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=Comparative Study of the Two Most Popular ADHD Medications Amphetamine and Methylphendidate=

Abstract
This comparative study attempts to examine 3 popular medications used for the treatment of ADHD. The study attempts to identify each drug’s effect on our bodies and label the risks and benefits of each medication.

Introduction and Background
Attention Deficit Hyperactivity Disorder, ADHD, is mental disorder that affects approximately 8% of children in the United States [1]. The mental disorder was identified as early as eighteenth and nineteenth centuries [2]and has been described as a condition where the affected may have difficulty in paying attention, in controlling behavior, or in maintaining hyperactivity. ADHD is a disorder that affects social and academic functions. The disorder is diagnosed through a list of criteria and symptoms mentioned in The Diagnostic and Statistical Manual of Mental disorders (DSM-IV), a classification and diagnostic tool published by the American Psychiatric Association. The causes of ADHD have not been pinpointed, but have been vaguely attributed towards genetic, environmental, and brain damage [3]. Due to the vague and limited knowledge in the causation of the disorder, there have been controversies around the disorder, questioning the need or usage of medication [1]. This study compares three of the most widely used medications used for treating ADHD: amphetamines, methylphendidate, and atomoxetine [4]. Because ADHD is a fairly vague disorder that is affected by many factors, such as other mental or physical conditions, the study looks at the efficacy of each drug and potential risks or disadvantages over the other two. The study tries to compare each drug's effect on the body as well efficacy reported by other studies.

=Amphetamine=

History and Background
dextroamphetamine levoamphetamine Alpha-methylphenethylamine, or more commonly known as amphetamine, is a central nervous system stimulant that was first synthesized in 1887 [5]. The chemical has two optical isomers that are dextroamphetamine and levoamphetamine. The first clinical use of amphetamine was in the early 1930s in the drug Benzedrine, which was a racemic mixture of amphetamine sold as a decongestant inhaler. Amphetamines were first discovered to have a positive effect on school performance in 1937 by Charles Bradley [2] and since have been studied for ADHD treatment since. In medications, amphetamine is often presented as a mixed salt in forms such as amphetamine sulfate. Popular medications today such as Adderall are presented as mixed salts while certain medications such as Dexedrine are simply one isomer (dextroamphetamine). The drug today is classified as a schedule II controlled substance by the FDA, indicating that the compound is a medically used drug that has a high potential for abuse which can lead to severe psychological or physical dependence

Amphetamine Synthesis
A simple reaxys search of amphetamine as a product gives 326 reactions, suggesting that amphetamine synthesis has been widely explored and is not something that is terribly difficult. One of the most simplest amphetamine creations seems to be Leuckart reaction where a mix of phenyl-2-propanone, formamide, and formic acid are heated until N-formylamphetamine is produced as an intermediary. The N-formylamphetamine intermediary is then hydrolized with HCl and washed with base. The amphetamine product is then isolated and distilled. [6]

Amphetamine in the body
Because the exact reasons and causes for ADHD is unknown there is no clear and definite reason as to why the drug has shown signs in alleviating the symptoms of ADHD. However, studies of ADHD causes have shown that genetics have a large impact on the development of ADHD. Data from twin and adoption ADHD studies have shown that many of the genes affecting ADHD are related to dopamine functions [7][8]. Amphetamine has shown to be related to many functions in the body that have to do with dopamine regulation. Amphetamine has beecn classified as a u A notable interaction has been that amphetamine is an inhibitor of two key proteins: vesicular monoamine transporter 2 (VMAT2) and dopamine transporter(DAT1). Dextroamphetamine has been found to bind to specific sites of VMAT2, disabling it[8]. It also affects DAT1 by reversing its function, releasing more dopamine[9]. This general interaction of increasing dopamines have seemed to help with ADHD symptoms.

Efficacy in Studies
Numerous studies have shown that amphetamine does improve ADHD symptoms. Studies have shown that amphetamine was able to lower the symptoms of ADHD. Methods of measuring its efficacy was through the DSM-IV test mentioned in the introduction of this paper. Throughout different tests, the amphetamine mixed salt prescription prevails over the placebo, affirming its actual effectiveness in treating ADHD.[10][11][12] The graph taken from [12] shows that the mixed amphetamine prescription shows the ADHD rating scale measured by DSM-IV lowering, showing reductions in the symptoms of ADHD. Graph (B) continues to show that after the switch in placebo and the actual drug, The actual drug shows its effectiveness within a week.

Adverse Effects
The amount of adverse effects is incredibly low. Outside of the rare side effects presented by the drug company (Abdominal Pain, Fever, Infection, Accidental Injury, Asthenia, etc.)[13], the most pertinent adverse effect may be addiction. As a schedule II controlled substance, addiction is possible. However, studies have shown that proper usage of the drug at non-recreational and recommended dosages should not cause addiction.[14][10] Graph from [14] shows the effectiveness of the drug over the placebo. Comparative results against

History and Background
Methylphenidate is another central nervous system stimulant drug that is commonly used for the treatment of ADHD. Synthesized in 1944 by Leandro Panizzon, methylphenidate, unlike amphetamine, was used for treating hyperactivity from the start. It was owned by Ciba-Geigy Pharmaceutical Company and was called Ritalin ever since. The drug is still being marketed under the name of Ritalin and is the first choice for ADHD treatment [4][15]. There are four possible isomers of methylphenidate, but only d-threo-methylphenidate of them is used in medications.[16] Methylphenidate also has two different forms commercially available. There is an immediate release form like Ritalin. But there is also a slow release, or extended release, in the form of Concerta or Ritalin-SR. Also, there are transdermal methods oral methods of taking the drug.

Methylphenidate Synthesis
Like amphetamine, methylphenidate does not seem to be a particularly hard compound to synthesize. Reaxys gave 144 reactions: significantly less than amphetamine, but ample reactions to show that it is a compound that has been synthesized often. A particular stereoselective synthesis for the d-threo-methylphenidate is shown in the scheme below.[17]

Methylphenidate in the Body
Much like amphetamine, methylphenidate has similar effects on the body with dopamine release. However, unlike amphetamine, methyphenidate is only a dopamine reuptake. Methylphenidate inhibits and blocks the membrane protein dopamine transporter (DAT), which manages dopamine through pumping dopamine out of the synapses [18]. Although it is not exactly known why exactly methylphenidate helps with ADHD symptoms, the dopamine increase is suspected to help with lessening the symptoms of ADHD.

Efficacy in Studies
Studies show that methylphenidate is effective in treating ADHD much like results for amphetamine did. Efficacy of the drug was usually measured with the DSM-IV just like the amphetamine was measured. Both the immediate release and extended release forms of methylphenidate seem to be effective. [11][19] The graph taken from [19] shows the significant effectiveness of methylphenidate over the placebo

Adverse Effects
There have been reports of methylphenidate being related to high blood pressure and cardiac arrest[20]. However, there have been no studies that support the one time incident of cardiac arrests that was reported by the FDA.

Comparative Analysis
The two drugs do not have much difference in effects at all. Although there are minor differences in its function throughout the body, both drugs show a decrease in ADHD symptoms without much adverse effects. Although there are differences between the efficacies of the drugs in comparison to their individual placebos, it is hard to definitely say that one or the other is more effective due to differences in population and circumstances.

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