attention deficit hyperactive disorder: pathophysiology ... · attention deficit hyperactive...

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.


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


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


(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


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


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-


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 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.


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).


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


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


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


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


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


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


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


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


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


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


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


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.


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


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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