Prescription Stimulants-Retaining the Benefits
While Mitigating the Abuse Risk
by Nora
Volkow, MD
Introduction
Stimulants are a class of drugs that elevate
mood, induce feelings of well-being, and
increase energy and alertness. Stimulants
like cocaine, amphetamines, methamphetamine,
methylphenidate, and ecstasy can produce a
feeling of euphoria, which is one reason they
are abused. This article focuses on
stimulant medications that, although
pharmacologically similar to their illicit
counterparts, are legally prescribed to treat
attention-deficit hyperactivity disorder
(ADHD) and other medical conditions. While
proper use of these medications can be
beneficial to those who need them, their
non-medical use can be dangerous, can lead to
addiction, and currently stands at
unacceptably high levels in the general
population.
People abuse prescription stimulants for
various reasons-to get high, to improve
academic or athletic performance, or to lose
weight-putting themselves at risk for
dangerous health consequences. Young people
are at particular risk-in 2005, 8.6 percent
and 4.4 percent of 12th graders reported
past-year non-medical use of amphetamine and
methylphenidate, respectively (1).
Additionally, the growing number of
prescriptions written for stimulants used to
treat ADHD increases their general
availability and heightens the chances of
diversion and abuse. The high rates of
stimulant abuse in our Nation call for
prevention strategies that minimize the
potential reinforcing effects of these
medications and decrease their diversion.
ADHD: one of the most prevalent and
researched of the psychiatric disorders
Attention Deficit Hyperactivity Disorder is
the most commonly diagnosed and treated
behavioral disorder of childhood. Its
current prevalence in the general US
population is estimated to be in the 3 to 6
percent range. And while the neurobiology of
ADHD is not completely understood, imbalances
in both dopaminergic and noradrenergic
systems have been implicated in the origin
and persistence of its core symptoms, which
include inattention, hyperactivity, and
impulsivity.
In 1937, a serendipitous observation revealed
that the stimulant drug dl-amphetamine
increased compliance, improved academic
performance, and reduced motor activity in
hyperactive children (2). The intervening years
witnessed a flurry of clinical research on
ADHD and a huge increase in the volume of
treatment data. Today, after the publication
of hundreds of randomized clinical trials,
the efficacy of the four stimulant
medications that have been approved for
clinical use-methylphenidate (MPH),
dextroamphetamine (DEX), mixed-salts
amphetamine (AMP), and pemoline (PEM)-is
beyond doubt, with improvements typically
reported in approximately 70 percent of
patients. Not surprisingly, these
medications (particularly MPH and AMP) have
become the most widely prescribed
psychotropic medications for children. The
fastest growth occurred during the 1990s,
which saw a 5-fold increase in the number of
prescriptions written for stimulant
medications, from less than 2 million to more
than 10 million by decade's end. Presently,
an estimated 6 percent of school-age children
are identified and treated annually with
these drugs (about 3 million/year in the
United States), a figure that can vary widely
among different regions or socio-economic
classes. At first blush, this rate may seem
high, given the difficulties in defining
clear boundaries between normal and
clinically significant inattention,
hyperactivity, and impulsivity behaviors,
particularly among preschoolers, who are only
beginning to develop attentive and inhibitory
skills. However, we cannot discount the fact
that prescription stimulants have helped
millions of children and their families
manage and overcome a mental disorder that
can severely disrupt normal patterns of
learning and socialization.
Interestingly, and in spite of the widespread
and growing clinical use of stimulant
medications with intrinsic abuse potential,
the available evidence indicates that abuse
has been minimal among those for whom these
medications are appropriately prescribed. In
addition, the results of a meta-analysis of
available clinical data suggest that
stimulant therapy in childhood does not
increase the risk of substance use disorders
(SUDs) and may, in fact, afford a measurable
level of protection (3). These preliminary
conclusions suggest many positive
(therapeutic) effects when stimulants are
properly prescribed and appropriately used
under medical supervision.
How do stimulants exert their
therapeutic effects?
While researchers have made significant
inroads in answering this question, much
remains to be learned about the molecular and
cellular bases of stimulants' actions on the
brain, so as to optimize their therapeutic
potential and enhance their margin of safety.
The evidence clearly suggests that people
with and without ADHD experience improved
focusing of their attention when using low
doses of prescribed stimulants. MPH-induced
increases in dopamine (DA), for example, are
associated with an enhanced perception of a
stimulus as salient. By amplifying DA, MPH
may enhance task-specific signaling in target
neurons, improving attention and decreasing
distractibility (4). MPH thus makes a
behavioral task more interesting and improves
performance. However, we must still gain a
better understanding of the specific
contribution of dopaminergic, or reward,
pathways versus noradrenergic pathways, and
the relative importance of cortical and
subcortical structures in determining the
therapeutic versus the reinforcing effects of
stimulants.
It is becoming apparent that not all of
stimulants' therapeutic actions may hinge on
the reward/motivation system. Animal
research suggests that the therapeutic
effects of stimulants may also involve
significant prefrontal cortex (PFC)
components, which are involved in attention
and executive function. Rats administered
low MPH doses, for example, display a
significant increase in the levels of both DA
and norepinephrine in the PFC (6). This may be
important in light of the evidence suggesting
that ADHD patients may have specific
deficiencies in PFC neurotransmission (7).
Indeed, the PFC is known to be extremely
sensitive to fluctuations in the level of
catecholamines (e.g., norepinephrine) with
moderate concentrations improving PFC
function, and high concentrations impairing
it.
Still, most of our current models and
strategies pertaining to stimulants' effects
on the brain reflect our understanding of the
DA system, which is, by far, the
neurotransmitter system that has been studied
most extensively.
The fine line between stimulants'
therapeutic and reinforcing effects
MPH and AMP increase extracellular DA in the
brain, as do cocaine and methamphetamine, the
most commonly abused stimulant drugs. MPH
increases DA by blocking the dopamine
transporter (DAT) interfering with DA
reuptake-the same molecular target as
cocaine-while high doses of AMP, like
methamphetamine, increase DA by releasing it
from stored sites along the terminal (8, 9).
The resultant rapid and large increase in DA
is why stimulants are self-administered by
animals, why humans abuse them, and why they
have the potential to cause addiction.
From animal studies, we have gathered a
rather detailed account of the mechanisms of
action and effects of stimulants. Again,
similar to the cellular and behavioral
actions of the psychomotor stimulants cocaine
and methamphetamine, MPH and AMP induce
dose-dependent increases in DA levels in the
same brain pathways activated by drugs of
abuse. Also, repeated exposure to
psychomotor stimulants can result in some of
the same long-lasting cellular, molecular,
and behavioral adaptations implicated in the
transition from drug abuse to addiction in
humans.
Naturally, one of the main goals of
researchers and clinicians addressing
prescription drug formulations is to minimize
the likelihood of effective medications such
as stimulants being diverted and abused (10).
However, the close relationship between the
therapeutic and reinforcing effects of MPH
and AMP in their ability to alter dopamine
levels makes discriminatory alteration of
their pharmacological properties difficult.
To inform this process, we must tease apart
the variables that influence
stimulant-induced DA elevations and
differences in response to abuse versus
clinical use. For example, rate of delivery
to the brain is a crucial determinant of
stimulant response. A positron emission
tomography (PET) study produced solid
evidence that slower rates of delivery (e.g.,
oral MPH) are less reinforcing than faster
rates (e.g. intravenous MPH). Indeed,
intravenous administration of MPH produced a
high similar to that of intravenous cocaine,
while orally administered MPH did not.
Interestingly, this difference emerged in
spite of the fact that two different rates of
MPH delivery resulted in nearly equivalent
levels of DAT blockade (about 70 percent).
The critical requirement for experiencing MPH
as reinforcing is not what the maximum level
of DAT blockade is, but how fast it is
reached. Thus, delivery systems that lead to
slow uptake of the drug and maintain steady
state levels for longer periods of time are
less likely to be abused than delivery
systems that lead to fast brain uptake and
abrupt changes in concentration.
Dosage is also a key variable influencing the
therapeutic-to-reinforcing ratio of stimulant
medications. Larger doses lead to higher
concentrations per unit of time, just as
administration modes other than oral (e.g.,
smoking, injection, and snorting) speed drug
delivery to the brain (11, 12). Because higher
doses and faster rates are more reinforcing,
people who abuse stimulant medications to get
high often snort or inject them. When taken
orally, as prescribed, these medications have
minimal or no reinforcing effects, and
instead produce the expected therapeutic
effects seen in many patients.
Significant effort has gone toward developing
and deploying stimulant medications with
slower rates of delivery and brain uptake to
negate or at least minimize reinforcing
effects. The resulting slow-release
formulations present significantly less abuse
liability when taken as prescribed, and may
improve adherence through less frequent
dosing requirements. However, we must
continue to seek creative ways to counteract
dangerous tampering methods used by abusers
who crush prescription pills to snort or
inject their contents.
The developing brain's increased
vulnerability to addiction
Along with dosing and route of
administration, misdiagnosis is another
factor that could heighten addiction risk.
If children or adolescents are misdiagnosed
with ADHD, then exposure of their
still-developing brains to stimulant
medications may put them at risk for serious
consequences. Research has demonstrated that
brain development continues beyond the first
few years of childhood, throughout
adolescence, and into early adulthood, a
maturation process involving dramatic changes
in neuronal growth, and connectivity. Animal
studies show that these developmental stages
comprise a long period of increased
susceptibility to the effects of drugs of
abuse, which can lead to brain and behavioral
changes that persist into adulthood.
Animal studies also show that developmental
stage at time of exposure influences future
risk of abuse and addiction. In one study
rats exposed to MPH during the period
equivalent to human adolescence experienced
changes in brain DA cells, likely to increase
cocaine self-administration. In another
study, earlier (pre-adolescent) exposure to
MPH made moderate doses of cocaine aversive
and higher doses less rewarding. Despite the
difficulties of extrapolating results from
healthy rodents to affected or unaffected
children, these studies have helped refine
important research questions that will shed
more light on the brain's neurochemical and
functional characteristics during childhood
and adolescence and elucidate the effects of
psychotropic drugs on brain development.
Ensuring proper ADHD diagnosis will help to
avoid the inappropriate prescribing of
stimulant medications and will thus mitigate
their abuse potential and undesirable
effects. To this end, strict criteria have
been delineated, including symptoms
observable in more than one setting.
Physicians need to be aware of these
guidelines, and watchful for patients who may
try to obtain stimulants by fabricating ADHD
symptoms.
The personalized medicine of the
future: predicting dose and response
Future research should lead to even more
reliable and generally acceptable
prescription practices that focus not only on
the most effective but also the most
appropriate route, release mechanism, and
administration schedule for a given patient.
Information from genetic research, still in
its infancy, will help to personalize
medicine by identifying genetic markers of
risk that influence the course and expression
of illness and the response to medications.
Increasing our understanding of neurobiology
and behavior will help in framing smarter,
more efficient, and safer strategies for
achieving optimal stimulant treatment
outcomes. Efforts to counter prescription
stimulant abuse must extend beyond clinical
practices and guidelines to prevention and
education strategies that emphasize the
dangers of prescription drugs to young
people-even if they are using them to enhance
cognitive performance or for reasons other
than to get high.
In order not to jeopardize the overwhelming
clinical benefits of stimulant medications
and the public's trust in this treatment
option, it is critical to do the following:
- Broaden our understanding of the
patterns and long-term effects of stimulant
use and abuse.
- Educate the public-particularly high
school and college students-about the health
consequences and considerable risk of
addiction associated with the non-medical use
of stimulants.
- Make treatment widely known and
available to those addicted to
stimulants.
NIDA continues to support research to counter
negative trends and to better focus our
prevention efforts. Additionally, clinical
neurobiological investigations using modern
brain imaging methods will further our
understanding of how prescription drugs
affect brain processes and systems over the
lifespan. Research targeting a reduction in
prescription drug abuse, particularly among
our Nation's youth, will continue to be a
priority.
Suggested Readings
1. MTF. University of Michigan: Monitoring
The Future 2005 Full Press Release on Drug
Use. Ann Arbor, University of Michigan News
Service, 2005; 2005.
2. Greenhill LL, Pliszka S, Dulcan MK, et al.
Practice parameter for the use of stimulant
medications in the treatment of children,
adolescents, and adults. J Am Acad Child
Adolesc Psychiatry. Feb 2002;41(2
Suppl):26S-49S.
3. Wilens TE, Faraone SV, Biederman J,
Gunawardene S. Does stimulant therapy of
attention-deficit/hyperactivity disorder
beget later substance abuse? A meta-analytic
review of the literature. Pediatrics. Jan
2003;111(1):179-185.
4. Volkow ND, Wang G, Fowler JS, et al.
Therapeutic doses of oral methylphenidate
significantly increase extracellular dopamine
in the human brain. J Neurosci. Jan 15
2001;21(2):RC121.
5. Madras BK, Miller GM, Fischman AJ. The
dopamine transporter and
attention-deficit/hyperactivity disorder.
Biol Psychiatry. Jun 1 2005;57(11):1397-1409.
6. Berridge CW, Devilbiss DM, Andrzejewski
ME, et al. Methylphenidate Preferentially
Increases Catecholamine Neurotransmission
within the Prefrontal Cortex at Low Doses
That Enhance Cognitive Function. Biol
Psychiatry. Jun 22 2006.
7. Arnsten AF, Li BM. Neurobiology of
executive functions: catecholamine influences
on prefrontal cortical functions. Biol
Psychiatry. Jun 1 2005;57(11):1377-1384.
8. Kahlig KM, Binda F, Khoshbouei H, et al.
Amphetamine induces dopamine efflux through a
dopamine transporter channel. Proc Natl Acad
Sci U S A. Mar 1 2005;102(9):3495-3500.
9. Jones SR, Gainetdinov RR, Wightman RM,
Caron MG. Mechanisms of amphetamine action
revealed in mice lacking the dopamine
transporter. J Neurosci. Mar 15
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10. NIH. National Institutes of Health
Consensus Development Conference Statement:
diagnosis and treatment of
attention-deficit/hyperactivity disorder
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11. Volkow ND, Wang GJ, Fischman MW, et al.
Effects of route of administration on cocaine
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human brain. Life Sci. Aug 11
2000;67(12):1507-1515.
12. Quinn DI, Wodak A, Day RO.
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Reprinted with permission from Child &
Adolescent Psychopharmacology News,
Guilford Publications, Inc.,
2006, Volume 11 No. 3
