—have a
complementary, “yin-yang” relationship, func-
tioning as pro-homeostatic constituents of cell
membranes and as precursors to smaller mol-
ecules (eicosanoids) that transduce informa-
tion inward to the cell interior, and outward
from each cell to influence other cells. The
longer-chain, 20- and 22-carbon species are
both crucial for prenatal and postnatal early
brain development. Some adult humans can
generate the longer-chain molecular species
from the shorter-chain, but infants are less
competent in this regard.
The C22:6 omega-
3 (docosahexaenoic acid, DHA) and the C20:4
omega-6 (arachidonic acid, AA) are
homeostatically balanced in human mothers
milk, and both are now added to infant feed-
ing formulas.
One reliable symptom of EFA defi-
ciency in both animals and humans is exces-
sive thirst (polydypsia), without matching
polyuria. Colquhoun and Bunday,
with the Hyperactive Children’s Support
Group of the United Kingdom, were the first
to report that children with hyperactivity were
significantly more thirsty (and without com-
parable polyuria) than children who were not
hyperactive. Mitchell et al
measured plasma
fatty acids in 44 hyperactive children and 45
matched control subjects, and found the hy-
peractive children had significantly lower con-
centrations of DHA, AA, and the AA precur-
sor DGLA (dihomo-gamma linolenic acid,
C20:3 omega 6). Stevens et al
extended these
promising results, and Stordy correlated the
symptoms with omega-3 deficiencies and
learning disabilities.
Stevens and her collaborators at Indi-
ana University measured plasma and red cell
fatty acid levels in 53 boys with ADHD and
43 controls, aged 6-12 years.
They also took
detailed histories, compared clinical symptom
patterns, and tracked daily dietary EFA intakes.
They confirmed Mitchell’s earlier report
lowered plasma concentrations of DHA and
AA (but not of DGLA); and found plasma
eicosapentaenoic acid (EPA, C20:5 omega 3)
was decreased, as was red cell arachidonic
acid. As tracked by the parents, the ADHD
group had significantly greater thirst, fre-
quency of urination, and dry skin—all indica-
tors of EFA deficiency—than did the control
Within the ADHD group, a sub-
group with higher scores for EFA deficiency
also had the lowest levels of plasma EFA.
The omega-6 fatty acid GLA (gamma-
linolenic acid) is a metabolic precursor to
GLA was administered to ADHD chil-
dren in two placebo-controlled studies. In the
first, parents’ ratings suggested benefit from
GLA but teachers’ ratings did not.
In the
second, parents’ ratings did not suggest ben-
efit but one teachers’ rating of benefit—the
Conners Hyperactivity Factor—did achieve
statistical significance.
Future studies might
be more definitive if objective measures are
taken to establish EFA status and if mixed
omega-3 and omega-6 long-chain fatty acid
preparations are administered.
The polyunsaturated, long-chain DHA
and AA affect the biological and physical prop-
erties of cell membranes, as well as the func-
tionality of numerous important membrane
proteins. The biochemical fates of DHA and
AA are structurally and functionally inter-
twined with the phospholipid substances that
make up the bulk of the cell’s membrane sys-
Phosphatidylserine (PS) and Other
Most of the reactions that collectively
amount to life occur on or in cell membranes.
These are the physical-chemical entities on
which the vast majority of the cell’s enzyme
assemblies are mounted. The phospholipids
(PL) are the main foundational molecules for
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 419
all cell membranes, serving much as building
blocks for the membrane matrix into which
the proteins are inserted. Within the membrane,
the phospholipid (PL) molecules act as “par-
ent” molecules for the long-chain, essential
fatty acid molecules. They hold the EFA in
position within the membrane, enabling en-
zymes of the membrane to metabolize the EFA
to eicosanoids and other regulatory messen-
ger molecules as appropriate.
Of the phospholipids, phosphatidyl-
choline (PC) is quantitatively the most com-
mon in all membranes. PC is also the body’s
main reservoir for choline, a small amine that
is a component of the neurotransmitter ace-
tylcholine. The PC precursor
dimethylaminethanol (DMAE) is a major sub-
strate for making PC in the body; it can have a
stimulant-type action in the ADHD brain, and
has been used with moderate success in the
treatment of children with ADHD and devel-
opmental disorders.
DMAE does have ad-
verse side-effects at high doses,
but was ef-
fective against “hyperkinesis” in one double-
blind trial and against learning disorders in
Phosphatidylserine (PS) is clinically
proven to benefit a wide range of brain func-
This phospholipid occurs in the brain
at far higher concentrations than it does in the
other organs. It is a key constituent of nerve
cell synaptic membranes, which are deeply
involved in the production of neurotransmit-
ters, their packaging for subsequent release,
and their action via receptors located at the
synaptic junctions. Ingested as a dietary
supplement, PS energizes the human brain,
facilitating synaptic connectivity and specifi-
cally boosting dopamine transmitter functions,
i.e., its production, release, and postsynaptic
receptor actions. In a physician in-office study
of 21 consecutive ADHD cases aged 4-19, di-
etary supplementation with PS benefited
greater than 90 percent of the cases.
At in-
takes of 200-300 mg/day of PS for up to four
months, attention and learning were most con-
sistently improved. Oppositional conduct
proved most resistant to PS treatment.
Other Nutrients
Many of the neurotransmitters are
metabolically derived from amino acids.
Analyses of plasma amino acid levels deter-
mined that phenylalanine, tyrosine, tryp-
tophan, and isoleucine were lower in ADHD
patients than in controls.
In adults with
ADHD, L-tyrosine treatment produced tran-
sient improvement.
Also in ADHD adults,
S-adenosyl methionine seemed beneficial in
one small, short-term, uncontrolled study.
A complex mixture of bioflavonoids
(oligomeric proanthocyanidins or OPCs),
which have potent antioxidant activity, were
reported to benefit ADHD in an undisclosed
proportion of children seen in a pediatric prac-
The symptom clusters related to atten-
tion and distractibility seemingly responded
more significantly than hyperactivity and im-
pulsivity. Side-effects were said to be minor.
Many among the wholistic/integrative
practitioners who have substantial experience
with ADHD believe intestinal dysfunction and
dysbioses are important contributors to ADHD
symptomatology. A proprietary mixture of oli-
gosaccharides, which sometimes serve as sub-
strates for probiotic intestinal bacteria, was
reported to decrease the severity of ADHD in
children during a six-week observation pe-
With the numerous nutrient deficien-
cies documented in ADHD, and the promise
offered by a range of nutrients in controlled
and non-controlled clinical trials, Galland’s
approach is a proven blueprint for success.
He tests for signs and symptoms of EFA defi-
ciencies, and corrects these through supple-
mentation. Using a similar approach, he se-
lects candidates for magnesium therapy. With
the B vitamins, to avoid the potential for para-
doxical responses he suggests careful titration
Page 420 Alternative Medicine Review
Volume 5, Number 5 2000
using individual vitamins rather than begin-
ning with mixtures; e.g., pyridoxine first, fol-
lowed by thiamine, then by the others one by
one. Serum ferritin and hair zinc levels can be
useful as rough guides for supplementation
with these minerals. In his view the nutrients
PS and DMAE are particularly deserving of
further study, especially for those ADHD chil-
dren with learning disabilities.
Developing an Integrative
Treatment Model
Modalities for medical management of
ADHD, other than the use of
psychostimulants, have historically been
minimized by the medical mainstream. Even
so, ADHD has become a testing ground for
modern wholistic/integrative medical
management, at least as an alternative to the
current “mainstream” predilection for carte
blanche prescription of
Safer and more
effective treatment options
are readily available to the
interested practitioner;
when combined and
individualized to the ADHD
child the success rate
approaches 100 percent.
First in order is dietary
revision: removal of food
additives, sensitizing foods,
and sugar (sucrose) from
the diet invariably results in
some degree of
Then the
child should be thoroughly
assessed for allergies,
nutrient deficiencies, and
intolerances to foods and
chemicals. The toxic burden
should be assessed and
corrected, including
lowering the body burden of
and potentially
toxic metals.
Lead contamination is an
obvious culprit in some cases of hyperactivity;
aluminum cookware and silver-mercury dental
fillings should be avoided.
In ADHD every effort should be ex-
erted to pursue the benefits from dietary modi-
fication and nutrient supplementation prior to
resorting to psychostimulant pharmaceuticals.
One clear benefit is that nutrients predictably
have broader effect spectra and superior ben-
efit-to-risk profiles. The foundational, pro-ho-
meostatic benefits afforded by vitamins, min-
erals, essential fatty acids, phospholipids, and
other nutrients to brain function would seem
more compatible with the wide range of be-
havioral and cognitive symptom overlap seen
in the ADHD population. Pharmaceuticals, by
contrast, are mechanistically much more ex-
clusive and therefore demanding of more pre-
cise symptom differentiation and diagnosis. Up
Figure 4: Integrative protocol for ADHD treatment
(adapted from Charles Gant, MD, PhD)
1. Establish subjective diagnosis (DSM-IV) and objective behavioral
(macroscopic) diagnosis using newer-generation neuropsychological
testing instruments such as the IVA/CPT of Sanford.
2. Move to the biochemical-physiologic (microscopic) level, using
laboratory tests such as hair, blood, stool, saliva, urine, or other,
based on risk factors reported in each case.
3. Prescribe nutritional supplements and other non-toxic biochemical
interventions that uniquely fit the lab results for each person. Use
anti-yeast medications and probiotics as necessary for intestinal
4. Attend to family/environmental risk factor(s) and/or recommend
family therapy as needed. Detoxify metals and organics as necessary.
5. Allow a minimum period (weeks to months) for these measures to
have an effect.
6. Retest using laboratory indicators, to assess progress at the
biochemical-physiologic level.
7. Retest at the behavioral level to determine if functional
improvement has occurred. This also allows publishing measurable
outcomes and comparing the data to other methodologies.
8. Retest or expand the range of testing at the behavioral and/or
biochemical levels at the first sign of relapse or if symptoms persist
past a reasonable period.
9. Retest/reassess several months or years later to ascertain long-
term results.
Attention Deficit Hyperactivity Disorder
Alternative Medicine Review
Volume 5, Number 5 2000 Page 421
to this point, nutrients and nutrient combina-
tions have not been given a fair evaluation
against ADHD and its constellation of co-
morbid conditions.
For the practitioner managing ADHD,
making a commitment to explore dietary
supplementation as a treatment modality does
not mean abandoning the use of stimulants and
other pharmaceutical medications. The use of
nutrients for symptom control in ADHD is not
incompatible with the use of drugs; nutrients
are compatible with drugs to a degree far su-
perior to the compatibility of drugs with other
Charles Gant, MD, PhD, is one practi-
tioner who has evolved from an allopathic
philosophy of medical practice to a fully inte-
grative practice for managing ADHD. He has
advocated striking a balance between the con-
ventional approaches to treating ADHD, with
the strikingly bad drug side-effects involved,
and the safer though less formally established,
“alternative” or “complementary” approaches.
Gant continues the tradition of other wholistic/
integrative physicians who employ a wide
spectrum of modalities to successfully treat
Gant’s idealized
“nine-point” program is summarized in Fig. 4.
Gant does an intake screening on the
patient suspected of having ADHD and
searches for seven target symptoms—hyper-
activity, impulsivity, inattention, mood labil-
ity, temper outbursts, disorganization, and
stress sensitivity. He then applies the more
extensive DSM-IV diagnostic criteria,
with the diagnosis established he proceeds
with his “Ideal Protocol” as summarized in
Figure 4. He treats approximately 50 percent
of his ADHD patients with antibiotics and
other medications, mostly to remove gas-
trointestinal dysbiotic organisms and to che-
late heavy metals.
Many children presenting with mental
and behavioral abnormalities have intestinal
bacterial imbalances from antibiotic overuse,
as from treatment for ear infections, which are
a proven risk factor for ADHD.
These chil-
dren tend to have impaired speech and lan-
guage development, and may have a two-fold
higher risk of becoming learning disabled.
Gut dysbiosis—imbalances of the symbiotic
bacteria, presence of nematode or protozoan
parasites, yeast (Candida) overgrowth caused
by antibiotic overuse—once corrected can
manifest as multisystem improvement, includ-
ing sometimes marked clearing of the mental-
behavioral symptoms.
Fungi and their me-
tabolites also play a role, and can be detected
and treated.
To most effectively treat ADHD, the
integrative medical practitioner must also work
closely with the subject and/or the parents to
further eliminate toxic metals (e.g., lead, mer-
cury) and chemicals (including cigarette
smoke, home building materials, pesticide-
contaminated foods, lawn and garden chemi-
cals, etc.) from the child’s environment—this
can have the added benefit of improving the
parents’ health. Allergies must be tested for
and eliminated, whether of the food-related or
the inhalant type (pollen, mold, dust, volatile
The next phase in the integrative medi-
cal management of ADHD is to identify and
correct nutrient deficiencies, especially of min-
erals (iron, magnesium, zinc, selenium, oth-
ers); essential fatty acids; B vitamins; and other
nutrients on a case-by-case basis. By this point
the vast majority of hyperactive ADHD chil-
dren are likely to be noticeably improved.
Objective testing of patients undergo-
ing treatment for ADHD is important. Con-
tinuous performance tests (CPT) measure re-
sponse preparation, planning and inhibition,
and neuropsychological performance via the
frontal lobes. CPT involve a period of testing
during which numbers or letters are presented
in rapid sequence on a computer screen and
the subject is asked to respond selectively to
them. Errors of omission are felt to represent
inattention, while errors of commission (pre-
mature responses) may represent impulsivity;
Page 422 Alternative Medicine Review
Volume 5, Number 5 2000
the total number of correct responses is thought
to represent capacity for sustained attention.
The IVA (Intermediate Visual and Auditory)
CPT is probably the best of these. In two pilot
projects, Harding, Judah and Gant used the
IVA CPT to objectively assess improvements
in ADHD children not sorted for co-morbid-
They treated with methylphenidate or via
nutraceutical interventions, and with or with-
out their usual full workups for metal toxicity,
gut dysbiosis, allergies and intolerances, and
nutritional deficiencies prior to intervention.
They found nutraceutical management was
statistically superior over pharmaceutical man-
agement for improving response control and
attention, including cases where the in-depth
workups were NOT carried out.
After 3-6 months of testing-retesting
and calibrating nutritional corrections, the use
of medication may be considered if the child
has not significantly improved or continues to
be particularly impaired or oppositional. In any
case, lower doses of medication can be used,
and titrated upward only as necessary to meld
with the benefits evident from the other inter-
ventions. The responsible integrative physician
will use medication only when the non-phar-
macologic protocols have been exhausted;
Crook suggests that the non-allergic, non-hy-
peractive ADHD children are the subpopula-
tion most likely to benefit from stimulant medi-
ADHD in the Future
The current extreme diversity of pro-
fessional opinion about ADHD—whether de-
bating the many possible contributory factors,
speculating on its neuropsychology and neu-
robiology, dogmatically supporting or oppos-
ing the use of stimulant medications, spawn-
ing honest disagreement as to whether the dis-
order truly exists—promises to continue into
the future. Some of the areas of controversy
should soon take on new clarity, most notably
the neurobiology of ADHD.
As the 1990s progressed, emphasis
began to shift away from a purely “attentional
deficit” as underlying ADHD, to a perhaps
“intentional” deficit involving inappropriate
response to an incoming stimulus, or a more
delocalized deficit in the development of the
inhibition of behavior.
Increasingly it is be-
coming evident that ADHD subjects do pay
attention, and do receive stimuli, but may have
trouble processing the information and formu-
lating an appropriate response.
With more research into the neurobi-
ology of ADHD, more focused wholistic/in-
tegrative treatment regimens might be forth-
coming. Increasing controversy over the wide-
spread use of methylphenidate and possible
life-threatening effects from its long-term use
make it essential that complementary/alterna-
tive treatment regimens be implemented for
ADHD management. Correction of nutrient
deficiencies commonly found in these patients,
along with dietary modification, allergy treat-
ment, detoxification, correction of intestinal
dysbiosis, family counseling, and behavior
therapy can ameliorate symptomatology and
allow the child diagnosed with ADHD to lead
a normal and productive life.
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... ADHD is associated with the presence of certain intestinal disorders of varying intensities [6]. This disorder manifests in many forms: asymptomatic, atypical, and/or associated with clinical signs and symptoms of celiac disease (CD) [5][6][7][8][9]. ...
... ADHD is associated with the presence of certain intestinal disorders of varying intensities [6]. This disorder manifests in many forms: asymptomatic, atypical, and/or associated with clinical signs and symptoms of celiac disease (CD) [5][6][7][8][9]. In addition, some studies point to ADHD as an extra-intestinal and neurological symptom of CD. ...
Purpose: The aim of this study was to evaluate whether the prevalence of celiac among attention-deficit/hyperactivity disorder (ADHD) patients is higher than among the normal population. Methods: The present study was a prospective one investigating ADHD children referred to the Neurology Clinic and Pediatric Ward at Amir Al-Momenin Hospital of Zabol (Sistan and Baluchestan, Iran) in 2019 after their parents' signing of a consent form. All patients underwent Biocard™ Celiac and serology tests. Data were analyzed with SPSS version 21 software. Results: Of all 76 ADHD children undergoing a serum IgA antibodies concentration test, 58 (76%) were male and 18 (23.7%) were female. The mean age of the children was 6.9 ± 2.4, ranging from 2 years to 12 years. The diagnosis of IgA immunodeficiency was rejected for all children based on total serum IgA antibody results. The overall mean anti-tissue transglutaminase (TTG) level was 6.8 ± 5.3 U/ml, ranging from 0.2 to 37 U/ml. There was no significant difference regarding TTG levels between boys and girls (5.1 vs. 6.0) U/ml. Based on the anti-TTG level results, no celiac case was found among the ADHD patients. Conclusions: There is as yet no evidence suggesting a link between celiac disease and ADHD. Thus, routine celiac disease screening when evaluating for ADHD (and is not recommended). However, the possibility of untreated celiac disease predisposing an individual to ADHD-like behaviors should be considered. Hence, physicians are recommended to evaluate a broad range of physical symptoms, in addition to typical neuropsychiatric symptoms, when evaluating ADHD patients.
... (Ward, 1997) Tocmai de aceea, eliminarea coloranților și conservanților artificiali din dietă ar putea fi una dintre măsurile adjuvante în tratarea ADHD. (Weber apud Kemp, 2008) Și alți autori subliniază necesitatea de a adopta o abordare integrativă în privința ADHD, care să includă intervenție nutrițională prin modificarea dietei și suplimentarea cu vitamine B, minerale, acizi grași esențiali omega-3 și omega-6, flavonoizi și fosfatidilserină (Kidd, 2000) sau cu vitamina D, fier, magneziu și zinc. (Villagomez& Ramtekkar, 2014) Modalitățile multiple prin care dieta influențează starea psihică, nu se opresc aici. ...
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... Children with ADHD following the Taekwondo Program Training showed greater gains than the control group on all the dimensions of the executive functions studied. ADHD is the most common behavioral disorder among young people [11]. Many causal factors have been implicated in the development and treatment of ADHD, including neurological, hereditary, pre-and post-natal care and various toxic influenced [12]. ...
... Our data revealed that there was a significant decrease in mitochondrial reduced glutathione amounts in the hippocampus of METH withdrawal mice in comparison to the control group ( Fig.3a, ***p<0.001). Statistically analysis established significant differences among all treated groups in GSH level in the hippocampus following the administration of selegiline [F (9,20) =5.529, p<0.05; Fig.3a]. ...
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Background: Methamphetamine (METH) is considered the second most commonly abused drug in the world. There is limited or no evidence concerning the effective treatment of METH withdrawal symptoms, such as depression and anxiety. Mode of action of selegiline (increase of the brain neurotransmitter activity) suggests that it might be useful in METH withdrawal syndrome treatment, being capable of diminishing the preference and depression involved in drug degeneration and addictive activities. Methods: Mice were randomly divided into 10 groups (n= 10): five METH-nondependent groups treated with normal saline intraperitoneal (i.p) for two weeks, to which, from the 15th day, selegiline (10, 20 and 40 mg/kg; i.p) or fluoxetine (5 mg/kg; i.p) was administrated for 10 consecutive days. Other groups injected METH (2 mg/kg, at 12-h intervals) for 14 days. From the 15th day, the 10-day period of METH abstinence started and the above-mentioned doses of selegiline or fluoxetine were injected. Then, the mice were evaluated for depression and biochemical assessments from the 25th day of the study. Results: Our data indicated that post-treatment with selegiline (10-40 mg/kg; i.p) for 10 days reversed METH-induced depressive-like behaviors in the forced swimming test (FST), tail suspension test (TST), and splash test with exerting no effects on the locomotor activity. Furthermore, none of the previously proposed treatments affected the behavioral abnormality in the control animals. Moreover, both selegiline and fluoxetine as standard antidepressant drug, substantially improved the levels of mitochondrial reduced glutathione (GSH), malondialdehyde (MDA), and adenosine triphosphate (ATP). Conclusion: Our findings demonstrated that selegiline produced antidepressant-like effects following METH withdrawal and prevented the mitochondrial dysfunction in the male mice.
... Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder of childhood that often persists into adulthood (Kidd, 2000). Individuals with ADHD show imbalances in neurobiological processes such as behavioral inhibition, self-regulation, and self-control, as well as altered reinforcement sensitivity (Hauser et al., 2014;Sebastian et al., 2014). ...
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Objectives: We examined serial mediating roles of low self-control and aggression in explaining relationships between levels of inattention and hyperactivity problems (IHPs) and severity of Internet gaming disorder (IGD) features when exposed to online games among adolescents without Attention deficit hyperactivity disorder (ADHD) stratified by gender using three-wave longitudinal study. Method: The sample comprised a total of 1,732 family dyads from a study that was conducted among seventh graders without diagnoses of ADHD at baseline. Levels of IHPs were assessed by the parent reported Korean version of the ADHD rating scale at baseline (wave1). Severity of IGD features was assessed by the Internet Game Use-Elicited Symptom Screen (IGUESS) at wave3. Both levels of self-control (wave1) and aggression (wave2) were assessed by self-report. The mediating role of low self-control and aggression in the relationships between level of IHPs and severity of IGD were evaluated using serial mediation analysis separately for each gender. Results: Levels of IHPs were related directly to severity of IGD features in both genders. The indirect effects via low self-control were also significant in both genders, however, the indirect effects via aggression was significant only in women. The serial mediation effect via low self-control and aggression between levels of IHPs and IGD features was significant in both genders (men, coefficient:0.009, 95%CI 0.005-0.019; women, coefficient:0.010, 95%CI:0.005-0.026). Conclusion: We revealed a possible mechanism underlying a serial mediation chain from low self-control to aggression explaining the effects of IHPs on severity of IGD features. However, this conclusion should be taken with a caution, because the effect sizes were very low.
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Background: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015. Objectives: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. Search methods: We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate. Selection criteria: We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non-serious, general behaviour, and quality of life. Data collection and analysis: Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel-group trials and first-period data from cross-over trials formed the basis of our primary analyses. We undertook separate analyses using end-of-last period data from cross-over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach. Main results: We included 212 trials (16,302 participants randomised); 55 parallel-group trials (8104 participants randomised), and 156 cross-over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross-over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male-female ratio was 3:1. Most trials were carried out in high-income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants. Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias. Primary outcomes: methylphenidate versus placebo or no intervention may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -0.88 to -0.61; I² = 38%; 21 trials; 1728 participants; very low-certainty evidence). This corresponds to a mean difference (MD) of -10.58 (95% CI -12.58 to -8.72) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD-RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68). Secondary outcomes: methylphenidate may cause more adverse events considered non-serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher-rated general behaviour versus placebo (SMD -0.62, 95% CI -0.91 to -0.33; I² = 68%; 7 trials 792 participants; very low-certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI -0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low-certainty evidence). Authors' conclusions: The majority of our conclusions from the 2015 version of this review still apply. Our updated meta-analyses suggest that methylphenidate versus placebo or no-intervention may improve teacher-rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non-serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear. Due to the frequency of non-serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials. Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.
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Attention Deficit Hyperactivity Disorder( ADHD)
Growing competitiveness in education and workplaces has led to increased interest in cognitive-enhancing substances. Abuse of prescription drugs purported to offer nootropic potential is increasing, and new brands of over-the-counter nootropics are being developed. However, the majority of research into the effectiveness and safety of cognitive-enhancing substances has been performed on adults, and the prefrontal cortex, the brain region in control of higher-order cognitive function, does not finish developing until adulthood, raising concerns that adolescent abuse of cognitive enhancers could result in lasting changes to the brain. In this chapter, we discuss the current trends in cognitive enhancement among adolescents and adults, examine several prescription drugs commonly used or being examined for their potential cognitive-enhancing effects, and discuss the potential risks of each substance. We also discuss the state of over-the-counter nootropics and the lack of reliable research into their efficacy and safety.
Full-text available
Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder which is characterized by impaired communication, and limited social interactions. The shortcomings of current clinical approaches which are based exclusively on behavioral observation of symptomology, and poor understanding of the neurological mechanisms underlying ASD necessitates the identification of new biomarkers that can aid in study of brain development, and functioning, and can lead to accurate and early detection of ASD. In this paper, we developed a deep-learning model called ASD-SAENet for classifying patients with ASD from typical control subjects using fMRI data. We designed and implemented a sparse autoencoder (SAE) which results in optimized extraction of features that can be used for classification. These features are then fed into a deep neural network (DNN) which results in superior classification of fMRI brain scans more prone to ASD. Our proposed model is trained to optimize the classifier while improving extracted features based on both reconstructed data error and the classifier error. We evaluated our proposed deep-learning model using publicly available Autism Brain Imaging Data Exchange (ABIDE) dataset collected from 17 different research centers, and include more than 1,035 subjects. Our extensive experimentation demonstrate that ASD-SAENet exhibits comparable accuracy (70.8%), and superior specificity (79.1%) for the whole dataset as compared to other methods. Further, our experiments demonstrate superior results as compared to other state-of-the-art methods on 12 out of the 17 imaging centers exhibiting superior generalizability across different data acquisition sites and protocols. The implemented code is available on GitHub portal of our lab at: .
The data on 50 patients with systemic manifestations due to allergy seen at the Children's Clinic, Jackson, Tennessee, during the period 1956 through 1960 is presented. Detailed case histories are recorded for four of these patients. The findings on the remainder are given in tabular form. Uniformly, the symptoms and signs in these children were fatigue, irritability, pallor in the absence of anemia, and infraorbital circles. Most of them also had nasal congestion, abdominal pain and headache. A variety of other signs and symptoms, including those of nervous system involvement, may also be present. The literature on this condition is reviewed in detail showing that this condition has been described under several different names by many observers during the past 40 years. In spite of these descriptions, few physicians are aware that allergy causes such systemic manifestations. In conclusion, it is suggested that allergy be included in the differential diagnosis of any child with generalized body symptoms of undetermined cause.
Attention-deficit hyperactivity disorder (ADHD) is the diagnosis used to describe children who are inattentive, impulsive, and hyperactive. ADHD is a widespread condition that is of public health concern. In most children with ADHD the cause is unknown, but is thought to be biological and multifactorial. Several previous studies indicated that some physical symptoms reported in ADHD are similar to symptoms observed in essential fatty acid (EFA) deficiency in animals and humans deprived of EFAs. We reported previously that a subgroup of ADHD subjects reporting many symptoms indicative of EFA deficiency (L-ADHD) had significantly lower proportions of plasma arachidonic acid and docosahexaenoic acid than did ADHD subjects with few such symptoms or control subjects. In another study using contrast analysis of the plasma polar lipid data, subjects with lower compositions of total n−3 fatty acids had significantly more behavioral problems, temper tantrums, and learning, health, and sleep problems than did those with high proportions of n−3 fatty acids. The reasons for the lower proportions of long-chain polyunsaturated fatty acids (LCPUFAs) in these children are not clear; however, factors involving fatty acid intake, conversion of EFAs to LCPUFA products, and enhanced metabolism are discussed. The relation between LCPUFA status and the behavior problems that the children exhibited is also unclear. We are currently testing this relation in a double-blind, placebo-controlled intervention in a population of children with clinically diagnosed ADHD who exhibit symptoms of EFA deficiency.
Attention-deficit/Hyperactivity Disorder (AD/HD) is the diagnosis used to describe children who are inattentive, impulsive, and hyperactive. AD/HD is the most common childhood behavioral disorder affecting 3 to 5 percent of the scnool-age population. In most children with AD/HD, the cause is unknown, but is thought to be multifactorial. In an earlier study, we reported that subjects with AD/HD who also had symptoms indicative of essential fatty acid (EFA) deficiency had lower levels of 20:4n-6, 20:5n-3 and 22:6n-3 fatty acids than control subjects and those subjects with AD/HD showing no symptoms indicative of EFA deficiency (Am. J. Clin. Nutr. 1995:62:761-8). The purpose of the study reported here was to compare the relationship between n-3 and n-6 fatty acid status and the severity of behavior, learning, and health problems in the population of subjects reported in the previous study. All subjects (both AD/HD and control) were included and divided into three groups based on their total plasma polar lipid fatty acid values. A contrast analysis between high and low n-3 and n-6 fatty acid levels and behavior, learning and health measures was performed. Subjects with lower total n-3 fatty acid levels showed a significantly greater number of behavior problems, assessed by the Gönners' Rating Scale, as well as temper tantrums, learning, health, and sleep problems. Very few contrast comparisons were significantly different with respect to total n-6 fatty acid levels. Only more colds and more antibiotic use were reported by those subjects with lower total n-6 fatty acids. These findings parallel the results of recent reports on the behavioral effects of n-3 fatty acid deficiency in experimentally deprived animals.
The close association of the exudative and neuropathic diatheses suggests a causal relationship. The frequent anaphylactic nature of the former¹ would seem to point toward a similar cause in the latter. It is my purpose in this paper to discuss certain nervous manifestations in infants and children from the standpoint of anaphylactic cause. It is hardly necessary to call attention to the frequent occurrence of the exudative and neuropathic diatheses in the same individual. All observers recognize the common association. However, it seems to have been generally held that this relationship is nothing more than accidental. Czerny considered it so.² He felt that the almost universal presence of the neuropathic diathesis in one or both parents of children with the exudative diathesis led, as a natural result, to the neurotic child. The degree to which the infant was affected by this nervous environment determined, to a certain extent,