Methylphenidate (MPH) is
the most commonly prescribed psychostimulant and is
indicated in the treatment of attention-deficit
hyperactivity disorder, Postural Orthostatic
Tachycardia Syndrome and narcolepsy, although
off-label uses include treating lethargy,
depression, neural insult and obesity. In North
America it is most commonly known as the brand name
Ritalin which is an instant-release racemic mixture,
although a variety of brand names, and formulations
exist. Methylphenidate is a potent central nervous
system stimulant derived from amphetamine thought to
exert its effect by enhancing dopaminergic
transmission in the brain.
History
Methylphenidate was
patented in 1954 by the CIBA pharmaceutical company
(now Novartis) as a potential cure for Mohr's
disease. Beginning in the 1960s, it was used to
treat children with ADHD or ADD, known at the time
as hyperactivity or minimal brain dysfunction (MBD).
Today methylphenidate is the most commonly
prescribed medication to treat ADHD around the
world. Production and prescription of
methylphenidate rose significantly in the 1990s,
especially in the United States, as the ADHD
diagnosis came to be better understood and more
generally accepted within the medical and mental
health communities.
Most brand-name Ritalin is produced in the United
States, and methylphenidate is produced in the
United States, Mexico, Argentina and Pakistan. Other
generic forms, such as "methylin", are produced by
several U.S. pharmaceutical companies. Ritalin is
also sold in the United Kingdom, Germany and other
European countries (although in much lower volumes
than in the United States). These generic versions
of methylphenidate tend to outsell brand-name
Ritalin four to one. In Belgium the product is sold
under the name "Rilatine" and in Portugal as "Ritalina".
Another medicine is Concerta, a once-daily
extended-release form of methylphenidate, which was
approved in April 2000. Studies have demonstrated
that long-acting methylphenidate preparations such
as Concerta are just as effective, if not more
effective, than IR (instant release) formulas.
Time-release medications are also less prone to
misuse
Therapeutic uses
Methylphenidate 10 mg Tablet (Mallinckrodt)Methylphenidate
is the most commonly prescribed psychostimulant and
works by increasing the activity of the central
nervous system.] It produces such effects as
increasing or maintaining alertness, combating
fatigue, and improving attention. The benefits and
cost effectiveness of methylphenidate is well
established in the short term treatment of ADHD. The
benefits and cost effectiveness of methylphenidate
long term are unknown due to a lack of research. The
long term effects of methylphenidate on the
developing brain are unknown. Methylphenidate is not
approved for children under six years of age.
Attention deficit hyperactivity disorder
Methylphenidate is
approved by the FDA for the treatment of
attention-deficit hyperactivity disorder The
addition of behavioural modification therapy (e.g.
CBT) has additional benefits on treatment outcome.
There is a lack of evidence of the effectiveness in
the long term of beneficial effects of
methylphenidate with regard to learning and academic
performance. A meta analysis of the literature
concluded that methylphenidate quickly and
effectively reduces the signs and symptoms of ADHD
in children under the age of 18 in the short term
but found that this conclusion may be be biased due
to the high number of low quality clinical trials in
the literature. There have been no placebo
controlled trials investigating the long term
effectiveness of methylphenidate beyond 4 weeks thus
the long term effectiveness of methylphenidate has
not been scientifically demonstrated. Serious
concerns of publication bias regarding the use of
methylphenidate for ADHD has also been noted. A
diagnosis of ADHD must be confirmed and the benefits
and risks and proper use of stimulants as well as
alternative treatments should be discussed with the
parent before stimulants are prescribed. The dosage
used can vary quite significantly from individual
child to individual child with some children
responding to quite low doses whereas other children
require the higher dose range. The dose therefore
should be titrated to an optimal level which
achieves therapeutic benefit and minimal side
effects. Therapy with methylphenidate does not and
should not be indefinite. Weaning off periods to
assess symptoms are recommended.
Substance dependence
Methylphenidate and amphetamine have been
investigated as a chemical replacement for the
treatment of cocaine dependence in the same way that
methadone is used as a replacement for heroin. Its
effectiveness in treatment of cocaine or other
psychostimulant dependence has not been proven and
further research is needed.
Early research began in 2007-8 in some countries on
the effectiveness of methylphenidate as a substitute
agent in refractory cases of cocaine dependence; the
fact that it can satisfy cravings for cocaine in a
way which is subjectively and pharmacologically
equivalent but longer-lasting as well as easier on
the body and somewhat safer and easier to manage has
long been part of the 'street lore' associated with
stimulants in many parts of the world in much the
same way that other substitutionmittel drugs such as
methadone, buprenorphine, LAAM, butorphanol,
extended-release oral morphine, dihydrocodeine, and
clonidine were amongst opioid users in various times
over the past century.
Pervasive developmental disorders
Given the high co-morbidity between ADHD and autism,
a few studies have examined the efficacy and
effectiveness of methylphenidate in the treatment of
autism. However, most of these studies examined the
effects of methylphenidate on attention and
hyperactivity symptoms among kids with autism
spectrum disorders. Aman and Langworthy (2000)
attempted to examine the effects of methylphenidate
on social-communication and self-regulation
behaviors among kids with ASDs.
The sample included 33 children with pervasive
developmental disorder (29 boys) with a mean age of
6.93 years (range 5-13). This was a 4-week
randomized, double-blind, cross-over placebo study,
with treatment changing each week between 4
conditions: placebo, low dose, medium dose, and high
dose. In this design, neither the experimenters nor
the families know which of the 4 treatments the
child is receiving at any given time. In addition,
the treatment condition changes randomly each week,
without anyone knowing the nature of the old or new
condition. This allows the experimenters to assume
that consistent changes in behaviors that occur
during a particular treatment is truly due to the
effect of that treatment and not to the expectation
of the treatment (placebo effect).
The results indicate that children showed
significantly more joint attention behaviors when
receiving methylphenidate than when receiving the
placebo (although the most effective dosage varied
by individual). Furthermore, at a group level, the
low dose of methylphenidate resulted in
significantly improved joint attention behaviors
when compared to the placebo, but no differences
were noted between the low, medium, and high doses.
Low and medium doses of methylphenidate also
resulted in improved self-regulation behavior when
compared to placebo.
The study presents compelling preliminary evidence
suggesting that methylphenidate is effective in
improving some social behaviors among children with
autism spectrum disorders.
Adverse effects
Some adverse effects may emerge during chronic use
of methylphenidate so a constant watch for adverse
effects is recommended. Some adverse effects of
stimulant therapy may emerge during long term
therapy but there is very little research of the
long term effects of stimulants. The most common
side effects of taking methylphenidate are
nervousness and insomnia. Other reactions include
pupil dilation, hypersensitivity (including skin
rash, urticaria, fever, arthralgia, exfoliative
dermatitis, erythema multiforme with
histopathological findings of necrotizing vasculitis,
and thrombocytopenic purpura); anorexia; nausea;
dizziness; palpitations; growth retardation,
headache; dyskinesia; drowsiness; blood pressure and
pulse changes, both up and down; tachycardia;
angina; cardiac arrhythmia; abdominal pain;
addiction and drug dependence, suicidal thoughts,
personality changes, and weight loss during
prolonged therapy. Very rare effects include reports
of Tourette's syndrome, seizures, toxic psychosis,
and neuroleptic malignant syndrome.
Known or suspected risks to health
Researchers have also looked into the role of
methylphenidate in affecting stature, with some
studies finding slight decreases in height
acceleration. Other studies indicate height may
normalize by adolescence. In a 2005 study, only
"minimal effects on growth in height and weight were
observed" after 2 years of treatment. "No clinically
significant effects on vital signs or laboratory
test parameters were observed."
A 2003 study tested the effects of
dextromethylphenidate (Focalin), levomethylphenidate,
and (racemic) detro-, levomethylphenidate (Ritalin)
on mice to search for any carcinogenic effects. The
researchers found that all three preparations were
non-genotoxic and non-clastogenic; d-MPH, d, l-MPH,
and l-MPH did not cause mutations or chromosomal
aberrations. They concluded that none of the
compounds present a carcinogenic risk to humans.
Current scientific evidence supports that long-term
methylphenidate treatment does not increase the risk
of developing cancer in humans.
The use of ADHD medication in children under the age
of 6 has not been studied. Severe hallucinations may
occur. ADHD symptoms include hyperactivity and
difficulty holding still and following directions;
these are also characteristics of a typical child
under the age of 6. For this reason it may be more
difficult to diagnose young children, and caution
should be used with this age group.
However, it was documented in 2000, by Zito et al.
“that at least 1.5% of children between the ages of
two and four are medicated with stimulants,
anti-depressants and anti-psychotic drugs, despite
the paucity of controlled scientific trials
confirming safety and long-term effects with
preschool children.”
On March 22, 2006 the FDA Pediatric Advisory
Committee decided that medications using
methylphenidate ingredients do not need black box
warnings about their risks, noting that "for normal
children, these drugs do not appear to pose an
obvious cardiovascular risk." Previously, 19
possible cases had been reported of Cardiac arrest
linked to children taking methylphenidateand the
Drug Safety and Risk Management Advisory Committee
to the FDA recommend a "black-box" warning in 2006
for stimulant drugs used to treat attention
deficit/hyperactivity disorder.
Doses prescribed of stimulants above the recommended
dose level is associated with higher levels of
psychosis, substance misuse and psychiatric
admissions.
Long term effects
The effects of long-term methylphenidate treatment
on the developing brains of children with ADHD is
the subject of study and debate. Although the safety
profile of short-term methylphenidate therapy in
clinical trials has been well established, repeated
use of psychostimulants such as methylphenidate is
less clear. The long term effects of methylphenidate
such as drug addiction, withdrawal reactions,
psychosis and depression and effects in pregnancy
has received very little research and thus the long
term effects of using stimulants for ADHD are
largely unknown. There are no well defined
withdrawal schedules for discontinuing long term use
of stimulants. There is limited data which suggests
that there may be modest benefits in correctly
diagnosed children with ADHD but there are also
overall modest risks. Short term clinical trials
lasting a few weeks show an incidence of psychosis
of about 0.1%. A small study of just under 100
children which assessed long term outcome of
stimulant use found that 6% of children became
psychotic often months or years of stimulant
therapy. Typically psychosis would abate soon after
stopping stimulant therapy. As the study size was
small larger studies have been recommended. The long
term effects on mental health disorders in later
life of chronic use of methylphenidate is unknown.
Concerns have been raised that long-term therapy
might cause drug dependence, paranoia, schizophrenia
and behavioral sensitisation, similar to other
stimulants. Psychotic symptoms from methylphenidate
can include, hearing voices, visual hallucinations,
urges to harm oneself, severe anxiety, euphoria,
grandiosity, paranoid delusions, confusion,
increased aggression and irritability.
Methylphenidate psychosis is unpredictable in who it
will occur. Family history of mental illness does
not predict the incidence of stimulant toxicosis in
ADHD children. High rates of childhood stimulant use
is found in patients with a diagnosis of
schizophrenia and bipolar disorder independent of
ADHD. Individuals with a diagnosis of bipolar or
schizophrenia who were prescribed stimulants during
childhood typically have a significantly earlier
onset of the psychotic disorder and suffer a more
severe clinical course of psychotic disorder.
Knowledge of the effects of chronic use of
methylphenidate is poorly understood with regard to
persisting behavioral and neuroadaptational effects.
Stimulant withdrawal or rebound reactions can occur
and should be minimised in intensity, i.e. via a
gradual tapering off of medication over a period of
weeks or months. A very small study of abrupt
withdrawal of stimulants did suggest that withdrawal
reactions are not typical. Nonetheless withdrawal
reactions may still occur in susceptible
individuals. The withdrawal or rebound symptoms of
methylphenidate can include psychosis, depression,
irritability and a temporary worsening of the
original ADHD symptoms. Methylphenidate due to its
very short elimination half life may be more prone
to rebound effects than d-amphetamine. Up to a third
of ADHD children experience a rebound effect when
methylphenidate dose wears off.
Overdose
In 2004, over 8000 methylphenidate ingestions were
reported in US poison center data.The most common
reasons for intentional exposure were drug abuse and
suicide attempts. An overdose manifests in
agitation, hallucinations, psychosis, lethargy,
seizures, tachycardia, dysrhythmias, hypertension,
and hyperthermia. Benzodiazepines may be used as
treatment if agitation, dystonia, or convulsions are
present.
Abuse potential
Methylphenidate like other stimulants increases
dopamine levels but at therapeutic doses the
increase is slow and thus euphoria does not
typically occur except in rare instances. The abuse
potential is increased when methylphenidate is
crushed and snorted or when it is injected producing
effects almost identical to cocaine. Cocaine like
effects can also occur with very large doses taken
orally. The dose however, which produces euphoric
effects varies between individuals. Methylphenidate
is actually more potent than cocaine in its effect
on dopamine transporters. Methylphenidate should not
be viewed as a weak stimulant as has previously been
hypothesised. The primary source for
methylphenidate for abuse is diversion from
legitimate prescriptions rather than illicit
synthesis. Those who use to stay awake do so by
taking it orally, while intranasal and intravenous
are the preferred means for inducing euphoria.
V users tend to be adults whose use may cause
panlobular pulmonary emphysema. Methylphenidate has
a high potential for drug dependence and addictive
abuse due to its similarity pharmaologically to
cocaine and amphetamines. Abuse of prescription
stimulants is higher amongst college students than
non-college attending young adults. College students
misuse methylphenidate either as a study aid or to
stay awake longer to party or drink more. The
increased alcohol consumption due to stimulant
misuse has additional negative effects on health.
Methylphenidate pharmacological effect on the
central nervous system is almost identical to that
of cocaine. Studies have shown that the two drugs
are nearly indistinguishable when administered
intravenously to cocaine addicts.However, cocaine
has a slightly higher affinity for the dopamine
receptor in comparison to methylphenidate, which is
thought to be the mechanism of the euphoria
associated with the relatively short-lived cocaine
high. Controversy has surrounded whether
methylphenidate is as commonly abused as other
stimulants with many believing that its rate of
abuse is much lower than other stimulants. However,
the majority of studies assessing its abuse
potential and drug liking scores have determined
that it has a similar abuse potential as cocaine and
d-amphetamine.[111] Reports of users experimenting
with mixing methylphenidate with caffeine and
benzocaine to produce a powder for insufflation for
an even more cocaine-like effect began to appear in
the middle 1970s; this is apparently an
incrementation upon a mixture known as Toot
containing phenylpropanolamine, caffeine, and
benzocaine in the search for legal highs. As
moderate doses of cocaine have caffeine-like effects
and benzocaine produces a slight stimulant effect of
its own perhaps 5 per cent the strength of cocaine
with a ceiling in that range, the mixture is
reported to have at least some of the sought
effects.
Legal status
In the United States, methylphenidate is classified
as a Schedule II controlled substance, the
designation used for substances that have a
recognized medical value but present a high
likelihood for abuse because of their addictive
potential. Internationally, methylphenidate is a
Schedule II drug under the Convention on
Psychotropic Substances.
Delivery formulations
Ritalin 10 mg pill (Ciba/Novartis)All media are in milligrams.
Tablet
Ritalin: 5, 10 or 20 mg tablets.
Ritalin SR: 20 mg controlled-release tablets.
Attenta: 10 mg tablets.
Methylin: 5, 10 or 20 mg tablets.
Methylin ER: 10 and 20 mg controlled-release tablets.
Metadate ER: 10 and 20 mg controlled-release tablets.
Concerta: 18, 36, 54 and 72 mg controlled-release tablets.
Equasym: 5, 10, 20 or 30 mg tablets.
Rubifen: 5, 10 or 20 mg tablets.
Capsules
Ritalin LA: 10, 20, 30 or 40 mg controlled-release capsules.
Metadate CD: 10, 20, 30, 40, 50 or 60 mg controlled-release capsules.
Biphentin: 10, 15, 30, 40, or 60 mg suspended release capsules.
Patches
Daytrana 10, 15, 20 or 30 mg controlled-release patches (1.1, 1.6, 2.2 or 3.3 mg/hour for 9 hours)
External links
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Department of Energy 1998 September 29 press release on Ritalin at Brookhaven National Laboratory
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www.Erowid.org Online library of psychoactive plants, chemicals and related topics from Erowid.org