ADHD and reward deficiency syndrome

This PubMed article piqued my interest because of the following paragraphs which seem an uncanny description of the hyper-sensitivity that so many of us suffer from.

It may be that people with ADHD are afflicted with a defective filtering system such that their brainstem reticular formation does not block out irrelevant stimuli. These people appear to be aware of every sound, every object, every touch, and they all merge in disorganized behaviors that are difficult to tolerate

At a deeper level, ADHD is a problem of communication among brain cells, or neurons, possibly involving the neurotransmitters that carry inter-neural messages. If the messengers that inhibit incoming stimuli are deficient, too many signals get through and create confusion.

Attention-deficit-hyperactivity disorder and reward deficiency syndrome – free full-text PMC2626918 – 2008 Oct;  

Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD).

A consensus of the literature suggests that when there is a dysfunction in the “brain reward cascade,” especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings

This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings.

Moreover, this genetic trait is due in part to a form of a gene (DRD2 A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites.

This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities.

It has been proposed that genetic variants of dopaminergic genes and other “reward genes” are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype

We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD

Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.

Characteristics of attention deficit hyperactivity disorder (ADHD)

ADHD often is blamed on bad parenting, or a “bad” attitude. However, brain-imaging studies have shown that children with this disorder have an underlying neurological dysfunction, which likely accounts for their behavior (Zametkin et al 1990; Lou et al 1998).

ADHD is a widespread affliction that we are just beginning to understand. People with ADHD suffer from overload (Miller and Blum 2008). That is, they have heightened awareness of incoming stimuli, particularly sight, sound, and touch

They are so bombarded by the normal stimuli in their environment that they cannot filter out the background noise, and they have trouble focusing or concentrating on a problem or a task.

Because of their inability to focus, those with ADHD have trouble completing what they start. They have difficulties with making plans and even more difficulty in carrying out plans in an orderly fashion.

People with ADHD tend to be disorganized.

Many people with the disorder are highly intelligent, but they tend to be underachievers because they cannot concentrate or sustain interest.

People with ADHD also have trouble adapting to change. Their life is so full of tumult that even a minor additional change in their routine can be upsetting or can even create a crisis, eg, a parent goes away on a trip, a new teacher takes over a class, the family moves to a new city, or a pet dies.

ADHD afflicted people live under stress so severe they cannot tolerate frustration, and when they are frustrated, they are likely to become angry. The anger tends to come suddenly and explosively, accompanied by slamming doors, harsh words, tantrums, and leaving important meetings in a frenzy.

With their high level of frustration, people with ADHD are impatient. They hate to wait in line, and delays of any kind can make them frantic

People with ADHD have trouble with their orientation to time and space.

They may have trouble differentiating their right hand from their left; they may have difficulty following a set of instructions, reading a map, or telling time.

I started having difficulty with right and left in high school and to this day, when someone says “turn left”, I have to stop and look which hand my wedding ring is on to figure out which direction that is.

As adults, they are restless, easily bored, rebellious when asked to follow a routine, and always on the move

There has been increased interest in ADHD as a heritable neuropsychiatric condition linked to pathogenesis of brain dopamine  (Shaw et al 2007; Swanson et al 2007; Volkow et al 2007).

In the present paper, we discuss ADHD as an important putative complex subtype of a general condition or umbrella disorder known as reward deficiency syndrome (RDS)

At the level of individual neurons, the reward cascade is catalyzed by a number of specific neurotransmitters, each of which binds to certain types of receptors and serves a specific function. The binding of the neurotransmitter to neuronal receptors triggers a reaction that is part of the cascade. Disruption of these intercellular cascades results in aberrant behavior of one form or another in RDS, including ADHD.

Science of reward deficiency syndrome

RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among brain neurotransmitters in reward centers of the brain, which directly links abnormal craving behavior with a defect in at least the DRD2 dopamine receptor gene (Blum and Kozlowski 1990a).

Twin studies indicate that 75%–90% of ADHD is caused by genetic factors. If one person in a family is diagnosed with ADHD there is a 25%–35% probability that another family member also has ADHD, compared to a 4%–6% probability for someone in the general population.

Dopamine is a powerful brain neurotransmitter that controls feelings of well being (Blum and Kozlowski 1990b; Blum and Payne 1991; Blum et al 1996a).

Dopamine interacts with other powerful brain chemicals and neurotransmitters (eg, serotonin and the opioids), which themselves are associated with control of moods.

In individuals possessing an abnormality in the DRD₂ dopamine receptor gene, the brain lacks sufficient numbers of dopamine receptor sites to use the normal amount of dopamine in reward centers and thus reduces the amount of dopamine produced in this area.

The overall effect is inadequate dopaminergic activity in brain reward centers. This defect drives individuals to engage in activities that will increase brain dopamine function.

Consuming large quantities of alcohol or carbohydrates (carbohydrate bingeing) stimulates the brain’s production of, and utilization of, dopamine.

RDS can be manifested in relatively mild or severe forms that follow as a consequence of an individual’s biochemical inability to derive reward from ordinary, everyday activities.

Here, the article goes into considerable detail explaining the “Biology of reward” and the “Cascade theory of reward”.

This figure shows the Interactions in brain reward regions:

Science of ADHD

Neuropsychogenetics of ADHD

In ADHD, the picture emerges of individuals suffering from overload, trying to adjust to a world that is too bright, too loud, too abrasive, and too rapidly changing for comfort.

I’ve always considered myself simply over-sensitive, but this description perfectly fits how I feel, often overwhelmed by my environment.

Just protecting myself from over stimulation by the environment (temperature, hard surfaces, noise, crowds) takes up a great deal of my energy and I feel it’s responsible for much of my general fatigue.

What is the cause or basis of ADHD?

It is an impulse disorder with genetic components that results from imbalances of neurotransmitters. Its effects can be eased by treatment and counseling.

The biological basis for this disorder has been established by a number of investigators  (Comings et al 1991; Biederman et al 1992).

In one study individuals with ADHD were found to have abnormal brain wave patterns (Lubar 1991). Their beta waves (brain waves associated with concentration) are low, and their theta waves (associated with relaxation) are high, suggesting a state of drowsiness and daydreaming

It may be that people with ADHD are afflicted with a defective filtering system such that their brainstem reticular formation does not block out irrelevant stimuli.

These people appear to be aware of every sound, every object, every touch, and they all merge in disorganized behaviors that are difficult to tolerate

Non-essential stimuli get the same attention as those essential to work or relating to other people.

At a deeper level, ADHD is a problem of communication among brain cells, or neurons, possibly involving the neurotransmitters that carry inter-neural messages.

These brain messengers may be either in short supply for certain behaviors such as cravings (probably due to inadequate serotonergic and or dopaminergic function) or other attentional deficits, or they may be the result of too much norepinephrine rather than too little.

If the messengers that inhibit incoming stimuli are deficient, too many signals get through and create confusion.

At a still deeper level, the problem lies in the genes that lay down the blueprint for manufacturing neurotransmitters.

People with ADHD have at least one defective gene, the DRD2 gene that makes it difficult for neurons to respond to dopamine, the neurotransmitter that is involved in feelings of pleasure and the regulation of attention

Studies on genetic anomalies have implicated other dopaminergic genes such as the DRD4 receptor gene, the dopamine beta hydroxylase (DβH) gene, and the dopamine transporter genes as causative factors in ADHD (Cook et al 1995; Waldman et al 1996), as well as gene variants involved in multiple neurotransmitter pathways.

To some extent, people with ADHD can learn to cope.

They can

• avoid situations that generate stress;
• avoid crowds and noisy environments;
• give themselves plenty of time and avoid tight deadlines; and
• avoid rapid changes in their environment.

The inherent tragedy here is that the ADHD person may be genetically at risk of developing an addiction. Possibly the same neurochemical imbalance in their brain that produces ADHD also produces a predisposition to addiction, Tourette syndrome, ODD, CD, and as well as other related behaviors (Comings et al 1991; Blum et al 1996b; Miller and Blum 2008).

Behavioral and electrophysiological diagnostic tools

In clinical settings, a number of rating scales have been utilized with mixed results for the diagnosis of ADHD.

One set of commonly employed tools involves the Conners’ Rating Scales (Conners 2006), an instrument that uses observer ratings and self-reports to help evaluate problem behaviors in children and adolescents.

Another alternative utilized in a clinical setting to assist in properly diagnosing ADHD is a continuous performance test called T.O.V.A. (Test of Variables of Attention) (TOVA 2006).

The latest version of this test is computerized, and it is designed to identify a minimum of four types of attention failures.

1. One type is marked by omission abnormalities when the patient’s attention failure is measured by missing information.
2. The second type is marked by commission abnormalities associated with impulsive behaviors, and it frequently is co-morbid with a cluster of anxiety disorders (eg, obsessive compulsive behaviors, panic, and oppositional defiance).
3. The third type is marked by abnormalities in reaction time. It is believed that this type is not specific for ADHD and is associated with slowing of response times as seen in classic psychomotor retardation, dysthymia, and major depression
4. The fourth type is response variability (either fast or slow). Of all the above, this is more closely related to ADHD and is also common in adults that have obesity, alcoholism, and/or craving disorders.

However, it is important to note that results of T.O.V.A. tests have been associated with a number of false negative diagnoses.

ADHD is a common disorder

Table 2

Prevalence of various types of ADHD in the general population

Hyperactive/Impulsive	2.6
Inattentive	8.8
Combined	4.7
Total	16.1
	M/F ratio 4:1

ADHD is a spectrum disorder

t has been known for many years that if an individual inherits enough genes to develop any given behavioral disorder, the risk of developing a second behavioral disorder is two to four times greater than for the general population.

ADHD has lifelong effects

Again, we wish to emphasize there are many examples in which the restless, workaholic, always-have-to-be-doing-something, I-need-to-be-my-own-boss, characteristics of ADHD subjects result in very successful lives.

Thus, in the right combination, some of the symptoms we have been discussing in a negative light can be used to great advantage (Comings et al 2005).

Genes and ADHD

It has been proposed that ADHD is a polygenic disorder due to the additive effect of genes affecting

• dopamine,
• norepinephrine,
• serotonin,
• GABA, and
• other neurotransmitters.

Molecular genetics and ADHD

ADHD… is caused by biological and genetic factors that influence neurotransmitter activity in certain parts of the brain (Wallis et al 2008).

Studies at the National Institute of Mental Health using positron emission tomography (PET) scans to observe the brain at work have shown a link between a person’s ability to pay continued attention and the level of activity in the brain.

In people with ADHD, the brain areas that control attention used less glucose, indicating that they were less active. It appears from this research that a lower level of activity in some parts of the brain may cause inattention and other ADHD symptoms

A dopamine model

Defects in dopamine metabolism have long been implicated in the etiology of ADHD.

Here, the article goes into the details of various genes associated with ADHD under the following header topics:

• Dopamine D₂ receptor gene (DRD₂)
• Dopamine D₂ receptors, regional blood flow, and response to methylphenidate
• Heterosis at the DRD₂ gene
• Dopamine transporter gene
• Generational association studies of dopaminergic genes in RDS probands and family members.
• The role of polygenes as a diagnostic indicator

Comings (2001) summarized the role of multiple genes in ADHD providing a polygenic model for the etiology of ADHD including the following salient points modified herein:

 

• Multiple dopaminergic genes and other genes each contributing to a small percentage of the total variance.
• The co-morbidity between ADHD and substance abuse (common sets of genes affecting the frontal lobes and the reward pathways).
• The central role of the frontal lobes and ADHD and related disorders.
• The evidence from animals that defects of dopamine metabolism in the frontal lobes are important in ADHD.
• The secondary hypersensitivity of dopamine receptors in the basal ganglia leading to hyperactivity and tics.
• The close relationship between ADHD and Tourette syndrome.
• The role of norepinephrine genes in learning and language disorders involving parietal lobe attention centers.
• The role of serotonergic and GABAergic genes in the reward cascade.
• The role of enkephalinergic genes as they relate to dopamine release.

Treatments for ADHD

Symptoms of ADHD often are treated with drugs, an approach that conforms to mainstream medical and regulatory guidelines.

Common conventional therapies are targeted at suppressing symptoms by inhibiting, blocking, or (conversely) amplifying production, reception and/or disposal of various neurotransmitters (eg, serotonin with selective serotonin reuptake inhibitors).

Pharmacological treatments

Stimulants:

Pharmacological treatment with psychostimulants is the most widely studied treatment for ADHD.

Stimulant treatment has been used for childhood behavioral disorders since 1933.

While stimulant treatments are highly effective for 75%–90% of children with ADHD, at least four separate psychostimulant medications consistently reduce the core features of ADHD in literally hundreds of randomized controlled trials:

1. methylphenidate,
2. dextroamphetamine,
3. pemoline, and
4. a mixture of amphetamine salts.

These medications are metabolized, leave the body fairly quickly, and work for up to four hours.

Many double blind studies over the past 40 years have uniformly agreed that stimulants such as methylphenidate, dextro-amphetamine, as well as other substances, are very effective in the treatment of 70%–80% of children and adults with ADHD.

One of the myths of ADHD is that ADHD children show a paradoxical effect of being calmed by stimulants, while “normal” individuals are stimulated by them.

However, studies have shown that the activity levels are decreased and attention levels are increased by stimulants in individuals with and without ADHD.

The difference is that since the levels of hyperactivity and inattention are much higher in ADHD subjects, the improvement is relatively much greater, giving the impression that they respond, while non-ADHD subjects do not.

Figure 2 shows how the stimulants work in ADHD.

…many still worry that ADHD children are receiving a form of “speed”. Studies have shown that in order to obtain a “high”, stimulants need to reach the brain very quickly. This requires intravenous or nasal administration.

At therapeutic oral doses, the stimulants used for treatment of ADHD do not cause a euphoric high. Perhaps the best indicator of this is that one of the hardest parts of the treatment for ADHD children is to get them to take their medication.

Other medications:

For children with ADHD who do not respond to stimulants (10%–30%) or cannot tolerate the side effects, other alternatives may be available.

However, other competitive solutions also have been tried with mixed results (Friel 2007).

• The anti-depressant bupropion has been found to be superior to placebo, although the response is not as strong as stimulants.
• Well-controlled trials have shown tricyclic antidepressants to be superior to placebo but less effective than stimulants. 
• Clonidine can be an effective mode of treatment of ADHD. Since it also treats motor and vocal tics, it is especially useful in the treatment of Tourette-syndrome children who also have ADHD.
• Neuroleptics have been found to be occasionally effective, yet the risk of movement disorders, such as tardive dyskinesia, makes their use problematic.

Lithium, fenfluramine, or benzodiazepines have not been found to be effective treatments for ADHD, nor have serotonin re-uptake inhibitors such as fluoxetine.

After this, the article talks about the problems with over-prescription of stimulants and medication in general and then dives into:

Combination therapy: a long-term approach

The short-term safety and tolerability of psychostimulants has been reasonably well studied, and the risks associated with these compounds in the short term are generally acceptable.

However, the amount of long-term effectiveness and safety data related to psychostimulant therapy is relatively small.

Data that do exist suggest that long-term treatment with psychostimulants in appropriately diagnosed patients may be associated with salutary effects as well as relatively modest risks. (Kociancic et al 2004).

One important treatment goal is to develop a side-effect free natural product to augment psychostimulants with the ultimate goal of reducing the need for psychostimulants.

Alternative Treatments

Most clinicians agree that a combination of medication and behavioral modification is the most effective approach to the treatment of ADHD, even though the medications appear to contribute greater benefits. 

Neutraceuticals: 

Because a number of amino acids have direct or indirect effects on the levels of specific neurotransmitters, they have the potential of helping to control some of the symptoms of ADHD.

It is not unlikely that some combinations of the above compounds, carefully tested in double-blind studies, may play a supporting role in controlling some of the symptoms of ADHD (Blum and Trachtenberg 1988; Blum et al 2000, 2006b; Blum and Payne 1991; Chen et al 2004).

Diets and vitamin supplements:

…findings support the effectiveness of food supplement treatment in improving attention and self-control in children with ADHD and suggest food supplement treatment of ADHD may be of equal efficacy to Ritalin^® treatment.

Dopaminergic and serotonergic releaser combination therapy:

Previous data suggest that serotonin neurons can provide regulatory influence over mesolimbic dopamine neurons. Thus, it might be predicted that the balance between dopamine and serotonin transmission is important to consider when developing medications with reduced stimulant side effects.

For example, it has been shown that pharmacological manipulations increase extracellular serotonin attenuate stimulant effects produced by dopamine release.

Finally, they discuss their recently published data about PAL-287 (naphthylisopropylamine), a novel non-amphetamine dopamine/serotonin-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties (Hiebel et al 2007).

Using this concept we have developed the Synaptamine Complex (SG8839)^™ and have recently published on its effects (Chen et al 2004). \

Table 3 provides details about the ingredients of the synaptamine complex, as well as proposed brain targets and behavioral changes.

Table 3: Synaptamine complex review

Supplemental ingredient	Restored brain chemical	Addictive substance abuse	Amino acid deficiency symptoms	Expected behavior change
D-Phenylalanine or DL-Phenylalanine	Enkephalins Endorphins	Heroin, alcohol, marijuana, sweets, starches, chocolate, tobacco	Most reward deficiency syndrome (RDS) conditions sensitive to physical or emotional pain. Crave comfort and pleasure. Desire certain food or drugs. D-phenylalanine is a known enkephalinase inhibitor.	Reward stimulation. Anti-craving. Mild antidepression. Mild improved energy and focus. D-Phenylalanine promotes pain relief, increases pleasure.
L-Phenylalanine or L-Tyrosine	Norepinephrine Dopamine	Caffeine, speed, cocaine, marijuana, aspartame, chocolate, alcohol, tobacco, sweets, starches	Most RDS conditions. Depression, low energy. Lack of focus and concentration. Attention-deficit disorder.	Reward stimulation. Anti-craving. Anti-depression. Increased energy. Improved mental focus.
L-Tryptophan or 5 hydroxytryptophan (5HTP)	Serotonin	Sweets, alcohol, starches, ecstasy, marijuana, chocolate, tobacco	Low self-esteem. Obsessive/compulsive behaviors. Irritability or rage. Sleep problems. Afternoon or evening cravings. Negativity. Heat intolerance. Fibromyalgia, SAD (winter blues).	Anti-craving. Anti-depression. Anti-insomnia. Improved appetite control. Improvement in all mood and other serotonin deficiency symptoms.
GABA (Gamma-amino butyric acid)	GABA	Valium, alcohol, marijuana, tobacco, sweets, starches	Feeling of being stressed-out. Nervous. Tense muscles. Trouble relaxing.	Promotes calmness. Promotes relaxation.
L-Glutamine	GABA (mild enhancement) Fuel source for entire brain	Sweets, starches, alcohol	Stress. Mood swings. Hypoglycemia.	Anti-craving, anti-stress. Levels blood sugar and mood. GABA (mild enhancement). Fuel source for entire brain.

 

Summary

ADHD is a complex disorder, usually appearing first in childhood, and having multiple causes including genetics as impacted by one’s environment.

In order to dispel myths about ADHD, it will require examination of the additive effects of multiple genes.

Further, and because polygenic inheritance is far more complex than single gene inheritance, an ultimate understanding of the role of any one gene involved in polygenic inheritance will require a summation across many different studies

While the use of psychostimulants has resulted in attenuation of behavioral symptoms in a high percentage of ADHD children, parents have been concerned about potential side effects.

In this regard, the extant evidence tends to support the novel concept of an adjunctive polypharmacy approach for the prevention and treatment of ADHD rather than single neurochemical and/or neurogenetic targets (eg, D₁-D₅, DAT₁, DBH, COMT, 5HT1B, NR4A2, SLC1A3, BDNF, as well as loci at 4q13.2, 5q33.3, 11q22 and 17p11)