Do ADHD Drugs Take a Toll on the Brain?
Research
hints that hidden risks might accompany long-term use of the medicines
that treat attention-deficit hyperactivity disorder
A few years ago a single mother who had recently moved to town came to
my office asking me to prescribe the stimulant drug Adderall for her
sixth-grade son. The boy had been taking the medication for several
years, and his mother had liked its effects: it made homework time
easier and improved her son's grades.
At the time of this visit, the boy was off the medication, and
I conducted a series of cognitive and behavioral tests on him. He
performed wonderfully. I also noticed that off the medication he was
friendly and playful. On a previous casual encounter, when the boy had
been on Adderall, he had seemed reserved and quiet. His mother
acknowledged this was a side effect of the Adderall. I told her that I
did not think her son had attention-deficit hyperactivity disorder
(ADHD) and that he did not need medication. That was the last time I
saw her.
Attention-deficit hyperactivity disorder afflicts about 5
percent of U.S. children - twice as many boys as girls - age six to 17,
according to a recent survey conducted by the Centers for Disease
Control and Prevention. As its name implies, people with the condition
have trouble focusing and often are hyperactive or impulsive. An
estimated 9 percent of boys and 4 percent of girls in the U.S. are
taking stimulant medications as part of their therapy for ADHD, the CDC
reported in 2005. The majority of patients take methylphenidate
(Ritalin, Concerta), whereas most of the rest are prescribed an
amphetamine such as Adderall.
Although it sounds counter-intuitive to give stimulants to a
person who is hyperactive, these drugs are thought to boost activity in
the parts of the brain responsible for attention and self-control.
Indeed, the pills can improve attention, concentration and productivity
and also suppress impulsive behavior, producing significant
improvements in some people's lives. Severe inattention and impulsivity
put individuals at risk for substance abuse, unemployment, crime and
car accidents. Thus, appropriate medication might keep a person out of
prison, away from addictive drugs or in a job.
Over the past 15 years, however, doctors have been pinning the
ADHD label on - and prescribing stimulants for - a rapidly rising
number of patients, including those with moderate to mild inattention,
some of whom, like the sixth grader I saw, have a normal ability to
focus.
This
trend may be fueled in part by a relaxation of official diagnostic
criteria for the disorder, combined with a lower tolerance in society
for mild behavioral or cognitive problems.
In addition, patients are no longer just taking the medicines for a few
years during grade school but are encouraged to stay on them into
adulthood. In 2008 two new stimulants - Vyvanse (amphetamine) and
Concerta - received U.S. Food and Drug Administration indications for
treating adults, and pharmaceutical firms are pushing awareness of the
adult forms of the disorder. What is more, many people who have no
cognitive deficits are opting to take these drugs to boost their
academic performance. A number of my patients - doctors, lawyers and
other professionals - have asked me for stimulants in hopes of boosting
their productivity. As a result of these developments, prescriptions
for methylphenidate and amphetamine rose by almost 12 percent a year
between 2000 and 2005, according to a 2007 study.
With the expanded and extended use of stimulants comes
mounting concern that the drugs might take a toll on the brain over the
long run. Indeed, a smattering of recent studies, most of them
involving animals, hint that stimulants could alter the structure and
function of the brain in ways that may depress mood, boost anxiety and,
contrary to their short-term effects, lead to cognitive deficits. Human
studies already indicate the medications can adversely affect areas of
the brain that govern growth in children, and some researchers worry
that additional harms have yet to be unearthed.
Medicine for the Mind
To appreciate why stimulants could have negative effects over
time, it helps to first understand what they do in the brain. One
hallmark of ADHD is an underactive frontal cortex, a brain region that
lies just behind the forehead and controls such "executive" functions
as decision making, predicting future events, and suppressing emotions
and urges. This area may, in some cases, be smaller than average in
ADHD patients, compromising their executive abilities. Frontal cortex
function depends greatly on a signaling chemical, or neurotransmitter,
called dopamine, which is released in this structure by neurons that
originate in deeper brain structures. Less dopamine in the prefrontal
cortex is linked, for example, with cognitive difficulty in old age.
Another set of dopamine-releasing neurons extends to the nucleus
accumbens, a critical mediator of motivation, pleasure and reward whose
function may also be impaired in ADHD.
Stimulants enhance communication in these dopamine-controlled
brain circuits by binding to so-called dopamine transporters - the
proteins on nerve endings that suck up excess dopamine - thereby
deactivating them. As a result, dopamine accumulates outside the
neurons, and the additional neurotransmitter is thought to improve the
operation of neuronal circuits critical for motivation and impulse
control.
Not only can methylphenidate and amphetamine ameliorate a
mental deficit, they also can enhance cognitive performance. In studies
dating back to the 1970s, researchers have shown that normal children
who do not have ADHD also become more attentive - and often calmer -
after taking stimulants. In fact, the drugs can lead to higher test
scores in students of average and above-average intellectual ability
[see "
Smarter on Drugs," by Michael S. Gazzaniga;
Scientific American Mind, Vol. 16, No. 3, 2005].
Since the 1950s, when doctors first started prescribing stimulants to
treat behavior problems, millions of people have taken them without
obvious incident. A number of studies have even exonerated them from
causing possible adverse effects. For example, researchers have failed
to find differences between stimulant-treated children and those not on
meds in the larger-scale growth of the brain. In January 2009 child
psychiatrist Philip Shaw of the National Institute of Mental Health and
his colleagues used MRI scans to measure the change in the thickness of
the cerebral cortex (the outer covering of the brain) of 43 youths
between the ages of 12 and 16 who had ADHD. The researchers found no
evidence that stimulants slowed cortical growth. In fact, only the
un-medicated adolescents showed more thinning of the cerebrum than was
typical for their age, hinting that the drugs might facilitate normal
cortical development in kids with ADHD.
Altering Mood
Despite such positive reports, traces of a sinister side to
stimulants have also surfaced. In February 2007 the FDA issued warnings
about side effects such as growth stunting and psychosis, among other
mental disorders. Indeed, the vast majority of adults with ADHD
experience at least one additional psychiatric illness - often an
anxiety disorder or drug addiction - in their lifetime. Having ADHD is
itself a risk factor for other mental health problems, but the
possibility also exists that stimulant treatment during childhood might
contribute to these high rates of accompanying diagnoses.
After all, stimulants activate the brain's reward pathways,
which are part of the neural circuitry that controls mood under normal
conditions. And at least three studies using animals hint that exposure
to methylphenidate during childhood may alter mood in the long run,
perhaps raising the risk of depression and anxiety in adulthood.
In an experiment published in 2003 psychiatrist Eric Nestler
of the University of Texas Southwestern Medical Center and his
colleagues injected juvenile rats twice a day with a low dose of
methylphenidate similar to that prescribed for children with ADHD. When
the rats became adults, the scientists observed the rodents' responses
to various emotional stimuli. The rodents that had received
methylphenidate were significantly less responsive to natural rewards
such as sugar, sex, and fun, novel environments than were untreated
rats, suggesting that the drug-exposed animals find such stimuli less
pleasurable. In addition, the stimulants apparently made the rats more
sensitive to stressful situations such as being forced to swim inside a
large tube. Similarly, in the same year psychiatrist William Carlezon
of Harvard Medical School and his colleagues reported that
methylphenidate-treated preadolescent rats displayed a muted response
to a cocaine reward as adults as well as unusual apathy in a
forced-swim test, a sign of depression.
In 2008 psychopharmacologist Leandro F. Vendruscolo and his
co-workers at Federal University of Santa Catarina in Brazil echoed
these results using spontaneously hypertensive rats, which - like
children with ADHD - sometimes show attention deficits, hyperactivity
and motor impulsiveness. The researchers injected these young rats with
methylphenidate for 16 days at doses approximating those used to treat
ADHD in young people. Four weeks later, when the rats were young
adults, those that had been exposed to methylphenidate were unusually
anxious: they avoided traversing the central area of an open, novel
space more so than did rats not exposed to methylphenidate. Adverse
effects of this stimulant, the authors speculate, could contribute to
the high rates of anxiety disorders among ADHD patients.
Copying Cocaine?
The long-term use of any drug that affects the brain's reward
circuitry also raises the specter of addiction. Methyl-phenidate has a
chemical structure similar to that of cocaine and acts on the brain in
a very similar way. Both cocaine and methamphetamine (also called
"speed" or "meth") - another highly addictive stimulant - block
dopamine transporters just as ADHD drugs do [see "
New Weapons against Cocaine Addiction," by Peter Sergo;
Scientific American Mind,
April/May 2008]. In the case of the illicit drugs, the dopamine surge
is so sudden that in addition to making a person unusually energetic
and alert, it produces a "high."
Recent experiments in animals have sounded the alarm that
methylphenidate may alter the brain in ways similar to that of more
powerfully addictive stimulants such as cocaine. In February 2009
neuroscientists Yong Kim and Paul Greengard, along with their
colleagues at the Rockefeller University, reported cocaine like
structural and chemical alterations in the brains of mice given
methylphenidate. The researchers injected the mice with either
methylphenidate or cocaine daily for two weeks. Both treatments
increased the density of tiny extensions called spines at the ends of
neurons bearing dopamine receptors in the rodent nucleus accumbens.
Compared with cocaine, methylphenidate had a somewhat more localized
influence; it also had more power over longer spines and less effect on
shorter ones. Otherwise, the drugs' effects were strikingly similar.
Furthermore, the scientists found that methylphenidate boosted
the amount of a protein called ΔFosB, which turns genes on and off,
even more than cocaine did. That result could be a chemical warning of
future problems: excess ΔFosB heightens an animal's sensitivity to the
rewarding effects of cocaine and makes the animal more likely to ingest
the drug. Many former cocaine addicts struggle with depression, anxiety
and cognitive problems. Researchers have found that cocaine has
remodeled the brains of such ex-users. Similar problems - principally,
perhaps, difficulty experiencing joy and excitement in life - could
occur after many years of Ritalin or Adderall use.
Amphetamine and methylphenidate can also be addictive if
abused by, say, crushing or snorting the pills. In a classic study
published in 1995 research psychiatrist Nora Volkow, then at Stony
Brook University, and her colleagues showed that injections of
methylphenidate produced a cocaine like high in volunteers.
More
than seven million people in the U.S. have abused methylphenidate, and
as many as 750,000 teenagers and young adults show signs of addiction,
according to a 2006 report.
Typical oral doses of ADHD meds rarely produce such euphoria and are
not usually addicting. Furthermore, the evidence to date, including two
2008 studies from the National Institute on Drug Abuse, indicates that
children treated with stimulants early in life are not more likely than
other children to become addicted to drugs as adults. In fact, the risk
for severe cases of ADHD may run in the opposite direction. (A low
addiction risk also jibes with Carlezon's earlier findings, which
indicated that methylphenidate use in early life mutes adult rats'
response to cocaine.)
Corrupting Cognition
Amphetamines such as Adderall could alter the mind in other
ways. A team led by psychologist Stacy A. Castner of the Yale
University School of Medicine has documented long-lasting behavioral
oddities, such as hallucinations, and cognitive impairment in rhesus
monkeys that received escalating injected doses of amphetamine over
either six or 12 weeks. Compared with monkeys given inactive saline,
the drug-treated monkeys displayed deficits in working memory - the
short-term buffer that allows us to hold several items in mind - which
persisted for at least three years after exposure to the drug. The
researchers connected these cognitive problems to a significantly lower
level of dopamine activity in the frontal cortex of the drug-treated
monkeys as compared with that of the monkeys not given amphetamine.
Underlying such cognitive and behavioral effects may be subtle
structural changes too small to show up on brain scans. In a 1997 study
psychologists Terry E. Robinson and Bryan Kolb of the University of
Michigan at Ann Arbor found that high injected doses of amphetamine in
rats cause the major output neurons of the nucleus accumbens to sprout
longer branches, or dendrites, as well as additional spines on those
dendrites. A decade later Castner's team linked lower doses of
amphetamine to subtle atrophy of neurons in the prefrontal cortex of
monkeys.
A report published in 2005 by neurologist George A. Ricaurte
and his team at the Johns Hopkins University School of Medicine is even
more damning to ADHD meds because the researchers used realistic doses
and drug delivery by mouth instead of by injection. Ricaurte's group
trained baboons and squirrel monkeys to self-administer an oral
formulation of amphetamine similar to Adderall: the animals drank an
amphetamine-laced orange cocktail twice a day for four weeks, mimicking
the dosing schedule in humans. Two to four weeks later the researchers
detected evidence of amphetamine-induced brain damage, encountering
lower levels of dopamine and fewer dopamine transporters on nerve
endings in the striatum - a trio of brain regions that includes the
nucleus accumbens - in amphetamine-treated primates than in untreated
animals. The authors believe these observations reflect a drug-related
loss of dopamine-releasing nerve fibers that reach the striatum from
the brain stem.
One possible consequence of a loss of dopamine and its
associated molecules is Parkinson's disease, a movement disorder that
can also lead to cognitive deficits. A study in humans published in
2006 hints at a link between Parkinson's and a prolonged exposure to
amphetamine in any form (not just that prescribed for ADHD). Before
Parkinson's symptoms such as tremors and muscle rigidity appear,
however, dopamine's function in the brain must decline by 80 to 90
percent, or by about twice as much as what Ricaurte and his colleagues
saw in baboons that were drinking a more moderate dose of the drug. And
some studies have found no connection between stimulant use and
Parkinson's.
Stimulants do seem to stunt growth in children. Otherwise,
however, studies in humans have largely failed to demonstrate any clear
indications of harm from taking ADHD medications as prescribed. Whether
the drugs alter the human brain in the same way they alter that of
certain animals is unknown, because so far little clinical data exist
on their long-term neurological effects. Even when the dosing is
similar or the animals have something resembling ADHD, different
species' brains may have varying sensitivities to stimulant
medications.
Nevertheless, in light of the emerging evidence, many doctors
and researchers are recommending a more cautious approach to the
medical use of stimulants. Some are urging the adoption of strict
diagnostic criteria for ADHD and a policy restricting prescriptions for
individuals who fit those criteria. Others are advocating behavior
modification - which can be as effective as stimulants over the long
run - as a first-line approach to combating the disorder. Certain types
of mental exercises may also ease ADHD symptoms [see "
Train Your Brain," by Ulrich Kraft;
Scientific American Mind,
February/March 2006]. For patients who require stimulants, some
neurologists and psychiatrists have also suggested using the lowest
dose needed or monitoring the blood levels of these drugs as a way of
keeping concentrations below those shown to be problematic in other
mammals. Without these or similar measures, large numbers of people who
regularly take stimulants may ultimately struggle with a new set of
problems spawned by the treatments themselves.
Growing Problems
So far the best-documented problem associated with the
stimulants used to treat attention-deficit hyperactivity disorder
(ADHD) concerns growth. Human growth is controlled at least in part
through the hypothalamus and pituitary at the base of the brain.
Studies in mice hint that stimulants may increase levels of the
neurotransmitter dopamine in the hypothalamus as well as in the
striatum (a three-part brain structure that includes part of its reward
circuitry) and that the excess dopamine may reach the pituitary by way
of the bloodstream and act to retard growth.
Recent work strongly indicates that the drugs can stunt growth
in children. In a 2007 analysis of a National Institute of Mental
Health study of ADHD treatments involving 579 children, research
psychiatrist Nora Volkow, who directs the National Institute of Drug
Abuse, and her colleagues compared growth rates of unmedicated seven-
to 10-year-olds over three years with those of kids who took stimulants
throughout that period. Relative to the unmedicated youths, the
drug-treated youths showed a decrease in growth rate, gaining, on
average, two fewer centimeters in height and 2.7 kilograms less in
weight. Although this growth-stunting effect came to a halt by the
third year, the kids on the meds never caught up to their counterparts.
Further Reading
Head Lines: Practice Removes Prejudice--And More
MIND Reviews: A Healthy Mind
Pump Your Brain--And Other Stories from
MIND
Saving the Disadvantaged from Pollution
The Mind-Body Problem
Does Postpartum Depression Serve an Evolutionary Purpose?
Soldiers' Stress: What Doctors Get Wrong about PTSD
A Wiring Diagram in the Brain for Depression--
Parijata Mackey
University of Chicago
pari...@gmail.comwww.parijata.com--
"Have patience with all yet unsolved in your heart. Try to love the questions themselves, like locked rooms and foreign scripts. Do not now seek the answers. They cannot yet be given because you could not yet live them -- and the point is to live everything. At the present, you need to live the question. Perhaps you will gradually, without even noticing it, find yourself experiencing the answer, some distant day."
- Rainer Maria Rilke