Running head: METHYLPHENIDATE HYDROCHLORIDE

Alexander McClure
11/28/2016
Methylphenidate Hydrochloride
Introduction
Methylphenidate hydrochloride, hereafter referred to as MPH, is the active ingredient in
medications such as Ritalin and Concerta. These medications are central nervous system
stimulants and are used to treat attention-deficit hyperactivity disorder and, in the case of Ritalin,
narcolepsy (U.S. Food and Drug Administration). Side effects of MPH are primarily related to
the heart, psychiatric disorders, and circulation (U.S. Food and Drug Administration), although
other side effects exist.
Intended Treatment: Attention-Deficit Hyperactivity Disorder
The primary purpose of treatments using MPH is for attention-deficit hyperactivity
disorder for which it alleviates nearly all observed symptoms. According to the Fifth edition of
the American Psychiatric Associations Diagnostic and Statistical Manual, 5th ed. (2013),
hereafter referred to as the DSM-5, ADHD is defined by persistent inattentiveness and
hyperactivity-impulsivity. These are ranked based on how many symptoms among a predetermined set are expressed within each category. When an approximately equal number from
each category are expressed, the ADHD diagnosis is referred to as a Combined Presentation.
When inattentiveness is more prevalent it is referred to as Predominately Inattentive
Presentation, and when hyperactivity-impulsivity is more prevalent it is referred to as
Predominately Hyperactive-Impulsive Presentation.
Symptoms of inattention include failing to pay attention to details or makes careless
mistakes in tasks, lack of attention during activities, does not seem to listen when being spoken
to, failure to complete tasks, lack of organization, and multiple other similar symptoms.
Symptoms of hyperactivity and impulsivity include fidgeting, inability to remain seated even,

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inclination to run or climb in children or general restlessness in adults, inability to remain quiet,
difficulty waiting, and several other symptoms along similar lines. In regards to children up to
sixteen years of age, there must be six or more symptoms within each category displayed for at
least six months to be considered ADHD. For adults seventeen years and older there must be five
or more symptoms within each category displayed for at least five months to be considered
ADHD (American Psychiatric Association, 2013).
ADHD is caused by a lack of extracellular dopamine in the brain as a result of an excess
of dopamine transporters (Volkow et al., 2001). This means that afflicted individuals will
effectively not receive weak dopamine signals such as those responsible for task-focus and will
fail to receive the natural dopamine reward upon task completion (Volkow et al., 2001). Both
of these factors are responsible for the hyperactive-impulsive and inattentive effects in those
suffering from ADHD and the variability within each factor explains the wide variety of
potential symptoms.
Intended Treatment: Narcolepsy
In addition to ADHD, Ritalin is used as a potential treatment option for narcolepsy.
Narcolepsy is defined by excessive daytime sleepiness and can also cause cataplexy, the abrupt
loss of muscle tone that can result in complete loss of voluntary muscle control (Lee and Radin,
2016). The primary cause of narcolepsy is from a lack or acquired loss of a variety of neurons
that would produce hypothalamic hypocretin (orexin), which are required for the proper balance
of wakefulness. Along with these two characteristics of narcolepsy, the DSM-5 (2013) also
includes abnormal REM patterns when first falling asleep and when waking, resulting in sleep
paralysis or hypnopompic or hypnagogic hallucinations.

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As a central nervous system stimulant, MPH can be effective in encouraging wakefulness

as a treatment for narcolepsy (U.S. Food and Drug Administration).
Effects on Healthy Individuals
With a growing prevalence of usage of MPH among the healthy population, information
regarding its effects on individuals that do not suffer from ADHD or narcolepsy has become a
topic of greater focus (Bagot and Kaminer, 2014). Methylphenidate HCl is known to improve
reaction time and accuracy in tasks requiring cognitive attention even in individuals that do not
suffer from ADHD (Ernst et al., 2016). Additionally, methylphenidate improves declarative
memory, attention, response inhibition, and increases planning capabilities, adaptation
capabilities, and verbal memory when faced with unique problems. Each of these effects have
been show to become increasingly more effective as the difficulty of the task rises (Bagot and
Kaminer, 2014). However, while it improves verbal memory it has not been shown to improve
visual memory.
While there are some observed benefits of taking MPH while not suffering from ADHD
or narcolepsy, potential side effects remain a concern for those only seeking a cognitive boost
without physician supervision.
Side Effects
As a central nervous system stimulant that functions based on interactions with dopamine
transporters in the brain, there are a wide variety of potential side effects that MPH can cause.
The more dangerous side effects include problems associated with the heart such as stroke, heart
attack, elevated blood pressure, and elevated heart rate (U.S. Food and Drug Administration).
Reduced circulation to extremities is also a potential concern. Potential psychiatric side effects
include newly developed or worsening of pre-existing behavioral and thought problems, bipolar

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personality disorder, aggressive behavior, and in the case of teenagers and children, development
of psychotic or manic symptoms (U.S. Food and Drug Administration). Additionally, MPH can
increase feelings of anxiety (Ernst et al., 2016).
Less prevalent, although still dangerous, side effects include reduced growth in children,
seizures, decreased eyesight, and painful, long-lasting erections referred to as priapism. Lesser
but more common side effects include headaches, stomach aches, nausea, difficulty sleeping,
loss of appetite, and general nervousness (U.S. Food and Drug Administration).
Mechanisms
While the exact mechanism through with MPH interacts in the brain is not fully
understood, it is known that it is an antagonistic inhibitor to dopamine transporters (Volkow et
al., 2001). When active, dopamine transporters remove dopamine from the extracellular space.
As such, the inhibition of dopamine transporters will increase the concentration of extracellular
dopamine in the brain. This allows the extracellular dopamine to relay its signal more effectively,
producing a stronger response. A similar, although lesser, effect of MPH is found with
norepinephrine (NE) transporters as well (Berridge & Arnsten, 2013).
Both dopamine and NE are related to arousal and the waking state, explaining why MPH
is beneficial to those who suffer from ADHD and why it can be used to improve wakefulness in
those suffering from narcolepsy. However, a balance needs to be present in the concentrations of
NE and DA. Too much of either can have detrimental effects on working memory due to the
stress of stimulant abuse, while too little will result in their depletion and failure to signal the
desired response (Berridge & Arnsten, 2013).
Those that suffer from ADHD have an excessive amount of dopamine transporters
present in the extracellular space. This results in a lack of dopamine that is attributed to be the

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cause of the disorder. By inhibiting the dopamine transporters with MPH, the dopamine levels
are allowed to reach a concentration that is within the standard range. However, even in
individuals that do not suffer from ADHD, an increased amount of dopamine can produce
enhanced cognitive capabilities, indicating that the standard dopamine concentrations may
naturally be lower than would produce the optimum cognitive output (Berridge & Arnsten,
2013).
Dependence or Addiction
MPH increases the amount of extracellular dopamine in the brain. This is accomplished
by inhibiting the dopamine transporters that typically remove dopamine from the extracellular
space in the brain (Volkow et al., 2001). When taken by individuals who suffer from ADHD, this
serves to prevent the excessive amounts of dopamine transporters from severely reducing the
effectiveness of the dopamine. In individuals who do not suffer from ADHD it will also increase
the extracellular dopamine concentration, resulting in a larger than necessary dopamine
concentration. This will produce a euphoric feeling typically associated with excess dopamine
and a further increased dopamine response to task completion (Volkow et al., 2001). As such,
there is an amount of behavior reinforcement in healthy individuals who do not require MPH that
is not present in those who do have ADHD.
This said, the extent of which behavior reinforcement is encouraged is substantially less
than what is seen with cocaine or amphetamines despite the similar effects on dopamine levels in
the brain (Svetlov et al., 2007). This is likely due to the length of time between oral
administration of the drug and the start of its effects being too long to trigger the behavioral
reinforcement by association of taking the pill and its effects (Volkow et al., 2001; Svetlov et al.,

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2007). This, coupled with the short half life of MPH (Volow et al., 2001), results in it having
minimal addictive or dependence-causing properties (Svetlov et al., 2007).
Conclusion
Methylphenidate HCl is an effective active ingredient seen in medications such as Ritalin
and Concerta to treat ADHD and narcolepsy. Even though it functions by inhibiting dopamine
transporters to increase dopamine concentration in the extracellular space in the brain, it is
largely non-addictive and does not form dependencies. However, it is still abused in some cases
for its cognitive enhancements and the high associated with dopamine release. While there are
potentially dangerous side effects, most are manageable or detectable before damage occurs.
This, along with the general effectiveness of MPH, ensures that it will likely be used as a
medication for quite some time.

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References
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders,
5th edition. Arlington, VA: American Psychiatric Association.
Bagot, K. S. & Kaminer, Y. (2014). Efficacy of stimulants for cognitive enhancement in nonattention deficit hyperactivity disorder youth: A systematic review. Addiction, 109(4),
554-557. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24749160
Berridge, C. W. & Arnsten, A. F. T. (2013). Psychostimulants and motivated behavior: Arousal
and cognition. Neuroscience and Behavioral Reviews, 37, 1976-1984. Doi:
http://dx.doi.org/10.1016/j.neubiorev.2012.11.005
Ernst, M., Lago, T., Davis, A., & Grillon, C. (2016). The effects of methylphenidate and
propranolol on the interplay between induced-anxiety and working memory.
Psychopharmacology, 233(19-20), 3565-3574. Doi: 10.1007/s00213-016-4390-y
Lee, R. U. & Radin, J. M. (2016). A population-based epidemiologic study of adult-onset
narcolepsy incidence and associated risk factors, 2004-2013. Journal of Neurological
Sciences, 370, 29-34.
Svetlov, S. I., Kobeissy, F. H., & Gold, M. S. (2007). Performance enhancing, non-prescription
use of Ritalin: A comparison with amphetamines and cocaine. Journal of Addictive
Diseases, 26 (4), 1-6. Doi: 10.1300/J069v26n04_01
U.S. Food and Drug Administration. Medication guide Concerta (kon SER-ta) (methylphenidate
HCl) extended-release tablets CII. Retrieved from
http://www.fda.gov/downloads/drugs/drugsafety/ucm088575.pdf
U.S. Food and Drug Administration. Medication guide Ritalin (methylphenidate hydrochloride,
USP) tablets CII. Retrieved from
http://www.fda.gov/downloads/drugs/drugsafety/ucm089090.pdf
Volkow, N. D., Wang, G. J., Fowler, J. S., Logan, J., Gerasimov, M., Maynard, L., Ding, Y. S.,
Gatley, S. J., Gifford, A., & Franceschi, D. (2001). Therapeutic doses of oral
methylphenidate significantly increase extracellular dopamine in the human brain. The
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