What are the
Stimulants? When we talk about the use of stimulant medications in
psychiatry, we generally are referring to methylphenidate (Ritalin)
amphetamine (Dexedrine, Adderall) methamphetamine (Desoxyn) and pemoline (Cylert.)
The first two are by far the most commonly prescribed. The stimulant
medications increase the release or block the reabsorption of dopamine and
norepinephrine, two brain neurotransmitters. This increases the
transmission between certain neurons. Each stimulant has these effects in
slightly different ways. Thus each may have similar or different effects
on the AD/HD symptoms of a given individual. A recent study (using
specially bred mice) reported in the Jan. 1999 issue of Science (1)
suggests that methylphenidate elevates levels of serotonin, and that
this may account for some of its calming effects.
There have been
many studies showing the effectiveness of stimulants in children,
adolescents and adults. Generally, stimulants effectively decrease
inattention, distractibility, over activity and impulsivity in three
quarters of individuals with AD/HD.
the Brain: Self-regulation
and attention are complex phenomena. There are different types of
attention, including selective attention, sustained attention, strategy
development, flexibility and response inhibition. Researchers are just at
the beginning of their attempts to understand how different types of
attention correlate with brain anatomy and physiology. However, research
has shown some differences between the brain functioning of individuals
with AD/HD and that of normal subjects. Individuals with brain injury to
the frontal lobes of the brain may show attention problems similar to
those of AD/HD adults.
A study done at
NIMH showed that boys with AD/HD had a smaller prefrontal cortex, (part of
the brain just behind the eyes and forehead) caudate nucleus and globus
pallidus. The latter two structures are located deeper in the brain.
Xavier Castellanos, M.D. compared the prefrontal cortex to the brain’s
steering wheel with the caudate nucleus and the globus pallidus as the
accelerator and the brakes. (2) These size
differences are just averages. One cannot use a brain scan to diagnose
differences in brain activity and function have been found. It is believed
that the transmission of dopamine and norepinephrine in the circuits
between the frontal cortex and deeper brain structures play an important
role in AD/HD.
best known for their use in treating AD/HD. However, they have been used
in several other conditions.
can help the daytime sleepiness associated with narcolepsy.
can add a stimulant to an antidepressant if a depressed individual has
only partially responded to antidepressant therapy.
individuals with attention and organizational problems secondary to
brain damage may improve with stimulant treatment. SSRI (selective
serotonin reuptake inhibitor) medications may cause decreased sexual
functioning. Some individuals find that a low dose stimulant taken
before sexual activity can help.
have used stimulant medications to energize individuals who are
apathetic and lethargic due to a severe medical illness.
Methylphenidate is the most commonly prescribed stimulant. It is approved
for use in individuals ages six and older. It usually starts to work about
15 to 30 minutes after it is taken. It peaks an average of 90-120 minutes
after it is taken. This can vary from one individual to another. The
effect of a dose can be from 2.5 to 4 hours. Amphetamine (Dexedrine) is
approved for ages 3 and older. It is also short acting but usually lasts
an hour or so longer than methylphenidate.
It is important
to remember the short duration of these medications. Many individuals take
a morning dose of methylphenidate at 6:30 and a second dose at Noon. This
person may have little medication effect in the late morning. A school
might assume that a child is misbehaving for a particular teacher when it
is actually a temporary lack of medication.
Methylphenidate (Ritalin) is
a short-acting drug. It can be difficult to remember several doses per day.
Ritalin SR, often
seems to show inconsistent results. It only comes in 20mg pills and cannot be
split into smaller fragments. Metadate-ER, manufactured by
released in 10mg and 20mg sizes. Metadate-ER is similar to Ritalin-SR. The
active component, methylphenidate, is in a wax-like matrix that releases the
drug over time.
Celltech more recently released Metadate CD which uses a
different delivery system. Its peak effect is generally around 5 hours and its
effect lasts 8 hours. Metadate CD encapsulates the methylphenidate in two types
of beads. About 30% of the medication is released immediately. The remainder is
released over time through beads with a release-control membrane. If the
individual cannot swallow the capsule, one can open it and sprinkle it on food.
(Alza Pharmaceuticals) is a form of Methylphenidate that uses an osmotic system to deliver
methylphenidate in a pulsed pattern. This allows a 12 hour response from a
single daily dose. Concerta was released in August 2000. The osmotic "oros" system has been used
successfully for several years for a diabetes medication and a bladder control
medication. Concerta's osmotic system involves
a tri-layer inner core surrounded by a semi-permeable membrane with an
immediate-release overcoat. This technology features a semi-permeable
membrane surrounding an osmotic core, which contains a push layer and a
drug layer. Once in the gastrointestinal tract, water enters the osmotic
system and dissolves the drug in the core of the tablet. Osmotic
pressure then causes the rate controlled release of the active drug
through a laser-drilled hole in the membrane.
With Concerta, the methylphenidate level
starts relatively low and rises throug most of the duration of the
drug's action. Studies show that its usual duration of action is 12 hours, but I have
seen a number of patients who seem to get a shorter duration of effect at all
Novartis has released
Ritalin-LA which is an improvement over the
wax-like matrix delivery system used by Ritalin-SR. It encapsulates the
active methylphenidate in microbeads. Half of the beads release
the methylphenidate immediately. The other half of the beads are extended
release. Ritalin LA is a good medication for those who experience
Concerta as "too slow out of the blocks."
Novartis, the manufacturer of brand name Ritalin
and Ritalin LA, has recently
released a non-racemic form of methylphenidate, called Focalin.
Other forms of methylphenidate such as Concerta and Metadate are mixtures of two
mirror images (isomers) of the methylphenidate molecule. The body may metabolize
the dextro (right handed) form of a compound differently from its mirror image
the levo (left handed) form. In the case of methylphenidate, the dextro
isomer is the active compound, and the levo form has minimal activity. Thus, Novartis recommends that when
you switch from regular methylphenidate to Focalin, you start with half as much
Focalin. Head to head studies do not show that Focalin is superior to
a twice as big dose of Ritalin. However, some individuals experience it
as lasting longer and causing less irritability when it wears off.
Novartis is hoping to have FDA approval for a long-acting beaded
delivery form of Focalin in 2005.
methylphenidate or d-amphetamine are fairly inexpensive. However, many of the
longer acting stimulants can be quite expensive for those without a good pharmacy
New forms of
long-acting stimulants may be on the market soon. Methypatch from
Shire Pharmaceuticals, is a small patch, worn on the skin, under one's clothes.
It delivers methylphenidate directly through the skin into the bloodstream.
Since the medication does not need to go through the digestive system, smaller
doses should be effective. The medication blood level would fall immediately when the
patch was removed. This might provide greater flexibility for individuals with
irregular work and sleep schedules. It had been expected to make its debut in
early 2003, but the FDA did not allow its release and has requested more
studies. An amphetamine patch is also in development.
long-acting form of d-amphetamine, has been on the market for years. It
has a peak effect in 1-4 hours and lasts 6-10 hours. It tends to have a
more gradual tapering and thus may have less of a rebound effect. Adderall
is a mixture of four salts of d-amphetamine combined with a smaller amount
of the less active r-amphetamine. Some clinicians felt that Adderall had a
longer duration of action than regular d-amphetamine. However, there are
as of yet, no published studies showing that it lasts any longer than
short-acting d-amphetamine. Thus we cannot really classify regular
Adderall as a long-acting stimulant. In November 2001, Shire, the
manufacturer of Adderall, released Adderall XR. In this formulation, the
Adderall is encapsulated in coated beads inside of a capsule. Half of the
beads dissolve immediately, and the other half dissolve about 4-6 hours
later. There is little data directly comparing Adderall XR to
the less expensive Dexedrine Spansules. Spokesmen for Shire have indicated
that they do not intend to run such studies. However, I have found the Adderall XR useful for patients who cannot swallow pills. Shire has looked at the
metabolism of Adderall XR when the capsule is opened and the beads are
sprinkled on pudding.
individuals who have difficulty swallowing pills A significant number
of individuals have difficulty swallowing pills. This is more common in
children and the elderly, but some adults also have trouble with some of
the larger pills. Crushing some forms of stimulants may change rate of absorption
or duration of action. However there are now two forms of extended release
stimulants that have been studied when sprinkled on food. Adderall XR
showed a similar duration of action when the capsule was opened and the
contents were sprinkled on pudding. A recent study showed that Metadate
CD, when opened and sprinkled on applesauce, showed similar onset and
duration of action as the intact capsule.
Medications: Duration of Action
||2 or 3 times
||2 or 3 times
||Once in am
||Once in am
||3 times per
||2 times per
||1 or 2 times
||Once in am
||Once in am
Table adapted from Greenhill,
Laurence, "Are New Stimulants Really Better?" AACAP Oct. 2001
(Cylert) is approved for ages 6 and older. It takes about one or two hours
to take effect and lasts up to eight hours. Permoline may take days to
build up enough to have an effect. It should be given seven days a week.
There have been 15 deaths due to liver failure associated with pemoline.
It is now a second-line medication for AD/HD. Individuals who take it need
to have periodic blood tests.
(Desoxyn) may be effective in some individuals who do not respond to the
It has a higher potential for abuse than the other stimulants. Used
carefully in selected patients, it can be an effective treatment for
Beccause of the paucity of recent data on the legitimate use of this
medication, we need to follow patients on this medication closely. Blood
pressure should be checked periodically.
Stimulants Addictive? The
Food and Drug Administration (FDA) has classified the stimulants, except
for Cylert, as Schedule II. This means that the physician cannot write for
automatic medication refills. Schedule II medications generally have a
higher potential for abuse than most other types of medication. Some
people worry that they might become addicted to stimulants. If individuals
take their medication as prescribed, the potential for addiction to
methylphenidate or amphetamine is fairly low. Methylphenidate is absorbed
into the brain much more slowly than a compound like cocaine. This is why
methylphenidate does not produce the high experienced in drugs of abuse. A
study published in Pediatrics in 1999, (3)
showed that individuals with AD/HD who were treated with stimulant
medication had a lower risk of drug abuse than AD/HD individuals who had
not taken medication. Still we are cautious about prescribing stimulants
to individuals who are abusing drugs. Injecting stimulants intravenously,
inhaling them or mixing them with illegal drugs can lead to further
Stimulant Side Effects Many
individuals take stimulants with few side effects. Others experience mild
problems and some are unable to tolerate stimulants. Often we can treat
annoying side effects so the individual can continue to take the
appetite: This effect may
be worse in the very young. It may improve after several weeks or
months. If it continues to be problematic, one may reduce the dose; or
time a short-acting stimulant to wear off before mealtimes. In some
cases we resign ourselves to a eating a large breakfast and supper
along with a small lunch.
Some people who take short acting methylphenidate or amphetamine
experience irritability or depression for an hour as the stimulant
wears off. Sometimes this is worse than the individual’s baseline.
One can avoid rebound by spacing the doses closer together, giving a
smaller dose after the final larger dose, or by switching to a longer
If this does not improve with time, we may reduce the dose or switch
to another stimulant.
caffeine or other stimulant-type medications. A small dose of a beta-blocker
(a type of blood pressure medication) can block tremor or jitters.
upset Take the medication
with meals or eat smaller, more frequent meals.
difficulty: This is more
frequent with the longer-acting stimulants such as Dexedrine Spansules.
However, the sleep problem is sometimes due to the AD/HD not the
medication. If the sleep problem is truly due to medication effect,
give the last dose earlier in the day. Sometimes clonidine or
guanfacine help an individual settle down for sleep. We also counsel
the individual on establishing good sleep habits.
Sometimes irritability may be due to the AD/HD or another psychiatric
disorder. If the irritability is truly due to the stimulant, there are
several options. Reduce the stimulant dose, switch to another
stimulant preparation, add clonidine/guanfacine or use another class
of medications to treat the AD/HD.
This may be a delayed effect of stimulant medication. It may be more
common with the long-acting stimulants. Screening for a history of
depression, and treating co-existing depression can minimize this. If
the depression truly is related to the medication, one may switch to
another class of medications to treat the AD/HD. These second-line
medications would include the tricyclic antidepressants and bupropion
If an individual is anxious, the stimulants can exacerbate the
symptoms. The treatment of this side effect is similar to that of
Individuals with diabetes mellitus or borderline glucose tolerance may
experience a rise in blood sugar. Such individuals can often take
stimulants but may need closer monitoring.
blood pressure: Stimulants may cause small increases in blood
pressure or pulse. This is usually not significant at normal doses in
most people. Individuals on very high doses of stimulants or
individuals at risk for blood pressure problems should be monitored
more closely. Some adults may opt to continue the stimulant and add a
blood pressure medication
or paranoia: These are
rare side effects. They may occur in an individual who is already
predisposed to a psychotic reaction. They may also occur when someone
takes an overdose of the stimulant. It is important to screen for and
treat certain other psychiatric disorders prior to starting a
and stereotyped movements: In
the past we did not give stimulants to individuals with tics because
we believed that the medication would make the tics worse. Recent data
seems to indicate that low to moderate doses of amphetamine or
methylphenidate do not exacerbate tics. If an individual (usually a
child) has tics, or develops them while on a stimulant, discuss it
with the prescribing physician.
Stimulants to Treat AD/HD: Stimulants can decrease the inattention,
hyperactivity, and impulsivity associated with AD/HD It is
important to do a careful history and mental status examination before
starting an adult or child on stimulant medication. We often get outside
data such as relatives’ reports or school checklists to help verify the
diagnosis. Inattention is a fairly non-specific phenomenon. It may be
caused by anxiety, depression or medical illness.
Some people may have another psychiatric condition on top of their
AD/HD. Conversely; AD/HD can be mistaken for depression anxiety or
Seven Days Per Week? In the past, children often got medication coverage only
for the hours they were in school. Some clinicians still use stimulants
only for school or work situations. We prefer a more individualized
approach. Attention deficit disorder affects individuals differently
depending on the type of activity, and the severity and type of the AD/HD.
Some people have mild AD/HD or have learned to compensate in most
situations. Such an individual might take a short acting stimulant only to
cover school or difficult work situations. Even in these situations, three
doses of methylphenidate are often better than two larger doses.
individuals benefit from broader stimulant coverage. Impulsivity can be
problematic in the evenings and on the weekends. Children and adolescents
may need to concentrate to do their homework in the evenings or on
weekends. Sometimes we need to prescribe a longer acting stimulant twice a
day. Those who truly need coverage 24 hours per day may need to use one of
We often start
a patient out with a single dose of methylphenidate. This allows the
individual to compare the way he feels on and off the medication. We start
with a low dose and gradually increase the number and size of the doses
until we reach a satisfactory response or run into side effects. It may be
embarrassing or inconvenient for someone to take 3 or 4 doses of
medication each day. Even people without AD/HD have trouble remembering to
take medication this often! We may move to a longer acting stimulant such
as Adderall or Dexedrine Spansules. As time goes on, we “fine tune” the size and frequency of
the medication doses. Some people take the same dose every day. Others may
take a lower dose on weekends.
with AD/HD may need to use a pillbox or other reminders to help them
remember to take their medication. Children and adolescents should have
their medication supervised and dispensed by an adult.
Abusers with AD/HD:
Adolescents and adults with AD/HD are at increased risk for substance
abuse. Methylphenidate can be abused by crushing it and using it
intranasally. When an individual has both AD/HD and a drug problem,
treatment becomes more complex. Reducing the person’s impulsivity may
make it easier for him to make safe choices. However, we do not want him
combining stimulants with alcohol or illegal substances. Thus, we try to
avoid using methylphenidate and the other Schedule II medications in
individuals who are active substance abusers. Instead, we may try to treat
their AD/HD with an antidepressant. If these are not effective, we are
left with a dilemma. If the patient makes a commitment to stay clean and
if we have a way of monitoring him, we can cautiously prescribe
See our article on ADHD and addiction.
Are Stimulants Over-Prescribed? According
to a study by Safer et al (1995) (4)
the use of methylphenidate has more than doubled between 1990 and 1995 in
the U.S. About 2.8% of children between the ages of 5 and 18 are taking methylphenidate for AD/HD. AD/HD is
diagnosed more frequently in the U.S. than in most other countries. Most
researchers believe that this is due to an increased awareness of AD/HD,
not an actual increase in the number of individuals affected. Does this
mean that the stimulants are over-prescribed in America? This has been a
matter for hot debate.
individuals have an incomplete response to stimulants. Others cannot
tolerate the stimulants. See Non-stimulant
medication Treatment for AD/HD and New
Medications for AD/HD.
Gainetdov et al., Role of Serotonin in the Paradoxical Calming Effect
of Psychostimulants on Hyperactivity, Science, Jan. 15, 1999:
Castellanos, FX, et al, Quantitative Brain Magnetic Imaging in
Attention Deficit Hyperactivity Disorder, Archives of General
Psychiatry, July 53 (7) 607-616, 1996.
Biederman et al, Pharmacotherapy of Attention Deficit/Hyperactivity
Disorder Reduces Risk for Substance Abuse Disorder, Pediatrics, Vol
104, No 2, August 1999.
Safer, et al, Increased Methylphenidate Usage for Attention Deficit
Disorder in the 1990s.Pediatrics, Dec. 1996.
Parameters for the Assessment and Treatment of Children, Adolescents and
Adults with Attention Deficit/Hyperactivity Disorder Journal of the
American Academy of Child and Adolescent Psychiatry, Vol. 36, No 10,
and Gilman's The Pharmacological Basis of Therapeutics 9th Edition,
Goodman, Limbird, Milnoff, Gilman and Hardman, McGraw Hill Publishers,