final ritalin paper - nicole brooker · ritalin2! nicolebrooker!! ritalin is a stimulant drug that...

Ritalin Drug Discovery, Development, and ADHD

Nicole Brooker

Ritalin 2 Nicole Brooker

Ritalin is a stimulant drug that was prescribed to nearly 9 million people in

1999 and the statistics continue to rise by a significant rate each year. Ritalin

primarily treats ADHD, and it is ranked 39 among the top drugs in the United

States pharmaceuticals. In this paper the history and background of ADHD will

be discussed, the scientific discoveries that identified the disorder, and how

many people suffer with this disorder and why the drug is needed. The clinical

trials and efficacy will also be considered, including side effects and the Ritalin

developmental timeline. To delve deeper in the pathways and mechanisms, the

drug pathways of Ritalin and competing drugs will be examined, and finally the

sales and the patent of the drug will be analyzed.

The history of ADHD and Ritalin begins with Sir Alexander Crichton in

1798 who gave an example of a similar disorder to ADHD. Crichton’s work and

discoveries were due to his interests in mental illnesses, and he wrote a series of

books called “An inquiry into the nature and origin of mental derangement:

comprehending a concise system of the physiology and pathology of the human

mind and a history of the passions and their effects” during his clinical research

observing mental illnesses (Lange et al. 2010). In his second book, Crichton

wrote about attention and its alterations in mental illnesses, and how

inattentiveness was due to a nervous disorder and brain dysfunction (Lange et al.

2010). Following Crichton’s studies, modern medicine and science was able to

link his observations to the current idea of ADHD, suggesting that the disorder or

a related disorder dates back to the eighteenth century.


The history of ADHD continues on to 1844 with the German physician

Heinrich Hoffmann and his children’s stories titled “Fidgety Phil” (Lange et al.

2010). The stories tell of a young child, Philip, sitting at dinner with his family.

The father wonders whether his son will

behave at the dinner table or not, suggesting

that Phil had some behavior problems. Phil

squirmed and tilted in his chair, not listening

to what his father told him. The story

continues with Phil’s misbehavior until he

falls back in his chair, taking the tablecloth with the food, silverware, and drinks

with him crashing to the floor. This story represents inattentiveness and bad

behavior in the nineteenth century, and many scientists and authors are

convinced that this is another piece of evidence reflecting current ideas of ADHD

(Lange et al. 2010). In 1902, George Frederic Still gave lectures on post-

encephalitic behavior disorders demonstrating what most authors today believe

was the first scientific recognition of ADHD (Lange et al. 2010). In his lectures he

discusses origins of hyperactivity and minimal brain dysfunction in children,

which can be viewed as a precursor to ADHD. Later on in 1932, Franz Kramer

and Hans Pollnow reported “On a hyperkinetic disease of infancy” where they

discussed impulsivity and all of the signs and symptoms of what we know as

modern day ADHD (Lange et al. 2010). It wasn’t long after their discoveries that

treatment research started.

Figure 1: "Fidgety Phil" illustrates what appears to be ADHD in the 19th century.


We then move on to 1937 where we see the first treatment of the disease

by Charles Bradley (Lange et al. 2010). Bradley studied the positive effect that

stimulants had on children with behavioral disorders. Bradley’s discovery of the

positive effect of stimulant drugs was found by chance during his neurological

examinations (Lange et al. 2010). He tested the way children focused and did

school work while on Benzedrine. The improvement seen would be revolutionary

and lead to future studies in ADHD treatment.

After Bradley used Benzedrine, other scientists worked with stimulants to

correct behavior, including the most commonly used stimulant drug today:

“Ritalin” or Methylphenidate. Leandro Panizzone was the first to synthesize the

drug in 1944 and he named it after his wife, Rita (Lange et al. 2010). It was first

used to treat depressive behavior and lethargy, and wasn’t until later that it was

linked to and used for ADHD treatment.

Attention deficit hyperactivity disorder is characterized by inattention,

hyperactivity, and impulsivity, and is seen mostly in children. The average age of

diagnosis is 7 years ("Attention-deficit / hyperactivity," 2013). ADHD has three

subtypes: Predominantly hyperactive-impulsive, Predominately inattentive, and

combined hyperactive-impulsive and inattentive ("What is attention,”). Most

children have the combination of hyperactive-impulsive and inattentive behavior.

In order to diagnose a child with this disorder they need to have at least six

symptoms from these three subtypes. Some of the symptoms for hyperactive

behavior include fidgeting and constantly being in motion, unable to sit down at

dinner, and touching or playing with anything in sight. Symptoms of impulsive


behavior include blurting out inappropriately, impatience, and no restraint of

emotions. Inattentive behavior can include lack of focus, easily distracted,

daydreaming, inability to complete assignments, often losing things, and

becoming bored with a task unless its enjoyable ("What is attention,”).

As for the causes of ADHD, there have been studies on the potential

factors but it is still unknown if there is an underlying cause. Some of the factors

that have been found to cause ADHD include genes, environmental factors, brain

injuries, sugar, and food additives. Studies have shown that children with ADHD

have thinner brain tissue in the areas associated with attention that can be

causative by genes. Environmental factors such as cigarette smoking and

alcohol use during pregnancy have been seen in children with ADHD. Brain

injuries have caused ADHD in very few cases, and sugar and food additives such

as colors and preservatives are also being considered as factors causing ADHD

because they result in an increase in activity ("What is attention,”).

ADHD diagnosis has increased at a significant rate since the early 1990’s,

and over 6.4 million children are affected by this disorder. As of 2011, 11% of

children ages 4-17 years of age have been diagnosed with ADHD. The rate of

diagnosis continues to increase from an average of 3% per year from 1997-2006

to a 5% average per year from 2003-2011 ("Attention-deficit / hyperactivity,"

2013). The average age of diagnosis is 7 years of age and 13.2% of boys are

diagnosed versus 5.6% of girls who are diagnosed ("Attention-deficit /

hyperactivity," 2013). This is clearly an escalating issue among the younger

generations and an effective drug for treatment is necessary, and thus far Ritalin


has been proven to be a great solution for those who suffer with this disorder.

ADHD is an amenable target for Ritalin because the drug acts on the prefrontal

cortex of the brain. This anterior part of the frontal lobes is important in complex

cognitive and social behavior, which is the type of behavior that children with

ADHD lack ("Ritalin targets prefrontal," 2012).

Wiseberg and Robin did clinical trials in 1958 while testing the efficacy and

effects of Ritalin on depressive states (Robin & Wiseberg, 1958). Some patients

in the trial declined due to unpleasant side effects and those who stayed denied

any change to their depressive states, therefore the Ritalin was denied for use to

treat depression symptoms (Robin & Wiseberg, 1958).

Later in 2007, trials on methylphenidate had been done by Novartis to test

the safety and efficacy of Ritalin in children with ADHD with the variant being

different breakfast conditions (Novartis, 2011). The results from the trial showed

overall that the drugs are safe, and safe under all different breakfast conditions

(Novartis, 2011). Other studies have been done to test the efficacy of

methylphenidate among differently behaved children with ADHD. Although the

results didn’t show that Ritalin helped all children in reducing hand movements

and distracted behavior, it did show an overall decrease in aggressive behavior

(Wulbert & Dries, 1977). Ritalin might not work for every child with ADHD but the

efficacy and safety overall puts this drug in the category of best drugs for ADHD

treatment.

Lastly, there was a study done to test efficacy of Ritalin based on the

therapeutic doses given. The results of the study showed that the Ritalin


effectively reduced the “signal to noise

ratio” and the therapeutic amount of

dopamine was effective in improving

performance and motivation (Volkow et al.

2001). Considering that ADHD and Ritalin

use is fairly new, there have been very

few studies on long-term effects. There

has been a study, however, on the effects of oral methylphenidate use on the

brain after 12 months of use. These studies showed that as time progressed, the

density of dopamine transporters in the brain increased as drug use progressed.

This could eventually lead to a tolerance and resistance to Ritalin long-term if the

dopamine transporters begin beating the drug to binding the dopamine in the

synapse (“Long-term adhd treatment,” 2013).

Other studies have been released relating Ritalin to other dangerous

drugs such as cocaine. Many parents and other users had concerns about

possible “highs” that they could get

following Ritalin use. A study was done to

test if the cocaine and methylphenidates

did compete for the same binding sites in

the brain, and if so, was the uptake of the

drug different in either case (Volkow et al.

1995). The results suggested that

Figure 2: Red shows the higher amount of DAT's present after a year of methylphenidate use.


although both of the drugs inhibit the reuptake of the dopamine in the brain,

Ritalin does it at a significantly slower rate (90 minutes) compared to cocaine (20

minutes) (Volkow et al. 1995). Because of the very fast uptake of the Cocaine in

the brain, the user feels a high while Ritalin has a slower uptake and clearance of

methylphenidate from the brain. In Figure 3 above we can see that even with

different percent occupancies of dopamine transporters for those taking Ritalin,

most of the subjects reported zero for their self-

reported high.

Ritalin has several different side effects,

both common and more severe. Some

common side effects include nervousness,

anxiety, insomnia, nausea, loss of appetite, dry

mouth, increased heart rate, stomachache, and

headache. More severe side effects include

chest pain; shortness of breath, or irregular

heart beat in which immediate medical

attention is necessary (Barkley et al. 1990).

Insomnia and decreased appetite were seen to

increase in severity as the dosage increased.

Decreased appetite increased in severity from 7% to 18% while Insomnia

increased from 1% to 13% (Barkley et al. 1990). Research has also shown that

several different side effects decreased with a higher dose of Ritalin such as nail


biting, daydreaming, anxiety, and irritability.

These side effects were reported to decrease significantly when dosage was

increased from 0.3 mg/kg to 0.5 mg/kg (Barkley et al. 1990). Girls also reported

stomachaches, nail biting and headaches more often than boys (Barkley et al.

1990). Very few children experienced severe side effects and there were no

significant variations among different ages (Barkley et al. 1990).

The timeline for the development of Ritalin begins in 1944 when Leandro

Panizzon first synthesized it for his wife’s fatigue and depression. For the next six

years Ritalin was modified and improved by Panizzon and other groups for better

targeting of the disorder and the new formula was patented in 1950 (Lange et al.

2010). After the modifications were done, human trials began in 1954. CIBA filed


to trademark the drug and in 1956 the FDA approved the patent (Daemmrich &

Bowden 2005). CIBA began the marketing of Ritalin for depression, fatigue, and

narcolepsy in 1957 (Ritalin, 2013). During this time up to the 1960’s, the

therapeutic effects of Ritalin on ADHD were being studied. In 1960, Ritalin was

primarily made into a cocktail of vitamins and hormones called Ritonic, which

was used to increase mood and vitality (Ritalin, 2013). Finally in the 1970’s, after

Ritalin and its therapeutic affects on ADHD had been studied, Ritalin was being

prescribed to children with ADHD (Daemmrich & Bowden 2005). Starting in the

1990’s Ritalin sales boomed by 500% and the U.S. made 85% of the world’s

Ritalin. Today, methylphenidate is the most common drug prescribed in treating

ADHD (Lange, et al. 2010).

ADHD can be treated with several different drugs, classified as either

stimulants or non-stimulants. Today, the disorder is treated primarily by

stimulants. It was a strange finding when a stimulant was used to treat

hyperactivity. However, this works because it has a calming effect on those with

ADHD, but has an opposite effect on those who do not have the disorder.

Psychostimulants work in the nervous system and they all work by affecting the


release and reuptake of the neurotransmitters dopamine and epinephrine. The

following paragraph will discuss the different drug competition for Ritalin and

break it down more specifically into the difference between two classes of drugs

most used in treating ADHD: methylphenidates and amphetamines.

Ritalin has many competitors on the market including other brands of

methylphenidates, amphetamines, lisdexamfetamines, and

dexmethylphenidates. Drugs with similar mechanisms and structure include

Concerta, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin SR,

Ritalin LA, Daytrana, and Quillivant XR (Quinn, 2012). Each of these

methylphenidates is a pipiridine compound and has the formula C14H19NO2, and

they work by binding to the dopamine

transporters (DAT) in the synapse to reduce

reuptake of the dopamine from the synaptic

space (Sherzada, 2012). Ritalin therefore acts

as a norepinephrine-dopamine reuptake

inhibitor allowing these neurotransmitters to remain in the extracellular space,

thus allowing more motivation and concentration for the user. The inhibiting drug

increases concentration because there will be more norepinephrine in the

synapse for longer which is the monoamine responsible for concentrated

behavior. Motivation will be increased as well because of the greater amount of

dopamine, which is the reward-motivation neurotransmitter (Sherzada, 2012).

Perhaps the biggest question and competition involving attention deficit

disorder medications is whether methylphenidates or amphetamines are best,


which leaves Adderall and the other amphetamines (such as Dexedrine) to be

the most competition to Ritalin on the market. These two types of ADHD

stimulant drugs are different in their

structure, mechanism, and target. As

explained previously, Ritalin (or

methylphenidate) works primarily by

targeting and binding dopamine transporters in the brain and inhibiting reuptake

of these neurotransmitters. Amphetamines, such as Adderall, have the formula

C9H13N and work in an opposite manner. During metabolism the aromatic ring in

amphetamine oxidizes to form hydroxyamphetamine, which then deaminates to a

phenylacetone and finally oxidizes to benzoic acid (Sherzada, 2012). The goal of

Adderall and amphetamines is similar to that of methylphenidates, to increase

dopamine and norepinephrine levels in the synaptic space. However, they do it in

a much different way than Ritalin. It can be said that the amphetamines affect

DAT’s in reverse. Rather than binding to inhibit dopamine reuptake, the

amphetamine enters the presynaptic neuron and expels dopamine by creating an

action potential that forces the molecules out of their storage vesicles into the

synaptic space (Sherzada, 2012). Amphetamines can also inhibit monoamine

oxidase, the enzyme that is responsible for breaking down of neurotransmitters

(Sherzada, 2012).

The difference in the drug response is that typically Adderall is faster

acting, but for a shorter period of time. This is because of the rapid mechanism of

expelling the neurons stimulating monoamine release and inhibiting the enzyme


that breaks down these neurotransmitters. Ritalin is slower acting but over a

longer period of time because of the DAT binding and inhibition, which allows the

neurotransmitters to remain in the extracellular synaptic space.

Vyvanse is another type of ADHD drug that isn’t categorized as a

methylphenidate or amphetamine, but rather a Lisdexamfetamine. Its formula is

C15H25N3O. This drug is a

psychostimulant like the others

but it is also coupled with Lysine.

Vyvanse was developed so the amphetamine in it is activated and released

slower than the other drugs previously discussed. This happens when it is

metabolized, the drug is hydrolyzed which then allows cleaving off of the amino

acid (“lisdexamfetamine”). Focalin is another drug that didn’t fit in the previous

categories; it is classified as a dexmethylphenidate. Focalin has the formula

C14H19NO2. This drug functions most similarly to amphetamines, as in binds the

DAT’s and releases monoamines into the synaptic space by entering the neuron.

It is also a central nervous

system stimulant like the drugs

previously discussed.

As the diagnosis and

prescription of Ritalin increases,

so have the sales over the

years. In 1991 roughly 2 million

prescriptions of Ritalin were


given, and in 1999 over 9 million people have been prescribed (“Statistics on

stimulant”). As mentioned earlier, in 2003, 7.8% of children ages 4-17 were

diagnosed with ADHD and in 2011 that number grew to 11% and it continues to

be on the rise. Ritalin sales have drastically increased over the years from

roughly $180,000,000 in 2011 to over $350,000,000 in 2013 (“Methylphenidate

Sales Data,” 2013). The drug is currently ranked number 39 in the U.S. among all

pharmaceutical drugs.

We can also see that as demand goes up from increased diagnosis,

production goes up as well. There is a significantly greater amount of

methylphenidate produced compared to amphetamine. We can see that in 1990

around 2,000 kilograms of Ritalin was produced in the U.S., which has

skyrocketed over the following 10 years

to over 150,000 kilograms a year in the

U.S. (“Statistics of stimulant”). It is also

interesting to see the geographical


statistics, over the average amount of Ritalin is prescribed in northern U.S.

The patenting of the drug began in 1950, when CIBA filed for the

trademark of what would soon be the brand name drug Ritalin that was a

methylphenidate drug, derived from amphetamine to treat hyperactivity (Lange et

al. 2010). In 1956, the FDA approved the methylphenidate drug and it was put

on the market to treat depressive mood disorders, fatigue, and narcolepsy. It

wasn’t until 1967 when the patent expired that Ritalin was discovered to actually

treat ADHD (Daemmrich & Bowden 2005). Since the original patent expired,

Novartis Corporation now owns the patent and it expires in 2015.

Ritalin has had a lot of success in treating ADHD over the years,

especially when sales and production boomed in the 1990’s. According to

history, symptoms of ADHD date back to the 17th century and are still seen in

millions of children and some adults today. Ritalin is an important drug on the

market as the expected diagnosis of ADHD is increasing at a rapid rate over the

years. Methylphenidate has been shown to be the safest and most effective

among the ADHD stimulant drugs, as there are several other variants of

methylphenidate similar to Ritalin. The other competing drugs were discussed

such as Adderall and other amphetamines, and how their mechanisms differ from

methylphenidate, which can explain why their effects on people differ. Studies

showed that different drugs affected children in different ways, although each

drug had a lot in common with the others being tested. For future research it

would be relevant to study in depth the long-term effects of Ritalin on those with

ADHD. Brief studies have been shown that over time with extended use of


methylphenidate, the number of dopamine transporters is increased in the brain,

posing a potential threat for future tolerance or drug resistance. Another area of

research could be to study the reasoning behind the intellectual boost that those

who don’t have ADHD get when taking Ritalin. Few studies have been done on

the effects of Ritalin on college students and studying for exams. More studies

also need to be done on the actual mechanism of action in the brain, since it is

so closely related to Cocaine and its pathway of stimulus.

Ritalin has provided scientists today with

a lot of faucets for further drug discovery and

research for ADHD. It is important to recognize

that not all drugs end up treating the symptoms

and disorders one might expect, and often

discoveries can be surprising. It was an

unexpected revelation to find that Ritalin would be used to treat hyperactivity

rather than depression, and that a stimulant would be a great drug for

hyperactivity. The known history and discovery of Ritalin and its target in ADHD

is an important step in the direction of better understanding mental health and

childhood psychiatric development.


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Robin, A. A., & Wiseberg, S. (1958). A controlled trial of methyl phenidate (ritalin) in the treatment of depressive states. J Neurol Neurosurg Psychiatry,21(1), Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC497294/ Sherzada, A. (2012). An analysis of adhd drugs: Ritalin and adderall. JCCC Honors Journal, 3(1), Retrieved from http://scholarspace.jccc.edu/cgi/viewcontent.cgi?article=1021&context=honors_journal Statistics on stimulant use. PBS. Retrieved from http://www.pbs.org/wgbh/pages/frontline/shows/medicating/drugs/stats.html Volkow, N. et al. (1995). Is methylphenidate like cocaine? studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry., 52(6), Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7771915 Volkow, N. D. et al. (2001). Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. The Journal of Neuroscience, 21, Retrieved from http://www.jneurosci.org/content/21/2/RC121.full.pdf Wulbert, M., & Dries, R. (1977). The relative efficacy of methylphenidate (ritalin) and behavior-modification techniques in the treatment of a hyperactive child. Journal of

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