RITALIN: A MEDICATION OF PARADOX

       Report on Primary and Secondary Symptoms

               by Sandra D'Angelo

     Imagine having a disorder in which the mainstream
medication that you are given is a slightly milder form
of speed. Psychopharmacolygists and many lay persons know
how detrimental speed or other street amphetamines are to
a person's health.  Ritalin, otherwise know as
methlyamphenidate, is this drug. In fact, ritalin is
administered to children as young as six years old.  This
drug is used to treat Attention Deficit Hyperactivity
Disorder (ADHD) in children and adults, narcolepsy, and
at times, depression. However, there is a moderate amount
of illegal usage of this drug. Because it delivers
similar, yet milder effects of crystal methylamphetamine,
crank, or speed, and it temporarily improves academic
concentration
skills to an immense degree, many people who do not have
prescriptions for it, seek it for study and/or  for
pleasure. Users of ritalin have reported that it gives a
high that is more intense than caffeine but milder that
speed. Other amphetamine drugs that are used to control
ADHD are Dexedrine (d-amphetamine), and Cylert
(pemoline). The paradox of the administration of ritalin
to people with ADHD is that, these people are given
"uppers" to slow their hyperactivity down. One theory
behind this is that the
reason these children are so hyperactive is, in fact, a
defense mechanism to entertain and occupy themselves. In
other words, these children have a deficiency of internal
stimuli and in coping with this lack of inner excitement,
their own psycho-physical workings creates stimuli. Thus,
they are unnaturally hyperactive and can not focus their
attention. These children do not have much of a problem
with watching Saturday morning cartoons but when it comes
to something that is not intensely stimulating (like
social
studies homework), they are lacking in their internal
mechanism of self-entertainment and the homework becomes
ten times more boring than it would be for a child
without ADHD. In balancing out this abnormal
physiological boredom, these children are given ritalin.
Ritalin, being a stimulant then gives these
under-stimulated children some much needed stimulation.
Thus, the children's bodies do not need to
create hyperactivity to fill this excitement void and as
a result, they appear to "calm down". (Knight, personal
communication). This is not to say that ritalin is the
ultimate answer for ADHD, and as will be shown in this
report, there are many untoward side effects from this
medication.
      This drug comes in the form of a fine, white,
odorless, crystalline powder and is water and alcohol
soluble. Ritalin is a piperidine central nervous system
stimulant. It activates brain stem arousal and is rapidly
and extensively absorbed. The primary sites of activity
occur in the cerebral cortex and the reticular activating
system. Ritalin releases nerve terminal stores of nor
epinephrine which increases nerve impulse transmission.
The bioavailablity is low (only 30%) and large individual
differences exist, from about 11 to 52 percent. Rapid and
complete absorption occurs from this drug with the peak
plasma concentrations occurring at one to two hours.
Effects last from four to six hours but the sustained
release version can last up to eight hours.  Seventy
eight to 97
percent is excreted in the urine and one to three percent
is excreted in solid waste. The main urinary metabolite
is ritalinic acid. Ritalin is metabolized by the liver.
The
average dosage for children is five to ten milligrams a
day while the dosage for adults is 20 to 30 times a day.
It is best to coincide administration of the medication
with periods of greatest academic, behavioral, and social
difficulties. Parents are urged to abstain administration
to their children on weekends and during the summer. Non
medical users have been known to crush the tablet and
snort it or dissolve it in water and cook it for
intravenous injection. This drug is designed to improve
problems with  severe distractibility, short attention
span, emotional lability, impulsivity, hyperactivity,
behavioral and social problems, and concentration
difficulties.       Usually, the effect of ritalin on a
child with ADHD is seen almost immediately. Positive
effects are seen in 70 to 80 percent of ADHD children.
The main positive effects are increased attention span, a
decrease of disruptive,
inappropriate, or impulsive behavior. The child is more
compliant and obedient to authority and a reduction in
aggression is seen. Peer relations tend to improve and
the child acts out less in social situations. The child's
handwriting usually improves, he or she tends to make
better judgments, and can focus attention better, and is
more organized. (Wender) Children given ritalin tend to
become
more likable, personable, sensitive to the needs of
others, and are more in control. The activity the child
engages in seems to have more purpose, and he or she is
less likely to miss instruction and direction. Temper
tantrums and
stubbornness decline and the child will be able to calm
down in situations, where formerly he or she responded
with escalating anger. At times, self-esteem and grades
improve. More children will want to be friends with the
child than did before the child was administered
medication (Beugin). An interesting point is that the
effects of ritalin on ADHD children is markedly different
than the effects on normal adults. Normal adults may feel
high; they have brighter
spirits, euphoria, lessened fatigue, cognitive alertness,
and an increase in motor activity. Certain individuals
may praise it for causing weight loss but this is
generally seen as an unwanted side effect. There is also
a high chance of addiction for adults. Conversely, ADHD
children may feel calmed down and in rare instances even
sad. They do not get high. Normal adults, on the other
hand, do get high and at times do have to increase their
dosage to a hundred times as much to get the same high.
(Wender)      If individuals have any of the following
pre-existing conditions, they should not be administered
ritalin: anxiety, tension, agitation, thyrotoxicosis
(Grave's
disease; a disorder of excess thyroid hormone
production), tachyarrhythmias (a change in heart rate;
particularly beating faster), hypersensitivity to
sympathomimetic amines (a drug that causes affects that
look like those made normally by the sympathetic nervous
system), cardiovascular disease, hyperthyroidism,
depression, parkinsonism, seizures, a history of
diabetes, severe angina pectoris
(which is chest pain caused by artery narrowing),
glaucoma, motor tics, or Tourrette's syndrome. Ritalin
can exacerbate all these problems and it may cause some
of these conditions to occur even if they are not
occurring prior to administration of the drug, so if an
individual has any of these conditions, the
administration of ritalin could be quite detrimental.
Unfortunately, many individuals who are diagnosed with
ADHD also have such problems as being over anxious, or
agitated, or have pre-existing motor tics. High rates of
symptoms of ADHD and learning disabilities have been seen
in children who suffer from Tourette's Syndrome.
(Braswell) Ritalin lowers the seizure threshold of the
brain so if a person has a tendency for seizures or has
epilepsy, he or she is much more likely to have seizures
if on this drug.
     The side effects that are produced by reactions with
ritalin on the central and peripheral nervous system are
as follows: dizziness, drowsiness, headache, dyskinesia
(impaired ability to make voluntary movements),
hyperactivity, convulsions, muscle cramps, confusion,
ringing in ears, athetosis (slow, twisting, continuous,
involuntary movements of arms and legs), tics, Torrette's
syndrome, hallucinations, and psychotic episodes. Side
effects that may occur in the gastrointestinal symptoms
are the following: nausea, abdominal pain, vomiting,
diarrhea, and cramping. Adverse reactions caused by
ritalin that are housed in the cardiovascular system are
the following: chest pains, peripheral vasospasm
(weakness in legs),
hypertension, palpitations, blood pressure problems,
pulse changes (up and down), tachycardia (heart rate over
100 beats per minute), angina (cramping chest pain), and
cardiac arrhythmias (irregular heartbeat). The side
effects that pertain to the skin are as follows: rash,
pruritis
(itching), urticaria (hives), fever, arthrlagia (joint
pain), and alopecia (hair loss). Some isolated cases of
the epidermis are the following: exfoliative dermatitis,
erythema multi-forme (nodules, pimples, blisters, bull's
eye areas that occur on skin and mucous membrane) with
histopatholigical finding of necrotizing vasculitis (skin
turning dead), and thrombocytopenic purpura.
Thrombocytopenic purpura is a bleeding disorder caused by
a decrease in the number of blood platelets. This results
in red blood spots, bleeding into the tissues, and
bruises. This is most likely to occur if the individual
is allergic to ritalin. Hematologic (meaning blood
related) symptoms are as follows: isolated cases of
leukopenia (abnormal decrease in number of white blood
cells), anemia, and thrombocytopenia. Thrombocytopenia
occurs when the number of blood platelets is reduced. It
is an immune response to ritalin.
     If an overdose occurs it is a result of central
nervous system over stimulation and the following
symptoms of an overdose may occur: vomiting, agitation,
tremors,
hyperflexia (the forcible overbending of a limb) , muscle
twitching, convulsions (possibly followed by coma),
extreme euphoria, marked confusion and dementia,
hallucinations, sweating, flushing, headache,
hyper-pyrexia (extremely high fever), tachycardia,
cardiac arrhythmias, mydriasis (pupil dilation; the drug
causes the dilator to pull the iris outward), dryness of
mucous membranes, gangrene, dizziness, fluctuations in
blood pressure, weak pulse, chest pain, tingling, and
numbness and coldness in extremities. 
     Because ritalin activates the sympathetic nervous
system, it causes an increase in heart rate, blood
pressure, vasodilatation (the dilation of blood vessels),
and bronchodilation (the dilation of the air passages in
the
lungs). Bronchodilation is considered favorable for
sufferers of asthma but it is seen as unappreciated side
effect for the ritalin user. In fact, the motivation
behind the invention of amphetamines was for asthma
sufferers in the first place. 
     The primary side effect symptoms are decreased
appetite and insomnia. On a medium dose, 56 percent of
subjects showed a decreased appetite and 68 percent
exhibited
insomnia. Stomachaches were had by 35% and headaches were
seen in 21 percent of the cases. Fifty four percent were
more prone to crying and 28% reacted with tics and
nervous movements. Only seven percent became excessively
dizzy while 20 percent became drowsy. Twenty nine percent
nail bit more and twenty two percent talked less. Anxiety
was felt by 52% and a great lack of interest in others
was shown in 15 percent. Forty three percent were lucky
enough to experience euphoria but 41% experienced
sadness. A large amount of 66% acted irritable and 21%
developed excessive nightmares. Thirty eight percent
developed what other kids would term a "staring problem."
They stared excessively and did not even look away when
stared back at. Strangely enough, when given a low dose
of ritalin, four percent of the subjects developed an
extraordinarily severe "staring problem".
Adults are much more prone than children to experience
the side effect of euphoria (which can lead to tendencies
of dependence.)
     The least serious side effects are stomachaches,
headaches, decreased appetite, and insomnia. The serious
side effects that can cause immense social and
psychological difficulties are the tics and the onset of
Tourette's syndrome. Even scarier is, that ritalin can
cause an
irreversible Tourette's syndrome; that even when the
person has been taken off medication, he or she still has
the disorder. For readers who are not familiar with
Tourette's syndrome it is a neurological disorder that
consists of persistent motor tics and compulsive
vocalizations. Sixty
percent of sufferers of Tourette's syndrome shout
obscenities involuntarily and compulsively. The onset
usually occurs at four to seven years and the early
symptoms are facial tics that eventually spread to neck
tics, then shoulder tics, then arm tics, then trunk tics,
and in
extreme cases, leg tics. Soon after the initial advent of
tics, the sufferer develops repetitive and constant
sniffing, throat clearing, and coughing. Shortly after
this, guttural sounds, high pitched noises, and barking
sounds arise from the individual. On a neuronal level,
this
condition is a result of extreme sensitivity to dopamine
within the basal ganglia. Tourette's syndrome is
incurable but symptoms can sometimes be superficially
treated by the administration of Haldo (haloperidol).
Other tranquilizers and dopamine antagonists work as
well. Unfortunately as the child enters and undergoes
adolescence, the condition only gets worse. Thirty
percent show improvement but the rest either stay the
same or have a mild, gradual worsening of
symptoms. Symptoms can temporarily become especially
exacerbated when the sufferer has stress, excitement,
anxiety, or when he or she ingests stimulants like
caffeine, nicotine, speed, crank, or other drugs with
ampheteminic properties.
     As far as the long term side effects are concerned,
there have been no reported cases of addiction found in
children (although there have been in adults.) Growth
suppression is the main long term side effect. Numerous
studies have shown that ritalin does in fact suppress
growth during the active phase of treatment The average
amount of height suppression is 1.5 centimeters. Taking
medication holidays (i.e. as stated earlier, abstaining
from ritalin on weekends and summer vacation) can greatly
reduce the chance of growth retardation. Growth
suppression does not only refer to height, however. Low
body fat, low musculature,
impeded bone growth, retarded functioning of many
developmental processes, such as hormones, organ
function, and brain growth can also occur. There is a
generalized decrease of overall body growth. Another long
term side
effect that there has not been extensive research on, but
does raise concern in some people's minds is that ritalin
may be detrimental to the development of the
cardiovascular system. Since it is a stimulant, and all
stimulants tax heart rate, blood pressure, these children
may have
cardiovascular problems later in life.  
     Some further side effects and ritalin issues are as
follows: medication rebound effect, state dependent
learning, decreased sociality, and stimulant induced
disturbed thinking. (Braswell)
     The psychostimulant rebound effect is the behavioral
and social dilapidation that occurs in the evening or
afternoon of the day that the individual has taken the
drug (which is only to be taken in the morning). It is
sometimes also termed the "behavioral rebound
phenomenon". This behavior consists of extreme hostility,
emotional liability, and a large increase in restlessness
and inattentive social relating. This rings similar with
the street drug speed; when speed or crank users are
"coming down" they tend to
lash out at others, become irritable and snappy, and
intensely emotional. One third of children on ritalin
have shown this behavioral rebound effect.     
State-dependent learning refers to the idea that if one
is studying while under a particular influence (be it
drug or otherwise), they will perform higher on the
examination if they are in that same psychological state.
There is still a question to whether the positive
learning effects caused by ritalin are no more than a
mere case of state-dependent learning. This would be
detrimental if, for instance, the student ingested
ritalin during studying but not for the
examination, and therefore performed less well than he or
she would have if the drug had never been administered in
the first place.
     Certain isolated cases have shown that although
ritalin can reduce the child's negative, aggressive
interaction with others, it may also can lead to reduced
social interaction with other children all together.
Several studies were done to see if this was true and the
belief was not supported. Nevertheless, some parents have
reported that their child is no longer spontaneous like
he or she used to be, has lost his or her "childlike"
essence, and comes off as very aloof. They also said that
the children appear way too controlled and seemed to
premeasure and weigh out their behavior to an extreme
degree.         Some individuals have the very rare, but
serious
reaction to ritalin which is drug-induced psychosis.
Delusions and hallucinations (especially visual and
tactile) occur. In the past, this was only seen in adults
who ingested an incredibly high dose, but increasingly
more
frequently, professionals are observing children who have
the same reaction even with the recommended dose. One
case study involved a 15 year old girl who had been on 40
milligrams a day of ritalin for over five years. She
developed visual and olfactory hallucinations that
culminated in catatonia. As soon as ritalin was
discontinued, this psychotic behavior ceased. A child who
was given only .3 to 2.3 milligrams a day of ritalin,
developed facial twitches, extreme difficulty in
speaking, and inability to move the lips and tongue.
Another case example is of a ten year old boy who was
given ritalin
because of a diagnoses of dyslexia and severe behavioral
problems. After three doses of ten milligrams of ritalin,
he hallucinated and became physically abusive. Psychotic
effects occur in even the youngest of ritalin users as
well. Within one week of being medicated with 15
milligrams a day of ritalin, a six year old girl
exhibited a detached appearance, incoherent babbling,
extreme hyperactivity, and grossly bizarre behavior. An
even younger ritalin user, a female at age three
developed marked dyskinetic movements of the neck and
head and choreoathoid movements of the arms and legs. She
had this same reaction when given Dexedrin, otherwise
known as d-amphetamine (Denhoff). The difference between
Dexedrine and Ritalin is that Dexedrine has a slightly
higher potential for abuse. Growth suppression is more
likely to occur from Dexedrine. It is also cheaper than
Ritalin and can be administered in many more forms,
whereas Ritalin only comes in a capsule. The duration of
action of Dexedrine is longer than that of Ritalin.
However, they both have very similar chemical
compositions. The third drug that is often administered
to children with ADHD is Cylert (pemoline) as mentioned
previously. Compared to dexedrine
and ritalin, this drug is more likely to cause allergic
skin rashes. It was also more likely to increase lip
biting, lip licking, and it seemed to cause the child to
pick at his or her lip with the finger tips but not the
fingernails. Along with the other two medications, Cylert
can produce psychotic reactions with very high doses. 
Cases like these are very rare but should be taken into
consideration when a patient is administered ritalin or
when a person is using it for recreational purposes.   
REFERENCES:
1. Barkley, Russell. Attention-Deficit Hyperactivity
Disorder; Guilford Press. New York: 1990
2. Beugin, Mary. Coping, Attention Deficit Disorder;
Detselig Enterprises Ltd. Calgary, Alberta: 1990
3. Braswell, Lauren. Cognitive-Behavioral Therapy and
ADHD Children; Guilford Press. New York: 1991 4. Calwell,
John. Amphetamines and Related Stimulants; CRC Press.
Boca Raton, Florida: 1980   5. Coleman, Wendy. Attention
Deficit Disorders,
Hyperactivity and Associated Disorders; Calliope Books.
Winsconsin: 1988
6. Creese, Ian. Stimulants: Neurochemical, Behavoiral,
and Clinical Perspectives; Raven Press. New York: 1983 7.
Denhoff, E: Fluphenazine dihydrochloride elixir as an
adjunct in management of cerebral dysfunction syndromes.
Clin. Med. 72: 837-843, 1965
8. Knight, James. (personal communications)
9. Smith, David. Amphetimine Use, Misuse, and Abuse;
Medical Publications. Boston: 1979 10. Uhr, Leonard.
Drugs and Behavior; John Wiley and Sons. New York: 1960
11. Wender, Paul. Attention-Deficit Hyperactivity
Disorder in Adults; Oxford Press. New York: 1995 12.
Wender, Paul. The Hyperactive Child, Adolescent, and
Adult; Oxford Press. New York: 1987 
     

Chemistry of methylphenidate

by: Elliott Mcdonough


    Methylphenidate is the drug that is used to help
people with Attention Deficit Hyperactive Disorder (ADHD)
and Narcolepsy; the first two reports in this project
should
have discussed both the physiological and behavioral
aspects of this drug.  The methylphenidate molecule is
just as interesting as the behavioral and physiological
effects. 
This paper will be split into four main parts.  The first
section of the paper will be discussing the preparation
of the molecule before it is ready for ingestion.  The
second part will talk about the chemical composition of
the drug and some physical data.  The third part of the
report will deal with the route that the drug takes once
it has been ingested by the patient.  The fourth section
will discuss
the side effects of the drug from a chemical and
physiological standpoint.  
   
    The preparation of the drug is a very important when
looking at methylphenidate.  The molecule methylphenidate
does not normally dissolve in water because its London
forces (attraction between atoms in a covalent molecule)
are stronger than the dissociation forces of the water
molecule.  However, when methylphenidate is treated in a
very dilute solution of hydrochloric acid and this
changes the molecule and its charge.  A hydrogen atom
bonds with the one nitrogen atom in the methylphenidate
molecule, location of this action will be discussed in
the chemical composition
section, the effect is that the molecule changes into
what is known as methylphenidate hydrochloride.  The
change is also that the methylphenidate receives a
positive charge
from the hydrogen atom as well as the chloride atom
receiving a negative charge.  The overall change in the
molecule is that it becomes a salt.  The salt is composed
of the methylphenidate + the hydrogen cation, and the
chloride anion; the body treats the methylphenidate as a
normal salt.  After ingestion the methylphenidate
hydrochloride dissociate into its cation form,
methylphenidate + hydrogen, and its anion, chloride. This
molecule is easily dissolved in water so it can be
ingested orally and absorbed quickly into the patient’s
system.     
    This section will talk about the chemical composition
of the drug.  The overall molecule is split up into three
main sections.  The parent part of the molecule is the
amine.  The amine is composed of five carbons and a
nitrogen aligned in a hexagonal formation.  Each of the
six main atoms are saturated; that is they form four
bonds and have no free
electrons.  One of the carbon atoms forms a bond with
another carbon to reach the two constituents of the
parent.  These two carbon atoms will be designated as the
second carbon on the amine and its carbon bond; their
significance will be discussed later in this section. 
The carbon outside the amine forms three bonds.  The
first is to the benzene ring constituent, the second is
to the carboxylate
constituent, and the third is to a hydrogen molecule. 
The benzene ring is formed of six carbons and six
hydrogen.  The actual alignment of the atoms is that the
carbons are on the inside of the rings with a hydrogen
bonded to each one on the outside.  The carbons have
three double bonds among the six of them; the strange
part about the inner three double bonds is that they are
shared equally by the six carbons.  The benzene ring is
also one of the major reasons that methylphenidate has
such strong side effects with certain
prescription drugs like the tricyclics, and the anti
convulsants, and the anticoagulants (rxlist.com).  The
last constituent is called the carboxylate constituent. 
It is composed of a methyl group (a carbon with three
hydrogen
bonded to it); an oxygen that connects the methyl group
with the carboxyl group.  And a carboxyl group; that is a
carbon double bonded to an oxygen. 
    Methylphenidate appears as a white crystalline
powder.  The molecular weight of the drug is 269.80
grams/mole of methylphenidate hydrochloride.  The melting
point of the
drug is 224-226 C.  It is soluble in such substances as:
water, ethanol at 95% purity, and methanol.  All of these
solutions are polar so they can dissociate the molecule
easily.  Other solutions that are made up of non-polar
molecules have a harder time dissociating the molecule
because they cannot break the London forces of the
molecules.  The chemical formula of the drug is
C14H19NO2.HCl.  The percentage breakdown of the
methylphenidate molecule is: 72.07% carbon, 8.21%
hydrogen, 6.00% nitrogen, and 13.72% oxygen.  It is
odorless, it is stable under normal lab conditions, and
is slightly acidic to litmus; this makes sense when you
think of the preparation of the drug in dilute
hydrochloric acid.  The
LD50 of the drug when administered orally to rat is
367mg/kg (ntp dp.niehs.nih.gov). 
    Methylphenidate has four possible isomers.  These
four isomers are dependent on the position of the number
two carbon in the parent amine and the carbon outside the
amine group.  These two carbons are able to form mirror
images of the molecule.  Because each carbon can form two
isomers the total number of isomers is four.  In order to
prepare the methylphenidate for patients the chemists
must separate all four isomers and then treat that isomer
with the hydrochloric acid.

    Now that I have explained the finer details of the
molecule methylphenidate I can move on to the greater
overall effects of the drug.  In this section I will be
discussing the route of the drug and the area of the
brain where it has its main effects.  Methylphenidate is
a mild Central Nervous System stimulant.  It has been
categorized as a Schedule II controlled substance by the
DEA (gsm.com).  Methylphenidate is related to the drug
amphetamine and you can see the relationship in their
excitatory effects on the user.  The dosage for
methylphenidate comes in three levels: 5mg, 10mg, 20mg. 
The factors that determine the dosage level for a patient
using this drug is their age, their body weight, and
their sex.  The actual pill comes in two forms the normal
release and the extended release pill that stays in the
patient’s system longer and thus extends the length of
the overall effects of the drug on the user.  

    Methylphenidate is administered orally and absorbed
rapidly through the Gastrointestinal tract.  In one study
the administration of methylphenidate with food increased
the rate with which it was absorbed into the system
(mentalhealth.com).  However, it is metabolized rather
quickly due to first pass metabolism and bioavailability
is low, roughly 30%, because of the rapid metabolism of
the drug (mentalhealth.com); the subject variation for
the first pass metabolism is rather high so it can differ
among patients the speed with which the drug takes
effect.  The
duration of the action of methylphenidate ranges from 3
to 6 hours for the normal tablets; the range for the
extended release tablets is about eight hours (gsm.com). 
The
metabolism of the drug occurs in the liver through the
hydroxylation of methylphenidate to ritalinic acid (alpha
phenyl 2 piperidine acetic acid, PPAA) (gsm.com). 
Methylphenidate is almost completely released from the
body through the urine of the user.  About 97% of the
dose being released as metabolites in the urine within 90
hours after ingestion; roughly less than 1% is released
as unchanged methylphenidate in urine (gsm.com).  About
3% of the
methylphenidate is excreted in the feces.  
    
    Methylphenidate and its metabolites are distributed
in the blood in erythrocytes and plasma.  The total
percentages of distribution is 57% in plasma and 43% in
erythrocytes; the drug also exhibit low protein binding
(mentalhealth.com).  “Peak plasma concentrations of 10.8
and 7.8 ng/mL were observed on average, 2 hours after
administration of 0.30 mg/kg in children and adults,
respectively” (mentalhealth.com).  The results from the
peak plasma concentration showed a large variability
among the patients.  Methylphenidate has a half life in
the plasma of 2.4 hours in children and 2.1 hours in
adults; both of these results were found from the 0.30
mg/kg dose.  It appears that the drug is similar to
amphetamines in the specificity of location of action in
the CNS; however, methylphenidate seems to have more of
an effect on mental activities than amphetamines. 
Methylphenidate seems to stimulate the brain stem arousal
system and the cerebral cortex (rxlist.com).  The drug’s
action on the CNS is not yet fully understood, but its
primary sites of action seem to be in the
dopaminergic neurons. It seems to block the re uptake of
this neurotransmitter, thus creating an increase in
activity of dopamine in the CNS.  The physiological
result is an increase in motor activity and an increase
in mental
alertness (gsm.com).  “The action of methylphenidate
results in a decrease in hyperactivity and an increase in
the child’s attention span” (gsm.com).  However, the side
effects of methylphenidate may decrease the patient’s
ability to learn.

    The side effects of the drug are a major part of the
controversy that surrounds the drug.  It has been
theorized that the arousal brought on by the drug may
have some effects on the patient’s sleeping patterns. 
Specifically it may reduce the amount of REM sleep the
patient receives.  REM sleep has been related to the
learning patterns in
subjects; that is when you reduce levels of REM sleep you
also reduce the ability to learn.  The drug also has some
interactive effects with other drugs as well as with some
of the biological functions of the body.  The benzene
ring constituent of the molecule can be seen as having a
major
effect in this aspect of the drug.  Benzene rings are
planer structures that like to bond with other benzene
rings in a stacking type of formation.  Thus when you
have methylphenidate and other drugs that have benzene
rings in their structure you tend to see that these drugs
have a tendency to interact at the benzene ring area of
the drugs.  Drugs that have benzene rings in their
chemical composition are the tricyclics, the anti
coagulants, and the anticonvulsants, some of which are
MAO inhibitors
(rxlist.com).  The drug also decrease the effect of
guanethidine (rxlist.com).  Other note worthy side
effects range from long term use of the drug in children. 
There has been some evidence to suggest that
methylphenidate may decrease the growth in children.

    This drug has become very popular in treating people
with ADHD and also Narcolepsy.  Hopefully after reading
this report you can better understand the different
aspects of the drug and how it works.  This report should
have also
helped you weigh the positive effects of the drug against
the bad effects of the drug.  Like most drugs there are
some aspects of methylphenidate that are surrounded by
philosophical questions like is it worth it to use the
drug?  I found myself asking this question a lot
throughout my research of this drug.  I think the point
that must be
stressed is that this drug is not yet fully understood,
but with continuing research we will hopefully better
understand the total spectrum of this drug. 


WORK CITED

Clark, T; Phd.  HSU(11/01/96).  Discussion of
methylphenidate and its chemical structure.  Interview
(Discussion).  

Mental Health. (No date).  Methylphenidate, [Online].
Available: http://www.mentalhealth.com/drug/p30 r03.html

Merck Publishing.  The Merck Index 12th Edition.  Merck
Research Laboratories, 1996.  USA.

Radian Corporation.  (08/29/91).  Methylphenidate
Hydrochloride, [Online].  Available: http://ntp
db.niehs.nih.gov/NTP_Reports/NTP_Chem_H&S/NTP_Chem2/

RxList Generic Information.  (No date).  Methylphenidate,
[online]. Available:
http://www.rxlist.com/cgi/generic/methylphen.html

Rybacki, James; Long, James.  The Essential Guide to
Prescription Drugs.  Published by Harper Perenial, 1996. 
New York, NY. 





Neurological Effects of Ritalin


By
David Puerta

     Methylphenidate (MPH) is a central nervous system
(CNS) stimulant.  Its CNS actions are milder than those
of the amphetamines and have more noticeable effects on
mental
activities than on motor activities. 
Methylphenidate-induced CNS stimulation produces a
decreased sense of fatigue, an increase in motor
activity, mental alertness, mild euphoria, and brighter
spirits[Schatzberg AF, Nemeroff, 1995; p417-32].  In the
periphery of actions of MPH are minimal at therapeutic
doses.  The CNS stimulation effects of methylphenidate
can be additive when used concurrently with other CNS
stimulants.  In addition to drugs with CNS stimulating
effects, caffeine may also cause excessive CNS
stimulation if used by patients receiving
methylphenidate.  Methylphenidate can provoke ties and
can mask their cause [Methylphenidate drug interactions,
1996].  Also, it's an anticholinergic; a drug that blocks
cholinergenic receptors in the brain.  This effect can be
additive with other anticholinergics.  Methylphenidate
metabolism is inhibited by anticonvulsants, and a drug
called warfarin, which can lead to increased serum
concentrations.  Serum concentrations of tricyclic
antidepressants can be increased by concurrent use with
MPH due to inhibition of antidepressant
metabolism[Methylphenidate drug interactions, 1996]. 
Methylphenidate shares the abuse potentials of the
amphetamines and is a DEA schedule II controlled
substance.  It is clinically approved in the treatment of
narcolepsy and is adjunctive treatment in children with
attention deficit hyperactivity disorder (ADHD) [Volkow
ND, Fowler JS, 1996].      There are some adverse effects
of MPH in the central and peripheral nervous system that
include dizziness, drowsiness, headaches and dyskinesia. 
There are other isolated incidence that may also occur,
but typically the only other effects include
gastrointestinal problems such as nausea and abdominal
pain, cardiovascular problems such as palpitations, blood
pressure and pulse changes, tachycardia, angina and
cardiac arrhythmia.  Also, problems with skin and
hypersensitivity such as rash, pruritus, urticaria,
fever, arthralgia, and alopecia, and sometimes weight
loss occur during prolonged therapy [Methylphenidate
Brand Name, 1996].      Before speaking any more about
Methylphenidate I must review some basic neuropsychology. 
First, neurons are nerve cells specializing in
communication.  The particular types of neurons that I
will be analyzing are located in the human brain. 
Neurons are composed of three basic parts: the soma, or
cell body which forms the nucleus; dendrites, or
tendril-like branches extending from the soma whose
function is to respond to excitations from other neurons
and transmit them into the soma;  and the axon, a single
long process extending from the soma that carries the
nerve impulse to the adjacent cells.  The end of the axon
is shaped similar to a button.  This formation is called
a terminal button, or a synaptic knob.  It is these
buttons whose job it is to store small bubbles, called
vesicles, which are full of a substance called a
neurotransmitter.  Outside these buttons are fluid filled
cavities called synapses.  These are the junctions of
axons with any part of another neuron; they include the
presynaptic terminal, or button, the synaptic gap, and
the post synaptic membrane, or dendrite[Palfai J,
Jankiewicz H, 1997; p90-95].      In order for the
neurons to fire, information must be given from one
neuron to another.  This job is performed by the
neurotransmitters.  The neurotransmitters bridge the gap,
or synapse, between the neurons, and feed information to
receptors on other neuron's dendrites.  This information
leads to the firing of the second neuron, and the process
continues down the line.[Palfai J, Jankiewicz H, 1994;
p105-7].       There are different types of
neurotransmitters, and
different types of neurorecepters.  One of the most
commonly known is called Dopamine (DA).  There are 5
differently types of DA, DA1-DA5.  DA cell bodies
originate in two brain areas, the substantia nigra and
the ventral tegmental area..  The main clustering of
dopaminergic cell bodies is the midbrain area known as
the substantia nigra.  From there, connections run up to
the basal ganglia and the frontal lobes.  The names of
these sites are as follows: the nucleus accumbens,
olfactory tuberche, condate-putamen nucleus, mesolimbic
pathway, central amygdaloict nucleus, nigrostriatal
pathway, median eminence, substantia nigra, and ventral
tagmentum.  The DA map of the brain suggests that DA is
important in autonomic functions (hypothalamus), body
posture and fine motor movements (basal ganglia) and the
regulation of thinking (frontal lobes)[Fieldman RS,
Quenzer LF, 1984; p256-8].      The DA molecule fits into
a slot that is specially designed for its shape.  These
slots are found all over the DA-receiving dendrites. 
When enough DA molecules fit into these receptors,  the
response of the neuron connected is to fire.  One can
imagine that if these molecules were aloud to continually
roam around the synaptic gaps and bump into these
receptors without cause, neurons would fire randomly. 
Imagination can make short work of how the human body
would react to such stimulation.  So, the body has
natural mechanisms which take care of these DA molecules
after they have been given off from the synaptic
vesicles.  One of these is called reuptake, or uptake. 
This is a task performed by the synaptic knob.  the knob
sucks about 10% of the neurotransmitters from the
synaptic gap into its vesicles.      This is how
methylphenidate is able to produce its effects.  It is
believed that MPH inhibits this reuptake mechanism by
blocking it off, much the same as cocaine does.  Actually
MPH and cocaine compete for the same binding sites in the
striatum [Valkow ND, Ding YS, 1996].  The activation of
DA is terminated largely by reuptake - that is
reabsorbtion by active transport through the presynaptic
membrane and back to the vesicles[Methylphenidate
Ritalin, 1996].
     MPH also seems to be a catalyst to the release of DA
from the vesicles.  For a long time it was understood
that amphetamine and MPH worked the same way, until
recently it was found that amphetamine seems to release
newly synthesized DA, whereas MPH seems to release
vesicular (stored) DA.  This hypothesis is based on the
finding that drugs which interfere with DA storage (e.g.
reseprine) block the action of methylphenidate
[Methylphenidate Ritalin, 1996].  It seems that
methylphenidate inhibits firing of the DA cell groups A10
and A9, both of which lie in branches of the substantia
nigra.  These effects may be due to the stimulation of
the dendrite autoreceptors or a neuronal feedback pathway
that runs from the corpus stratum to the substantia nigra
and that regulates the activity of the cells in A9 and
A10 [Feldman RS, Quenzer LF, 1984 p194].  Also, MPH
appears to release DA stored in the vesicles alone,
whereas amphetamine releases DA from newly synthesized
pools and increases DA diffusion from the vesicles into
the cell.  MPH is less potent than amphetamine because of
the above.  MPH reacts directly with the cytoplasmic
storage of DA, therefor it is more easily prevented from
effectiveness than amphetamines which cause alkalization
which leads to low intravesicular pH and reacts with the
inward proton pump to increase in DA production therefor
creating a greater number of DA neurotransmitters inside
of the synapse which increases the likelihood that the DA
type receptors would be more likely to fire [Schatzberg
AF, Nemeroff CB, 1995; 417-32].      Methylphenidate can
potentiate the actions of both exogenous (such as DA and
epinephrine, another type of neurotransmitter) and
endogenous (such as norepinephrine) vasopressors. 
Because methylphenidate and MAOI s (mono amine oxidase
inhibitors) both potentiate the effects of catecholamine
(catecholamine (CA) have a structure containing a
catechol ring, such as DA and norepinephrine [Palfai T,
Jankiewicz H, 1997; 105-7])
neurotransmitters, concomitant use these agents should be
avoided.
     There has been quite a bit of research done on MPH,
most of which includes that of ADHD children because they
are one of MPH s primary users.  The following are some
of the studies which have been done on this topic.     
(1)  Cognitive and neuropsychological characteristics of
ADHD children receiving stimulant medications.   Summery:
10 children receiving MPH for ADHD were compared to
normal children on cognitive and neuropsychological
dimension in a pilot study.  The ADHD children showed
significant differences on cognitive measures, including
the Wechsler Developmental Index, the Bender Visual-motor
Gestalt Test, and the Benton Revised Bisual Retention
Test.  Elevated levels of polyspike EEG activity were
also noticed.  This research suggested that ADHD children
receiving MPH may have persisting neuropsychological
difficulty.  Is this because of the long-term over
stimulation of DA receptors, or perhaps some other effect
of MPH that remains unknown?  The research isn t
conclusive enough to tell us [Risser MG, Bowers TG, 1993;
p1023-31].      (2)  Methylphenidate-induced changes in
ADHD information processors.   Summary:  In a randomized
double-blind placebo-controlled crossover study, 17
hyperactives clinically considered as drug responders
were administered a battery of information processing
talks to assess the efficacy of MPH.  the investigation
concentrated on sustained attention, and following a
linear stage model of information processing (dividing
and focused attention, encoding, filtering, selective set
and response organization operations).  MPH did not
effect short-term memory or visual retention, baseline
motorspeed and encoding.  MPH improved vigilance aspects
of sustained attention.  The Drug did not improve
filtering but it did enhance selective set (target
search) operations.  The decline in speed variability as
a result of medication could not readily be explained in
terms of response organization processes.  An attempt was
made to unite the experimental results through the
concept of single-response frequency [de Sonneville LM,
Njiokiktjien C, 1991; p285-95].      (3)  A divided
attention analysis of the effects of methylphenidate on
the arithmetic performance of children with ADHD.  
Summary:  13 boys with ADHD completed 80 mathematical
problems presented on a computer screen by typing in a
two digit answer.  On half the trails, a foot press was
required end a tone presented by the computer presented 2
seconds before, 1 second before, 1 second after, and 2
seconds after the problems were presented.  Compared to
placebo, MPH resulted in significantly faster reaction
times to tome probes and faster answers to the problems
when the two tasks did not overlap in time, but not when
simultaneous processing was required when the probe was
presented in 2 seconds after arithmetic problems.  When
dual processing taxed cognitive capacity, methylphenidate
still improved accuracy on the primary arithmetic task
relative to placebo, but at the expense of speed of
performance on the secondary reaction time task.  When
ADHD children fail to allocate available resources to a
primary cognitive task, treatment with methylphenidate
may result in reallocation of existing cognitive capacity
from a secondary task to the primary task [Carlson CL,
Pelham WE Jr, 1991; p463-71].      (4)  Creativity, and
the effects of  methylphenidate.   Summary:  Given that
children with ADHD are more impulsive than peers, this
study explored whether they are correspondingly more
creative, and whether creativity declines when
impulsivity is decreased through MPH therapy.  A
repeated-measures quasi-experimental design was used to
compare to performance of 19 boys with previously
diagnosed ADHD and 21 comparison boys aged 8 through 11
on two administrations of alternate forms of the Torrance
Tests of Creative Thinking-Figeral (nonverbal).  Boys
with ADHD received prescribed methylphenidate only for
the first session.  Overall, mean Torrance summary scores
for comparison boys (mean =115.1, SD =16.1) were small
(7%) and did not meet the 25% criterion for a clinically
significant difference.  no changes in performance over
time (comparison group) or medication state (ADHD group)
were observed.  These data suggest that, when measured
nonverbally, the creative thinking performance of boys
with ADHD is not superior to that of peers who do not
have ADHD.  Regarding the effects of methylphenidate,
prescribed therapy did not influence performance on these
measure of creative thinking [Millhouse RJ, 1993;
p816-9].      (5)  Methylphenidate and Thioridazine in
the treatment of intellectually subaverage children:
effects on cognitive-motor performance.   Summary:
Twenty-seven children (or smaller subgroups depending
upon task difficulty and subject ability) with subaverage
IQs took part in a double-blind, placebo-controlled,
cross-over study of methylphenidate (0.4 mg/kg/day) and
thioridazine (1.75 mg/kg/day).  The children were tested
for IQ performance, breadth of attention, and performance
on a series of electronically controlled cognitive-motor
tests.  MPH improved accuracy on a memory task, reduced
omission errors on an attentional task, and reduced seat
movements on two tasks.  MPH appears likely to enhance
sustained attention and motivation in appropriately
selected children with mild developmental delays [Aman
MG, Marks RE, 1991; 816-24].      (6)  Behavioral and
Biochemical Effects of methylphenidate in schizophrenic
and nonschizophrenic patients.   Summary:  The authors
examined the specific behavioral and biochemical effects
of intravenous MPH in a sample of schizophrenic and
nonschizophrenic patients.  Twenty drug-free patients
participated in a double-blind, placebo randomized study
of methylphenidate, with multiple samples of plasma
homovanillic acid (HVA) and serum growth hormone (GH)
obtained during the infusion procedure.  MPH caused a
significant increase in positive symptoms that was
relatively specific to the
schizophrenic patients and was evident even in those with
otherwise dormant symptamatology.  When behavioral
response was correlated with the biochemical responses
(i.e., changes in plasma HVA and GH), there was a
significant positive relationship between the increase in
the BPRS-positive symptoms as well as the
hostility/suspiciousness factor, and the increase in GH. 
These results suggest that the expression of psychotic
symptoms may be associated with increased dopaminergic
postsynaptic sensitivity, although then nonspecific
nature of MPH s actions discourages a stronger
interpretation of the results. [Sharma RP, Javaid JI,
1991;459-66].      There is a controversial side to MPH
which has some people up in arms.  According to the
essential Guide to Psychiatric Drugs,  depression may
also be treated with drugs called psychostimulants.  Use
of such drugs is reserved for only two situations (1)
patients who have failed to respond to at least two other
antidepressants and psychotherapy and who are seriously
depressed, and (2) patients with serious and usually
terminal medical illnesses such as cancer or AIDS who are
depressed and too sick to take other  kinds of
antidepressants.   MPH is a psychostimulant, but it does
not fall under these guidelines.  Also, stimulant drugs
have the potential to induce tolerance.  People who take
MPH need to take drug holidays during their use of the
drug because otherwise their body needs to consume more
of the drug for it to have an effect.  This is not
healthy.      In an excerpt form the  People s Pharmacy  
Avon Books, St. Martin s Press (1976), the author says 
It is my belief that if these drugs were outlawed,
children would not be at all deprived of essential
medication, but that doctors would be forced to make more
accurate diagnoses and seek better means of handling the
hyperactive behavior of a certain small percentage of
their patients.   Is this the view that we should take on
Ritalin?  Are the adverse effects of Ritalin to the
neuroprocessors of humans more harmful than the positive
effects are helpful?  We don t know all that there is to
know about the neuropsychological effects of this
psychostimulant.  More research needs to done in order to
understand the processes by which this drug works.  

Sources:

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 Methylphenidate and thioridazine in the treatment of
intellectually subaverage children: effects on
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American Academy of Child & Adolescent Psychiatry;
30(5):816-24.  
(2)Boulton, Baker, Greenshaw.  Psychopharmacology; Humana
Press, Clifton, New Jersey (1989): 401-33. 
(3) Charlson CL, Ppelham WE Jr, Swanson JM, Wagner JL.  A
divided attention analysis of the effects of
methylphenidate onthe arithmetic performance of children
with attention deficti hyperactivity disorder   (1991). 
Journal of Child Psychology & Psychiatry & Allied
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(13) Sharma RP, Javaid JI, Pandey GN, Janicak PG, David
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Copyright © 1995, Dr. John M. Morgan, All rights reserved - This page last edited October 23, 1996
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