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Running head: ATTENTION DEFICIT HYPERACTIVE DISORDER 1
Attention Deficit Hyperactive Disorder: Pathophysiology, Pharmaclogical, and Nutrition
Treatments.
Derek Sandberg
Weber State University
ATTENTION DEFICIT HYPERACTIVE DISORDER 2
Abstract
Attention deficit hyperactive disorder (ADHD) is one of the most common neurological
disorders among children with approximately 5.4 million children diagnosed in the United Sates.
Inattention and hyperactivity are two major symptoms associated with ADHD interfering with
the ability to function well at school or work. The etiology of ADHD is very complex involving
genetics, brain structure and function, and neurotransmitters. Stimulant medication is the most
common method for treating ADHD, though nutritional therapies are becoming more popular
due to the side effects of stimulant medication. Holistic approaches to ADHD treatment have
shown promise as an effective treatment for the disorder.
ATTENTION DEFICIT HYPERACTIVE DISORDER 3
Introduction
Attention deficit hyperactivity disorder (ADHD) is one of the most common
neurocognitive disorders among children with eight to twelve percent of children being
diagnosed with the disorder (Verlaet, Noriega, Hermans, & Savelkoul, 2014). Approximately
5.4 million children in the United States between the ages of 4-17 have been diagnosed with
ADHD (Johnson et al., 2011). For as many as 60% of those diagnosed with ADHD as a child
the symptoms persist into adulthood representing 4-5% of the adult population (Dela Pena &
Cheong, 2013; Rucklidge, Johnstone, Gorman, Boggis, & Frampton, 2013). The main
symptoms of ADHD are hyperactivity, impulsivity, and inattention (Verlaet et al., 2014). Those
who have ADHD tend to achieve lower levels of both education and employment accompanied
by higher levels of unemployment (Mueller & Tomblin, 2012). ADHD is the subject of much
research because of its prevalence and the difficulties associated with the disorder.
The pathophysiology of ADHD has been studied a great deal, though the etiology of the
disorder are not fully understood. Neurological abnormalities lead to a decrease in
neurotransmitters crossing synapse in the brain of those with ADHD (Kar, 2013). The cause of
these abnormalities has been linked to structural changes in the brain, genetics, and
environmental factors all of which contribute the symptoms associated with ADHD (Bush,
Valera, & Seidman, 2005; Choudhry et al., 2012). It is difficult to determine the cause of the
disorder because of the complex interactions between the factors influencing ADHD.
Almost half of the children in the United States who have been diagnosed ADHD are
being treated with medication (Johnson et al., 2011). Stimulant medication is the most common
treatment for ADHD, with methylphenidate being the most frequently prescribed (Dela Pena,
Kim, Han, Kim, & Cheong, 2013). Stimulant medications have been shown to be an effective
ADHD treatment, though the occurrence of side effects is driving the search for alternative
ATTENTION DEFICIT HYPERACTIVE DISORDER 4
treatments (Karpouzis & Bonello, 2012; Ryan, Katsiyannis, & Hughes, 2011). Nutritional
therapies are a one of the most common alternatives to traditional medication with as many as
12% of children diagnosed with ADHD using alternative treatments (Karpouzis & Bonello,
2012).
Ever increasing data indicates possible treatments for this complex disorder. However,
more research needs to be conducted to understand the physical and chemical interactions and
make recommendations for treatment.
Pathophysiology
It has long been suspected that dopamine and norepinephrine play a critical role in the
pathophysiology of ADHD. This idea was first suggested in 1937 by Charles Bradley in a study
where Bradley observed 30 children that exhibited the symptoms now known to be associated
with ADHD. Bradley gave these children a mixture of amphetamine called Benzedrine for a
week. There were improvements seen in 15 of the subjects in school and in the way they
interacted with other children (Kar, 2013). This initial study lead to other studies examining the
effects of dopamine and norepinephrine on ADHD, and the etiology of the problems with these
neurotransmitters.
The problems with the dopamine and norepinephrine pathways most likely involve the
prefrontal cortex and subcortical regions of the brain (Mueller & Tomblin, 2012). Prefrontal
regions of the brain assist executive function. Thought processing in these areas is inhibited by
ADHD (Valera, Faraone, Murray, & Seidman, 2007.)
Studies have shown dopamine levels are affected by a combination of factors associated
with ADHA. First, an increase in the amount of dopamine transporter leads to an increased
reuptake of dopamine. This increased reuptake reduced the amount of dopamine in the synapse
ATTENTION DEFICIT HYPERACTIVE DISORDER 5
(Kar, 2013). However, the studies showing the increase in dopamine transporters were
conducted with children that had been treated with psychostimulant medications. Subjects tested
that were drug-naïve were found to have lower dopamine transporter levels, suggesting the
increased dopamine transporter may have been caused by the stimulant exposure (Fasar-Poli,
Rubia, Rossi, Sartori, & Balotn, 2012). Second, dopamine receptor activity and dopamine
transporters are reduced in the midbrain and striatal regions. Both areas are associated with
attention and motivation (Kar, 2013). Third, reduced dopamine synthesis has been shown in the
prefrontal cortex of ADHD subjects resulting in reduced amount of dopamine it the synapse
(Kar, 2013). The association of lower dopamine levels with ADHD is supported by these
findings.
Many researchers have used structural imaging techniques in an attempt to discover the
cause of dopamine deficiencies. In these studies normal brains and brains of people with ADHD
are compared looking for structural differences. The most common imaging techniques used in
studying ADHD are single photon emission computed tomography (SPECT), positron emission
tomography (PET), and functional magnetic resonance imaging (fMRI). The frontal, parietal,
occipital, and temporal lobes, as well as, the caudate, cerebellum, and regions of the corpus
callosum have all been shown to be smaller in children with ADHD (Valera et al., 2007).
Children with ADHD have been shown to have 3-5% smaller cerebrum, with the right
hemisphere having a larger disparity than the left (Seidman, Valera, & Makris, 2005).
The anterior cingulate cortex has been studied in great depth. This area is of interest
because it is thought to play a major role in cognitive processing, target detection, response
selection and inhibition, error detection, performance monitoring, and motivation, ADHD
subjects struggle with all these challenges (Bush et al., 2005). Using fMRI and the Counting
ATTENTION DEFICIT HYPERACTIVE DISORDER 6
Stroop test, Bush et al. (1999) showed the anterior cingulate did not activate in children with
ADHD the way it did in a control group of normal children. In this same study, Bush et al.
(1999) did see that different areas of the brain activated. Indicating that children with ADHD
may process information differently than children without ADHD.
The prefrontal cortex is associated with organization, planning, working memory,
attention, and motor movement. The knowledge that patients with prefrontal cortex damage
show impairment in some tasks associated with it contributed to the interest in the prefrontal
cortex activity in ADHD (Tsujimoto et al., 2013). The dorsolateral prefrontal cortex and orbital
frontal areas of the prefrontal cortex are thought to be involved with ADHD (Seidman et al.
2005). Structural imaging studies have shown the prefrontal cortex to have reduced volumes in
ADHD leading to the prefrontal cortex being an area of interest (Bush et al., 2005). Verbal
working memory tasks have shown reduced activation in the right prefrontal region in adults
with ADHD (Valera et al., 2007). Tsujimoto et al. (2013) using functional near-infrared
spectroscopy, showed hyperactivity in the prefrontal cortex in children with ADHD when
performing working memory tasks with distractors. Also using near-infrared spectroscopy
Negoro et al. (2009) found that the prefrontal cortex of ADHD children were not as active as
normal children when performing Stroop color-word tasks. Supporting the idea the prefrontal
cortex is an area involved in ADHD.
Basal ganglia or striatum which includes the caudate and the putamen is also associated
with executive functions. Therefore it is an area of interest in ADHD. Dopamine transporter
abnormalities have been found in the striatum adding to the suspicion the striatum is involved
with ADHD (Bush et al., 2005). Dopamine transporter binding in the basal ganglia has been
shown to be significantly higher in drug-naïve children with ADHD supporting the idea that
ATTENTION DEFICIT HYPERACTIVE DISORDER 7
dopamine abnormalities are a key cause of ADHD (Cheon et al., 2003). Boys with ADHD have
been shown to have smaller volume and different shaped basal ganglia than boys without ADHD
(Qiu et al., 2009). Qiu et al., (2009) used large deformation diffeomorphic metric mapping to get
more detailed structural images showing compressions and expansions of the basal ganglia of
boys with ADHD. The areas of the basal ganglia showing shape differences are associated with
many different frontal-subcortical circuits indicating ADHD has a multifractal pathophysiology
(Qiu et al., 2009). However, Qiu et al., (2009) did not find these same basal ganglia differences
in girls with ADHD.
The cerebellum is strongly linked with the prefrontal cortex and the basal ganglia
indicating a strong possible relationship with these areas and ADHD (Ivanov, Murrough, Bansal,
Hao, & Peterson, 2014). Attention shifting, visual-spatial processing, working memory, and
emotion have all been linked to the cerebellum (Ivanov et al., 2014). Reduced activation in the
left cerebellum as well as in the contralateral right prefrontal cortex during working memory
tasks in children with ADHD support the idea the cerebellum plays a role in the disorder (Valera
et al., 2007). Using diffusion tensor imaging Ashtari et al., (2005) found that children with
ADHD had reduced white matter tracts in the left middle cerebellar peduncle, and left
cerebellum. They also found the larger the deficit in white matter, the larger the severity of
inattention scores on the Conner’s Attention Deficit Scale. Reduced cerebellar volumes have
been consistently shown to negatively correlate with attention problems (Seidman et al., 2005).
Using magnetic resonance imaging, it has been shown that children with ADHD have smaller
volumes in the left anterior cerebellar hemisphere and right cerebellar crus when compared to
normal children (Ivanov et al., 2014). They also found increased symptoms of hyperactivity and
inattention have been associated with smaller cerebellar volumes. Magnet-resonance-
ATTENTION DEFICIT HYPERACTIVE DISORDER 8
spectroscopy has shown there are neurochemical alterations in the cerebellum of adults with
ADHD that may interfere with dopaminergic neurotransmission (Perlov et al., 2010).
Seidman et al. (2005) found differences in the size of the posterior portion of the corpus
callosum in children with ADHD. Differences were found in the splenium that links the parietal,
temporal, and occipital cortexes (Hutchinson, Mathias, & Banich, 2008). More severe attention
problems have been connected with smaller spleniums and overall corpus callosum volumes
(Kayl, Moore, Slopis, Jackson, & Leeds, 2000). Sustained attention and divided attention are
functions of the parietal region suggesting that smaller splenium volumes in children with
ADHD may lead to difficulties with inattention (Hutchinson et al., 2008). The memory
problems associated with ADHD may also be caused by inattention issues.
Single photon computed emission tomography has shown decreased activity in the
prefrontal cortex orbits, prefrontal cortex poles, posterior frontal regions, cerebella, right parietal,
and right occipital lobes in older ADHD patients (Amen, Hanks, & Prunella, 2008). Amen et al.
(2008) looked at 21 regions of interest and found differences in 16 of these regions with
significant differences in the areas previously listed. Amen et al. (2008) findings support the role
executive dysfunction is a part of the cognitive and behavioral manifestations of ADHD. A
study using functional magnetic resonance imaging found decreased activation in the parietal
cortex, including posterior cingulate, bilateral occipital, pons, cerebellum, and the temporal lobe
(Silk, Vance, Rinehart, Bradshaw, & Cunnington, 2008). Silk et al. (2008) results indicate there
may be a wide spread effect inhibiting the visuo-spatial information processing of children with
ADHD. Both studies support the idea that multiple areas of the brain are contributing to the
manifestations of ADHD.
ATTENTION DEFICIT HYPERACTIVE DISORDER 9
Attention deficit hyperactivity disorder is familial and inheritable indicating ADHD may
have a strong genetic factor. Approximately 30%-35% of children with a first degree relative
with ADHD will also have the disorder, making these children six to eight times more likely to
have the ADHD (Faraone & Biederman, 2000). Even nonaffected siblings of children with
ADHD have shown impairments when compared with controls who have no family history of
the disorder, indicating either a genetic factor, an environmental factor, or both are involved
(Albrecht et al., 2014). When looking at the possible genetic component of ADHD, it is
important to note that no single gene has been shown to have significant associations with
ADHD (Bralten et al., 2013). This suggests the combination of many small multiple genes
effects may be the cause of ADHD (Martin, Hamshere, Stergiakouli, O’Donovan, & Thapar,
2014). This combination effect makes it very difficult to determine which genes may cause
ADHD. Martin et al, (2014) suggest the traits that contribute to ADHD are common among the
general population. However, those with a clinical diagnosis of ADHD tend to display these
traits in a more extreme way.
Much of the genetic research has been focused on the DAT1 gene that helps to regulate
the neurotransmitter dopamine by signaling for reuptake at the synapse near the presynaptic
terminal (Azeredo et al., 2014). While examining the 5’ end of the DAT1 Azeredo et al. (2014)
found a strong correlation between the rs2652511 C-allele and ADHD. The rs2652511 C-allele
is a possible contributor to the increase of the neurotransmitter DAT in children with ADHD
(Azeredo et al., 2014). During a study of two different genes, one on the 3’ end of DAT1 known
as DAT1, SLC6A3 and the dopamine D4 receptor gene DRD4 7R, Albrecht et al. (2014) found
that polymorphisms on these genes may lead to a combination effect on those with ADHD.
DAT1, SLC6A3 may lead to an increase in the reuptake of dopamine at the presynaptic terminal.
ATTENTION DEFICIT HYPERACTIVE DISORDER 10
DRD4 7R may cause the D4 receptor to have decreased affinity for dopamine (Albrecht et al.,
2014).
Latrophilin3 (LPHN3) is another gene that has been shown to have a significant
association with ADHD (Arcos-Burgos et al., 2010). Arcos-Burgos et al., (2012) were able to
take the association of LPHN3 and ADHD across three generation of families. In addition, a
significant association of single nucleotide polymorphism of the LPHN3 gene was found in
children with ADHD whose mothers had smoked while they were pregnant (Choudhry et al.,
2012). This association shows a link between both environment and genetics when looking at
ADHD. The expression of LPHN3 has been affiliated with the areas of the brain that have been
shown to be implicated with ADHD. It may be possible to more effectively treat the disorder by
targeting the effects of LPHN3 expression (Arcos-Burgos et al., 2010).
ADHD etiology is very complex and not yet well understood. There are most likely
many genes that play a small role in ADHD. This idea of a polygenetic disorder magnifies the
difficulty of precisely determining the root cause of ADHD. The brains of people with ADHD
have many structural and volume differences including the frontal, parietal, occipital, and
temporal lobes, as well as, the caudate, cerebellum, and regions of the corpus callosum. These
structural and genetic differences play a role in how neurotransmitters interact in the brain
leading to ADHD symptoms.
Pharmaceutical Treatment
According to the American Academy of Pediatrics (2011), treatment for children with
ADHD should include both behavior therapy and the use of an appropriate medication.
Medications used to treat ADHD can be divided into two categories: stimulant medications and
non-stimulant medications. In the United States the number of people being prescribed ADHD
medication has increased from 1.2 percent to 3.5 percent since the 1970s (Singh, 2010).
ATTENTION DEFICIT HYPERACTIVE DISORDER 11
Stimulant medications are split into two classes: amphetamines and methylphenidate, with
methylphenidate being the most commonly used (American Academy of Child & Adolescent
Psychiatry and American Psychiatric Association, 2013; Dela Pena et al., 2013). Non-stimulant
medications can also be split into two classes: norepinephrine uptake inhibitors and alpha
adrenergic agents (American Academy of Child & Adolescent Psychiatry and American
Psychiatric Association, 2013). Simulant medication have a long history of use going back to
1937. When Charles Bradly first studied ADHD and the effects of amphetamines on children
with the disorder (Kar, 2013). Non-stimulant medication are relatively new having only been
approved by the FDA for the treatment of ADHD since 2002 (American Academy of Child &
Adolescent Psychiatry and American Psychiatric Association, 2013).
Methylphenidate has both a quick release and an extended release, and can be
administered by pill, transdermal patch, chewable tablets, and liquid form (American Academy
of Child & Adolescent Psychiatry and American Psychiatric Association, 2013). Some of the
different forms of methylphenidate include methylphenidate (Ritalin), extended release
methylphenidate (Ritalin LA), dexmethylphenidate (Focalin), extended release
dexmethylphenidate (Focalin XR), Daytrana methylphenidate in a transdermal patch, and
Quillivant XR an extended release liquid form of methylphenidate (American Academy of Child
& Adolescent Psychiatry and American Psychiatric Association, 2013). Methylphenidate works
by blocking dopamine and noradrenaline transporters that remove extracellular dopamine and
noradrenaline from the synapse resulting in an increase in the amount of dopamine and
noradrenaline remaining in the synapse (Dela Pena et al., 2013; Hodgkins, 2012). Eighty five to
ninety percent of prescriptions being written for methylphenidate are for ADHD (Ryan et al.,
2011). Methylphenidate is extremely fast acting with positive effects being seen in as little at 15
ATTENTION DEFICIT HYPERACTIVE DISORDER 12
minutes and lasting from 4 to 12 hours depending on rate of release (Ryan et al., 2001). The
most common side effects of methylphenidate are tiredness, appetite loss, irritability, insomnia,
and anxiousness (Hodgkins, 2012).
Amphetamines are the first class of drug to have been used in studying ADHD (Kar,
2013). There are several types of amphetamines currently used to treat ADHD including both
quick and extended release forms. The main amphetamines being used are mixed amphetamine
salts (Adderall), extended release mixed amphetamine salts (Adderall XR), dextroamphetamine
(Dexedrine), and lisdexamphetamine (Vyvanse) (American Academy of Child & Adolescent
Psychiatry and American Psychiatric Association, 2013). Amphetamines like methylphenidate
block the reuptake of dopamine and noradrenaline, however amphetamines also inhibit the
reuptake of 5-hydroxytryptamine also known as serotonin (Hodgkins, 2012). The positive
effects of amphetamines can be seen in 30 to 45 minutes with the effects lasting 3 to 12 hours
depending on the rate of release (Hodgkins, 2012). The most common side effects include
appetite loss, headache, and insomnia (Sibley, Kuriyan, Evens, Waxmonsky, & Smith, 2014).
Methylphenidate and amphetamines are often studied together, because of the similarities
in their mode of action and their effect. Stimulant medications have are very effective with 75%-
80% positive effect on the treatment of ADHD symptoms (Ryan et al., 2011). Ryan et al.,
(2011) also point out that since stimulants are fast acting the therapeutic effects are often seen
within minutes of taking the medication. Stimulant medications have been shown to have a
positive effect on task performance and self-reported motivation in children (Groen, Tucha,
Wijers, & Althaus, 2013). Groen et al., (2013) found that children treated with methylphenidate
responded to feedback similarly compared to typically developing children suggesting that
methylphenidate helps to normalize these responses. Improvements in attention span, impulse
ATTENTION DEFICIT HYPERACTIVE DISORDER 13
control, and decreased hyperactivity have been consistently reported by both parents and
teachers of ADHD children treated with stimulant medication (Ryan et al., 2011). Studies have
shown that medication treatment improves academic performance, with students scoring between
2.9 and 5.4 points higher on standardized tests depending on how long the child had been
medicated (Ryan et al., 2011). Ryan et al., (2011) did however point out that improvements seen
on standardized tests were not enough to eliminate the gap between typical children and those
with ADHD. Currie, Stabile, and Jones (2014) found stimulate medications to have no
significant effect on academic performance, and even suggested an increase in grade repetition
and a decrease in math scores. However, most studies using stimulant medications to treat
ADHD show positive outcomes with improvements in observed behavior and in clinical
diagnostic tests. In fact there is some evidence the splenial area of the brain may normalize with
long term treatment of stimulant medication (Schnoebelen, Semrud-Clikeman, & Pliszka, 2010).
There are several possible adverse side effects associated with stimulant medication,
though most can be managed so that treatment need not stop (Cortese et al., 2013). Ryan et al.
(2011) placed the side effects associated with stimulant medications into three categories:
common side effects, more serious side effects, and rare side effects as shown in Table 1. Loss of
appetite is one of the most common side effects of stimulant medications. Loss of appetite has
been shown to be a likely cause of growth delay associated with stimulant medications (Cortese,
2013). Cortese (2013) indicate that growth delay is attenuated over time and after discontinuing
treatment there is an accelerated growth rate which adjusts for the delayed growth in weight and
height. Insomnia is another common side effect reported by those taking stimulant medications
(Singh et al., 2010). Increased blood pressure and heart rate have been seen, but they are usually
ATTENTION DEFICIT HYPERACTIVE DISORDER 14
minor elevations and there is no evidence of long term cardiovascular damage caused by
stimulant medication (Cortese et al., 2013).
Common Side Effects More Serious Side Effects Rare Side Effects Blurred vision Difficulty urinating Chest pain Constipation Fast/pounding/irregular
heartbeat Confusion
Diarrhea Mental/mood changes Easy bruising/bleeding Dizziness Significant unexplained
weight loss Extreme tiredness
Dry mouth Uncontrolled movements Fainting Fever Verbal tics Fast/pounding/irregular
heartbeat Headache Signs of infection Irritability Jaw/left arm pain Lightheadedness Persistent sore throat Loss of appetite Shortness of breath Nausea/vomiting Severe headache Nervousness Seizures Stomach pain Slurred speed Trouble sleeping Swelling of the ankles/feet Weight Loss Weakness on one side of the
body Table 1: List of side effects of Stimulant medications.
One of the other major concerns of stimulant medications is the potential for abuse and
addiction. Stimulant medications increase dopamine concentrations in the areas of the brain
associated with substance abuse (Chang et al., 2014). Those with ADHD have a 1.5 times higher
risk for substance abuse and a three times higher chance of nicotine dependence (Cortese et al.,
2013). This increased risk is part of the concern about abuse and addiction of stimulant
medication. When studying rats Dela Pena et al. (2013) found the rats had a consistent and
sustained self-administration of stimulant medication showing a potential to develop
dependency. However, Chang et al. (2014) found that children with ADHD treated with
stimulant medication for three years were 31% less likely to be involved with substance abuse.
These two findings are not necessarily contradictory. Stimulant medication can reduce the risk
ATTENTION DEFICIT HYPERACTIVE DISORDER 15
of using other drugs and addictive substances yet still have a potential to be addictive. Thus, it is
important that clinicians monitor their patients for abuse (Chang et al., 2014). Changing the
pharmacokinetics of simulant medications such as using extended release is one way to help
avoid abuse of the medication. Using medications that do not become bioavailable until after
they have been ingested is another method use to try to avoid misuse (Sibley et al., 2014). After
studying nearly 40,000 individuals over a four year period Chang et al. (2014) concluded there
was no evidence stimulant medications lead to increased substance abuse and may actually
reduce the rate of abuse.
Non-stimulant medication are relatively new in comparison to stimulant medication in
treating ADHD. Stimulant medications were the only FDA approved pharmaceutical treatment
for ADHD until 2002 (American Academy of Child & Adolescent Psychiatry and American
Psychiatric Association, 2013). Non-stimulant medication are divided into two classes
norepinephrine uptake inhibitor atomoxetine (Strattera) and alpha adrenergic agents including
extended release guanfacine (Intuniv) and extended release clonidine (Kapvay) (American
Academy of Child & Adolescent Psychiatry and American Psychiatric Association, 2013).
Atomoxetine was the first FDA approved non-stimulant medication for treating ADHD
(Rains & Scahill, 2006). Atomoxetine is similar to tricyclic antidepressants, but considered to be
safer (Sibley et al., 2014). According to Sibley et al. (2014) atomoxetine has been shown to
improve ADHD symptoms, but not to the same degree as stimulant medications. Atomoxetine
takes longer to show the therapeutic effect. Atomoxetine works by inhibiting norepinephrine
reuptake which increases the amount of norepinephrine in the brain (Rains & Scahill, 2006).
The most common side effects are decreased appetite and weight loss, but headache, upper
ATTENTION DEFICIT HYPERACTIVE DISORDER 16
abdominal pain, nausea, irritability, dizziness, and somnolence have also be observed (Rains &
Scahill, 2006).
Clonidine and guanfacine work by blocking the firing of norepinephrine and help to
regulate the adrenergic system (Rains & Scahill, 2006). Guanfacine also acts on the prefrontal
cortex by stimulating norepinephrine receptors (Rains & Scahill, 2006). Both of these drugs
have been shown to improve the functioning of ADHD children when being used in concert with
methylphenidate (Rains & Scahill, 2006; Sibley et al., 2014). However, they have not been very
effective on their own. Drowsiness is the most common side effect with both clonidine and
guanfacine but there are very few other side effects (Corteses et al., 2013).
Stimulant medications are very effective for treating ADHD, helping with attention,
focus, and hyperactivity. Singh et al. (2010) found that young people reported feeling that
stimulant medication help them improve social behaviors, and their relationships with peers.
Young people also reported improvements in school, relationships with parents and siblings,
self-confidence, and self-esteem (Singh et al., 2010). Stimulant medications are an effective
treatment for ADHD even when the positive outcomes are weighed against the possible side
effects and potential for abuse. Non-stimulant medication tend to have fewer side effects, but are
not as effective.
Nutrition
Attention-deficit disorder has a very complex etiology including genetics, and brain
structure and function. It is well known that genetics by themselves do not tell the entire story of
what genes are expressed, but that environmental factors play a role in gene expression.
Environmental factors may influence the effects of ADHD by as much as 20-30% making them
very important in the expression and severity of the disorder (Verlaet et al., 2014). Some of the
environmental factors that have been found to influence ADHD include low socioeconomic
ATTENTION DEFICIT HYPERACTIVE DISORDER 17
class, family dysfunction, foster placement, low birth weight, premature birth, and prenatal
alcohol or tobacco smoke exposure (Verlaet et al., 2014). Another major environmental factor is
nutrition. Nutrition has long been suspected of influencing the symptoms of ADHD. In fact
dietary changes are the most commonly used alternative therapies for ADHD (Karpouzis, &
Bonello, 2012). Areas that have been identified as contributors to ADHD are the intake of food
additives such as artificial food coloring and preservatives, vitamin and mineral deficiencies, and
the influence of omega 3 and omega 6 fatty acids. It has also been long suspected that sugar
intake may play a role in increased hyperactivity in children with ADHD.
Dr. Benjamin Feingold an allergist and pediatrician was one of the first to suggest the
influence diet had on the hyperactivity of children with ADHD (Schwing, 2009). Dr. Feingold
stated the removal of artificial colors and from a child’s diet would benefit the child by the
reduction and possible elimination of ADHD related symptoms (Eagle, 2014). The Feingold diet
was a diet free of certain food additives, especially azo dye food colors, and naturally occurring
salicylates, an aspirin-like compound found in many fruits and some vegetables (Stevenson,
2009). Feingold claimed that these dietary changes benefitted about 50% of children with his
diet (Schwing, 2009). In 1983, a meta-analysis of the Feingold diet found the diet’s effect size
too small to be of value, creating uncertainty in the benefit of dietary treatment of ADHD (Nigg,
Lewis, Edinger, & Falk, 2012).
The uncertainty of the effects of artificial food colors remained until Schab and Trinh
(2004) performed another meta-analysis of the previous twenty years of research. Schab and
Trinh (2004) concluded that artificial food colors had a significant effect on the hyper activity of
children with ADHD. This finding reignited the artificial food color argument. There is some
evidence that artificial food colors and some preservatives may increase the hyperactivity of
ATTENTION DEFICIT HYPERACTIVE DISORDER 18
children even if they have no history of ADHD (Verlaet et al., 2014). Verlaet et al (2014)
indicate there is strong evidence that at least a subgroup of children with ADHD would benefit
from a diet free of artificial food color. Nigg et al (2012) indicate that as many as 30% of
children with ADHD may benefit from restricting artificial food colors. Nigg et al (2012) did
point out that when only FDA approved food colors where considered the results were not
consistent and they may not have the same negative effects. There has even been some evidence
that artificial food colors may have a positive effect in some subgroups of children with ADHD
(Eagle, 2014).
Sugar is often associated with ADHD and increased hyperactivity in children. Some
studies have indicated as many as 24% of children can benefit from a reduced sugar intake,
though restricting sugar intake is less effective then medication (Schwing, 2015). This finding
however is controversial. Kim and Chang (2011) concluded there was no link between sugar
intake and behavior in children with ADHD. Kim and Chang (2011) based their conclusion on
findings indicating sugar intake had no influence on behavior and learning of children in Korea
with ADHD. Johnson et al (2011) put forth the idea that chronic excessive sugar intake leads to
a decrease in dopamine receptors and dopamine receptor-mediated signaling. This decrease in
dopamine receptors and signaling then leads to the development of ADHD. The hypothesis put
forth by Johnson et al (2011) is based on two main ideas. First, excessive sucrose intake
increases the amount of dopamine released. The chronic increase of dopamine leads to a
desensitization of dopamine-stimulated responses. Johnson et al (2011) also point out the
majority of studies that show no association between sugar intake and ADHD symptoms are
comparing sugar to artificial sweeteners, suggesting artificial sweeteners may have the same
ATTENTION DEFICIT HYPERACTIVE DISORDER 19
effect as increased sugar intake. It may not be an acute reaction to increased sugar intake, but a
prolonged exposure to higher amounts of sugar that exacerbates ADHD symptoms.
Iron and zinc deficiencies have been associated with increased ADHD symptoms (Oner
et al., 2010; Rucklidge et al., 2014). Iron is closely associated with dopamine metabolism.
Brains with lower iron levels have been shown to have decreased numbers of dopamine receptors
and transporters (Oner et al., 2010). There is evidence linking ADHD with other disorders
associated with inflammation such as, atopic eczema (Rucklidge et al., 2013). Blood ferritin
levels indicate iron status and can also reflect reduced inflammation possibly improving ADHD
symptoms (Rucklidge et al., 2013). Oner et al (2010) showed an association with low ferritin
levels and hyperactivity. There has been limited research treating iron deficiency with ferrous
sulfate that indicate a significant benefit for children with ADHD, but more research is needed
associating iron studies with ADHD (Bloch & Mulqueen, 2014).
Low zinc levels in children have been associated with ADHD diagnosis (Bloch &
Mulqueen, 2014). Bloch and Mulqueen (2014) point out that symptoms of zinc deficiency
include inattention, jitters, and delayed cognitive development all of which are similar to ADHD
symptoms. Low zinc levels have been associated with hyperactivity, increased anxiety, and
conduct problems, however lower zinc levels were not associated with learning problems (Oner
et al., 2010). Oner et al (2010) suggested this finding indicated that zinc levels are linked closer
to the hyperactivity and impulsiveness aspect of ADHD rather than the inattention aspect. Zinc
is a dopamine transporter inhibitor. Low zinc levels have been linked to low synaptic dopamine
levels (Oner et al., 2010). Zinc supplementation has had mixed results reflected through the
effects on ADHD scores, one study showing benefits on hyperactivity and impulsiveness, and
another study showing no effects (Ghanizadeh & Berk, 2013). There is some evidence that using
ATTENTION DEFICIT HYPERACTIVE DISORDER 20
zinc in combination with stimulant medications will help to improve ADHD symptoms and
possibly lead to lower dose requirements, with as much as a 37% reduction in the dose of
medication (Bloch & Mulqueen, 2014).
Fatty acid intake has become an area of high interest in treating ADHD, because fatty
acids have been linked to neurological development (Karpousiz & Bonello, 2012). In particular
omega-3 and omega-6 fatty acids have been linked to behavioral and cognitive development
(Stevenson, 2010). Stevenson (2010) also pointed out that eating oily fish, a good source of
omega-3 fatty acids, during early pregnancy had a positive effect on hyperactivity of the child at
age nine. Children with ADHD have been shown to have consistently lower blood levels of
ogega-3 fatty acids compared to normally developing children (Hawkey & Nigg, 2014). There is
also evidence that fatty acid abnormalities may effect adult behavioral disorders. Furthermore,
omega-3 fatty acids have been linked mood disorders and impulsivity (Richardson, 2006). These
links between fatty acids and ADHD have made them one of the largest areas of study in regards
to nutritional therapies for ADHD.
Most studies have shown positive effects from the treatment of ADHD with omega-3 and
omega-6 fatty acids with results varying from strong to slight improvements (Barragan, Breuer,
& Dopfner, 2014; Hawkey & Nigg, 2014). Barragan et al (2014) compared treatment with
omega-3 and omega-6 fatty acids alone, with methylphenidate alone, and with a combination of
methylphenidate and omega-3 and omega-6 fatty acids. They found that the fatty acid treatment
alone improved ADHD scores by 60%, methylphenidate alone improved scores by 80%, and the
combination treatment improved scores by 93%. Hawkey and Nigg (2014) did not report such
strong results, but did state that fatty acid intake has a reliable significant effect on ADHD
symptoms. Richardson (2006) agrees that supplementing the diet of children diagnosed with
ATTENTION DEFICIT HYPERACTIVE DISORDER 21
ADHD with omega-3 fatty acids can alleviate symptoms. Omega-3 fatty acid treatment has been
shown to be more effective in treating hyperactivity and impulsivity than inattention (Barragan et
al., 2014; Hawkey & Nigg, 2014; Richardson, 2006). Supplementation of omega-3 fatty acids
have been shown to be safe with little to no side effect, and may provide other positive health
benefits such as improved lipid profiles (Manor et al., 2013). Even with the many positive
studies on fatty acids, the outcomes are not totally consistent and some contrary result have been
seen indicating a need for more study (Karpouzis & Bonello, 2012).
Nutrition is a key component of all areas of health including those associated with
ADHD. Good nutrition will help to improve any health problem while a poor diet may
deteriorate function and health. Junk food diets or diets with high amounts of chocolate, chips,
and larger amounts of sugar have been associated with hyperactivity (Karpouzis & Bonello,
2012). Karpouzis and Bonello (2012) also point out the western-style diet or a diet high in
takeout foods, processed meats, high-fat dairy products, and soft drinks contribute to ADHD.
While healthy diets that are high in whole grains, fruit, vegetables, legumes, and fish do not have
the same connection with ADHD (Karpouzis & Bonello, 2012). In support of this ADHD has an
increased association with obesity, as children with ADHD have shown to have as much as twice
the proclivity for being in the top 85% of BMI (Johnson et al., 2011). All of this evidence points
to a need to manage diet, whether by supplementing to correct for deficiencies or merely eating
healthy it may improve ADHD symptoms.
Discussion
ADHD is multifactorial, consequently it is difficult to isolate the cause. The genetics of
ADHD are just beginning to be understood and there is much more to learn. As ADHD genetics
are better understood it should lead to enhanced treatment options. Arcos-Burgos et al. (2010)
indicate that certain genes associated with ADHD may also be of use in determining if a
ATTENTION DEFICIT HYPERACTIVE DISORDER 22
medication will be effective in treating ADHD. Genes associated with ADHD may also be of
use in predicting what side effects may be seen with specific medications (Johnson et al., 2013).
It is becoming clear that as the understanding of AHDH genetics improves treatments will
become more effective.
Insight into the underlining genetics will also help to more fully understand the brain
areas associated with ADHD and what effect changes in those areas of the brain may have.
Using the various imaging techniques it has become clear there are many structural and volume
differences in the brains of those with ADHD. These structural differences probably play a key
role in the functional problems in dopamine signaling among those with ADHD. As these
structural differences are better understood it should assist development of treatments focusing
on the functional issues they cause.
Stimulant medications are the most commonly used treatments for ADHD, because they
have a positive effect on the symptoms of ADHD for 75 to 80% of those treated (Ryan et al.,
2011). Consequently stimulant medications have become the first line of AHDH treatment. Both
classes of stimulant medications have been shown to be equally effective in treating ADHD
symptoms, but methylphenidate has a lower rate of adverse effects (Hodgkins et al., 2012). It is
common practice to try the other class of simulant medication if one class of stimulant
medication is ineffective (Hodgkins et al., 2012). Side effects and addiction are two of the major
concerns associated with stimulant medications. Side effects and lack of effectiveness are the
main reasons for those with ADHD to stop using their medication (Toomey, Sox, Rusinak, &
Finkelstein, 2015). Knowing what leads those with ADHD to discontinue medication use may
help find alternative treatment options. Those options may be designed to reduce or possibly
eliminate the need for medication.
ATTENTION DEFICIT HYPERACTIVE DISORDER 23
One of the major options that has been looked for at least fifty years is nutrition. It is
intuitive to consider nutrition as everything ingested will have some effect on the body. As with
any medication some effects will be positive and some will be negative, making it important to
consider both things that should be eliminated from or added to the diet. Artificial food color
and some preservatives have been shown to effect the hyperactivity of children with ADHD, and
though these conclusions can be disputed there is enough evidence to continue studying the
effects of these additives (Nigg et al., 2012; Schab & Trinh, 2004). Artificial food color and
preservatives do not offer any nutritional value, they are just additives. Avoiding these food
additives even if they have not been shown beyond doubt to increase hyperactivity may still be
beneficial.
Supplementation of certain nutrients, including iron, zinc, and omega-3 and omega-6
fatty acids, has been shown to be beneficial in treating ADHD. Fatty acids have been the most
frequently studied nutrient in treating ADHD and have shown promising results with as high as
60% improvement on ADHD scores (Barragan et al., 2014). Omega-3 fatty acids have been
associated with improvement of overall health including reducing the risk of heart disease and
stroke. In addition to the other positive health benefits associated with omega-3 fatty acids, they
are very safe as there are little to no side effects (Barragan et al., 2014). Iron and zinc have not
been as conclusive when showing positive effects as fatty acids have, but there is enough
positive results to continue studying them.
When treating a complex disorder like ADHD it is best to look at the individual as a
whole as well as all possible aspects involved with the disorder. Hodgkins et al. (2011) indicate
that medication with behavior therapy provides superior outcomes to medication alone. Barragan
et al. (2014) were able to show improvement in the reduction of ADHD symptoms with a
ATTENTION DEFICIT HYPERACTIVE DISORDER 24
combination of methylphenidate and an omega-3 and omega-6 supplementation regimen with a
93% improvement over a twelve month period. Both these studies indicate that combining
treatment methods improves outcomes for those with ADHD. Exercise has been shown to
improve performance on attention orientated task, as well as, improving social behavior, motor
skills, strength, and neuropsychological parameters (Silva et al., 2015; Kamp, Sperlich, &
Holmberg 2014). All of these areas of treatment including medications, nutrition, behavior
therapy, and exercise have been shown to be effective in treating ADHD. Studies that combined
different treatments have been shown more effective in reducing ADHD symptoms than
individual treatments. It would make sense that a treatment plan focused on all aspects of an
individual with ADHD including multiple treatment approaches would have the most benefit.
Holistic treatment methods need further research.
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