Literature Review Journal of Attention Disorders

Volume 11 Number 1
July 2007 8-16
2007 Sage Publications
10.1177/1087054706295605
http://jad.sagepub.com
hosted at

Update on Amphetamine Neurotoxicity and Its http://online.sagepub.com

Relevance to the Treatment of ADHD

Claire Advokat
Louisiana State University

Objective: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to
obtain information on the long-term neurological consequences of this therapy. Method: Several databases were accessed
for research articles on the effects of amphetamine in the brain of laboratory animals and ADHD diagnosed individuals.
Results: In early studies, high doses of amphetamine, comparable to amounts used by addicts, were shown to damage
dopaminergic pathways. More recent studies, using therapeutic regimens, appear contradictory. One paradigm shows sig-
nificant decreases in striatal dopamine and transporter density after oral administration of therapeutic doses in primates.
Another shows morphological evidence of trophic dendritic growth in the brains of adult and juvenile rats given systemic
injections mimicking therapeutic treatment. Imaging studies of ADHD-diagnosed individuals show an increase in striatal
dopamine transporter availability that may be reduced by methylphenidate treatment. Conclusion: Clarification of the neu-
rological consequences of chronic AMPH treatment for ADHD is needed. (J. of Att. Dis. 2007; 11(1) 8-16)

Keywords: attention-deficit hyperactivity disorder (ADHD); amphetamine; neurotoxicity; review

Introduction In contrast to this clinical literature, several reviews of

For nearly 70 years, since recognition of the paradoxi-
cal effect of amphetamines (AMPH) in hyperactive boys
(Bradley, 1937), the use of stimulants in the treatment of
attention-deficit hyperactivity disorder (ADHD) has raised
concern about their potential for increasing the risk of
subsequent substance abuse or inducing symptoms of
psychopathology (Barkley, Fletcher, Fischer, & Smallish,
2003; Ellison & Eison, 1983; Fone & Nutt, 2005;
Robinson & Becker, 1986; Vitiello, 2001; Volkow &
Insel, 2003; Volkow & Swanson, 2003; Wilens, Faraone,
Biederman, & Gunawardene, 2003). Direct neurotoxic
effects on the brain have received less discussion, presum-
ably because of the low doses, brief duration, and the oral
route of administration used in the treatment of ADHD,
and the fact that methylphenidate (MPH; Ritalin), one of
the most commonly prescribed stimulants, produces mini-
mal brain damage in animal models even after extremely
high doses (McCann & Ricaurte, 2004; Volkow & Insel,
2003; Wagner, Ricaurte, Johanson, Schuster, & Seiden,
1980; Yuan, McCann, & Ricaurte, 1997; Zaczek, Battaglia,
Contrera, Culp, & De Souza, 1989).
stimulants in the context of drug abuse and dependence
have emphasized the neurotoxic effect of AMPH and its
analogs, particularly methamphetamine (METH) and meth-
ylenedioxymethamphetamine (MDMA). There is substan-
tial evidence that when these drugs are administered to
nonhuman animals, in a manner that mimics patterns of
abuse in humans (high doses over several days), they are
neurotoxic to biogenic amine neurotransmitter systems in
rodents and primates (Fuller, 1985; Gibb et al., 1999;
ODell, Weihmuller, & Marshall, 1991; Ricaurte, Guillery,
Seiden, Schuster, & Moore, 1982; Seiden & Sabol, 1996;
Sonsalla, Jochnowitz, Zeevalk, Postveen, & Hall, 1996;
Villemagne et al., 1998; Woolverton, Ricaurte, Forno, &
Seiden, 1989). Recent results of imaging studies in human
METH abusers show changes in dopaminergic neural path-
ways that are consistent with the observations in nonhuman
models suggesting possible neurotoxicity (McCann et al.,
1998; Thompson et al., 2004; Volkow et al., 2001).
Authors Note: Address correspondence to Claire Advokat, PhD,
Department of Psychology, 236 Audubon Hall, Louisiana State
University, Baton Rouge, LA 70803; cadvoka@lsu.edu.

8

The difference in neurotoxicity between MPH and
AMPH has been attributed to the difference in their respec-
tive mechanisms of action. MPH blocks the synaptic reup-
take transporters for the monoamines, particularly for
dopamine. AMPH also prevents monoamine reuptake, but
unlike MPH, AMPH crosses the cell membrane into the
terminal and also interacts with the transporters that are
responsible for vesicular storage of dopamine. As a result,
AMPH displaces dopamine from vesicles, which increases
its cytoplasmic concentration, causing it to be released
from the terminal in a process termed reverse transport.
Importantly, this release does not require the nerve cell to
be stimulated and occurs even during periods of inactivity.
Finally, AMPH also acts inside the terminal to block
monoamine oxidase, the enzyme that normally breaks
down dopamine and norepinephrine, allowing the trans-
mitters to remain active longer. These differences produce
a more rapid and greater increase in synaptic monoamines
with AMPH compared with MPH (Schiffer et al., 2006)
particularly after oral administration (Fone & Nutt,
2005), which may account for its greater toxicity.
Amphetamine (AMPH) is therefore, unusual among the
psychostimulants (and most psychoactive agents) in that it
is a drug of abuse with neurotoxic potential, and a primary
medication (Robinson & Becker, 1986). Approximately
40% of children with the diagnosis of ADHD respond
equally well to both MPH and AMPH, although 35%
respond better to AMPH (Conner & Steingard, 2004).
However, like METH, AMPH has consistently been found
neurotoxic in nonhuman models of stimulant abuse. In
many cases these studies involved continuous, systemic
administration of high doses (>15 mg/kg) that increased
blood, and presumably brain concentration for several
days, followed by abrupt drug termination and eventual
assay of the brain several days or weeks later. Such proce-
dures were used to mimic human abuse patterns, and the
subsequent neurotoxicity was presumed to be predictive of
possible brain damage in stimulant addicts.
In contrast, the standard AMPH treatment for core
ADHD symptoms has, in the past, consisted of oral
administration of low doses, 0.1 to 0.5 mg/kg, often twice
a day during school hours, as immediate-release prepara-
tions in children aged 6 to 12 years (Conner & Steingard,
2004). Therapeutic effects begin within 30 min, peak at
about 2 hr and last about 5 hr (Solanto, 2000).
Recently, however, significant changes have occurred in
the diagnosis and treatment of ADHD. First, it has been rec-
ognized that the disorder can persist into adulthood, with
adverse occupational, academic, and interpersonal conse-
quences. This has meant acceptance of continued treatment
for children with the diagnosis as they mature and start col-
lege or careers and families, and initiation of treatment for
Advokat / Treatment of ADHD 9
newly diagnosed adults. As a result, extended coverage of
symptoms throughout the day has become common (and
presumably throughout the summer months), with some
evidence that adults may require higher doses, 0.9
mg/kg/day, for maximal benefit (Conner & Steingard,
2004; Wilens, 2003; Wilens, Faraone, & Biederman, 2004).
Second, in parallel with these new treatment goals, the
need for longer-lasting formulations to provide coverage
throughout the day was recognized (Greenhill et al., 2003)
and accommodated, with the recent development of four
long-acting compounds. One of these, Adderall XRTM,
which is an extended release capsule of mixed AMPH salts
(approved in October of 2001), appears to have a longer
duration of action than the other commercial long-acting
AMPH formulation, Dexedrine SpansulesTM improving
symptoms for up to 12 hr postadministration. However, to
date, no direct clinical comparisons of these two com-
pounds have been published.
These developments of extended long-term treatment
and newer long-lasting formulations have raised concern
about illicit diversion of AMPH prescribed for ADHD.
Adults have control of their prescribed medications,
including drugs with a high abuse potential. There are
now numerous anecdotal reports and several published
articles describing the illegal use of stimulant drugs by
college students, who may obtain them with fraudulent
prescriptions or buy them from those who have a legiti-
mate prescription (McCabe, Knight, Teter, & Wechsler,
2005; Teter, McCabe, Cranford, Boyd, & Guthrie, 2005).
Although much of this use is stated to be for academic
purposesas a means of improving concentration or to
stay awake while studying, recreational use is also
acknowledged.
Given that the half-life of AMPH is 2 to 3 times longer
in adults than in children (Brown, Hunt, Ebert, Bunney, &
Kopin, 1979), that more adults are being prescribed these
drugs, and that there is reportedly an increase in illicit use
among college students (who may not only take the drug
orally but also dissolve and inject it), it is understandable
that a recent review acknowledged an urgent need to
better understand their potential long-term adverse
effects (Fone & Nutt, 2005, p. 88). The purpose of this
review is to summarize the evidence specifically describ-
ing AMPH-induced neurotoxicity and to discuss the
implications of this literature for the treatment of ADHD.
Chronic High-Dose Amphetamine:
Neurochemical Toxicity
Like METH, early studies were designed to evaluate the
neurotoxic effects of AMPH in the context of substance
10 Journal of Attention Disorders
abuse. Several procedures were used to produce continu-
ous prolonged AMPH exposure in nonhuman subjects.
One early method was by gradual escalation of AMPH in
the drinking water of rats for 14 days followed by with-
drawal for up to 7 days (Lynch, Kenny, & Leonard, 1977).
A more common approach was subcutaneous (SC) implan-
tation of pellets or Alzet Osmotic Minipumps containing
d-amphetamine base or sulfate, to mice or rats, which
provided continuous exposure to the drug for 3 to 7 days,
at doses that varied from 0.6 mg/day (25 g/hr) to about
4 or more mg/day. Animals were killed either while the
pellets or pumps were still implanted or from 1 to several
days or weeks after removal of the drug delivery system
(Ellison, Eison, Huberman, & Daniel, 1978; Ellison &
Ratan, 1982; Jonsson & Nwanze, 1982; Nwanze &
Jonsson, 1981; Ricaurte, Seiden, & Schuster, 1984; Ryan,
Martone, Linder, & Groves, 1988; Steranka & Sanders-
Bush, 1980).
Results have generally been consistent in showing that
during drug administration, and for about 2 weeks after
drug removal, whole-brain dopamine and synaptosomal
dopamine uptake were decreased by about 40 to 50%,
and activity of the biosynthetic enzyme, tyrosine hydrox-
ylase was reduced. Weeks to months after drug removal,
there was usually some, incomplete, recovery of
dopamine content (Jonsson & Nwanze, 1982). By com-
bining the injection of a priming dose (15 mg/kg) with a
16 hr minipump-infusion (1.36 mg/hr), a steady-state
brain AMPH concentration of 12 to 25 g/g was pro-
duced during 0.5 to 16 hr. This resulted in marked
decreases in striatal dopamine, [and the metabolites]
DOPAC [3,4-dihydroxyphenylacetic acid] and HVA
[homovanillic acid] and the synaptosomal uptake of
dopamine (Steranka, 1983, p. 162) which lasted for
at least 12 weeks. By 24 weeks, DOPAC, HVA, and
synaptosomal uptake had recovered to control levels, but
the dopamine decrease persisted (Steranka, 1983).
Results of these studies were consistent in showing that
the effects were stereoselective for d-amphetamine
(Steranka, 1981), predominantly selective for dopamine
(although sometimes affecting norepinephrine as well)
and for the striatum.
Although daily injections of high doses (25 mg/kg 2
per day, for 30 days) also depleted dopamine and
dopamine uptake in the caudate (Wagner et al., 1980), it
was soon realized that even a single dose of AMPH could
become toxic to rats if it was prevented from being metab-
olized and persisted in the brain for an extended period of
time. This was shown when a dose of 18.4 mg/kg was
given in conjunction with iprindole, a drug that blocked
AMPH metabolism and increased its half-life from 1 to
about 4 hr. Although, neither drug alone affected dopamine
levels, 1 week after injection of the combination dopamine
concentration was reduced by 31% in the cerebral hemi-
spheres and striata (Fuller & Hemrick-Luecke, 1980).
Subsequent studies showed that a single injection of 6.9
mg/kg or 9.2 mg/kg of d-amphetamine to iprindole-treated
rats produced significant decreases in striatal dopamine
and dopaminergic metabolites DOPAC and HVA, 1 week
later (Steranka, 1981). Similar results were obtained with 5
mg/kg fluoxetine, a 5HT reuptake blocker, which also
increased the depletion of dopamine measured 2 weeks
after a series of 5 AMPH injections (15 mg/kg) spaced 6 hr
apart. Although fluoxetine alone didnt change the
dopamine (or serotonin) concentration, it increased
dopamine depletion from 32% to 65%. This treatment also
increased brain levels of amphetamine, suggesting that flu-
oxetine was acting like iprindole (Ricaurte, Fuller, Perry,
Seiden, & Schuster, 1983). These results were confirmed
and extended, by demonstrations that dopamine depletion
did not occur when dopamine uptake was prevented, or
when dopamine synthesis was blocked (Fuller & Hemrick-
Luecke, 1982; Ricaurte, Guillery, Seiden, & Schuster,
1984). Together, these data were interpreted to mean that
adequate levels of dopamine were required for ampheta-
mine-induced dopaminergic toxicity, manifested as a
decrease in dopamine concentration, dopamine uptake
capacity, and tyrosine hydroxylase activity.
Although most studies have been done in rodents,
vervet monkeys appear to be even more susceptible to
amphetamine-induced neurotoxicity (Owen, Baker, Ridley,
Cross, & Crow, 1981). In one early report (Ridley, Baker,
Owen, Cross, & Crow, 1982), five animals were adminis-
tered 4 mg/kg/day of d-amphetamine sulfate for 11 days.
This dose was increased to 6 mg/kg for 9 days, then to 8
mg/kg for 7 days, 10 mg/kg for 5, and 12 mg/kg for 3. The
drug was given in flavored drinking water that was con-
sumed in small quantities throughout the day. On the
morning following the last drug administration, brains were
removed for biochemical analysis. Results showed dramatic
reductions in the concentration of dopamine (75% to 93%)
and its metabolites, especially DOPAC (~ 60% to 85%) and
tyrosine hydroxylase activity (~60% to 70%) in the corpus
striatum and nucleus accumbens.
Similar results were obtained by Melega and col-
leagues (Melega et al., 1996; Melega, Raleigh, Stout,
Hung et al., 1997; Melega, Raleigh, Stout, Lacan, et al.,
1997) when they injected d-amphetamine sulfate intra-
muscularly once a day to each of five vervet monkeys,
starting from 4 mg/kg and increasing to 18 mg/kg on
the 9th and 10th days. By conducting PET scans using
6-[ 18F]fluoro-L-DOPA (FDOPA) and biochemical
analyses, they found decreases in both dopamine syn-
thesis and striatal concentration. Dopamine synthesis

was initially reduced to approximately 30% of control
and, after 2 years, had recovered to only 53% of pre-
drug values. Likewise, dopamine content was approxi-
mately 95% depleted throughout the caudate and
putamen at 1 to 2 weeks but had recovered to 80% and
then baseline, at 1 and 2 years, respectively.
The sensitivity of vervet monkeys to AMPH-induced
neurotoxicity was replicated in a second study in which
two IM injections of 2 mg/kg each, were given 4 hr apart
in a single day. Analyses showed a decrease of 45% to 67%
in the index of striatal dopamine synthesis capacity at 3 to
6 weeks with recovery to about a 16% decrease at 32
weeks. Striatal dopamine concentrations were decreased
by 75% at 3 to 4 weeks and were still only 55% of baseline
10 to 12 weeks later.
Recent observations in aged rats suggest developmental
factors may also influence the severity of amphetamine-
induced neurotoxicity even in nonprimate populations
(Bowyer et al., 1998).
Chronic High-Dose Amphetamine:
Neurological Toxicity
In early studies of neurotoxicity produced by chronic
high-dose amphetamine, histological indices indirectly
indicated that dopamine terminals in the caudate nucleus
had been damaged (Ellison et al., 1978; Jonsson &
Nwanze, 1982; Nwanze & Jonsson, 1981). Direct evi-
dence of neuroanatomical damage in rats was soon
confirmed with the Fink-Heimer method of selective silver-
impregnation of degenerating nerve fibers. This was
shown after administration by subcutaneous minipump or
iprindole treatment (Fuller & Hemrick-Luecke, 1980,
1982; Ricaurte, Guillery, Seiden, & Schuster, 1984). Ryan
and colleagues (Ryan, Linder, Martone, & Groves, 1990)
describe extensive ultrastructural damage produced by
20 to 60 mg/kg /day administered for 3 days, by SC
minipumps. Degeneration was reported for various corti-
cal structures, such as the somatosensory neocortex and in
some frontal motor areas, depending on the particular
strain of rat. Cases where dopamine levels recovered for
several months after AMPH exposure were suggested to
indicate regeneration of dopamine nerve terminals, or col-
lateral sprouting of dopamine fibers.
Chronic Low-Dose Amphetamine:
Neurochemical Effects
Neurotoxicity is not usually seen in rats after admin-
istration of lower amounts, either by continuous expo-
sure via SC minipump, or repeated injection, if the doses
Advokat / Treatment of ADHD 11
are less than about 15 to 20 mg/kg/day, or if the exposure
lasts for 3 days or less (Ryan et al., 1988). In mice, infu-
sion of about 17 g/hr (0.408 mg/day) for 7 days did not
change dopamine concentration, although 25 g/hr for 7
days caused a 50% reduction in the striatum (Jonsson &
Nwanze, 1982). Numerous studies found no change in
striatal dopamine content or tyrosine hydroxylase activ-
ity, in rats, after single, multiple, or even escalating doses
of AMPH. This was the case for Seiden and colleagues
(Pearl & Seiden, 1979) after either a single or daily
repeated administration of 2.5 mg/kg of d-AMPH for
more than 30 days, and with Ellison et al. (1978) after 7
daily injections of 3.7 mg/day, or 30 daily injections of
3.2 mg/kg/day. Striatal dopamine levels, determined 2
days after treatment, were unchanged when AMPH was
injected either 3 times a day, at doses that escalated from
1 mg/kg up to 12 mg/kg, or the drug was given daily at
3 mg/kg for 6 days (Kuczenski & Leith, 1981). Robinson
and Camp (1987) administered two daily injections, 8 to
10 hr apart, for 5 days a week for 6 weeks. The doses
increased from 1 to 10 mg/kg (20 mg/kg/day) for the last
4 days. When the brains were removed 12 days later,
there was no change in dopamine concentration in the
striatum, nucleus accumbens, or medial frontal cortex.
(One exception is a report of a significant decrease in
caudate dopamine levels after only a single 4.0 mg/kg
injection [Ellison & Ratan, 1982].)
These data are consistent with the conclusion that low
daily AMPH doses, even when gradually increased to a
total of 20 mg/kg/day, do not produce long-term dopamine
depletion in rats, although such treatment does acutely
cause dopamine release. For example, Karoum, Speciale,
Chuang, and Wyatt (1982) showed that both a single dose
of 2.5 mg/day (measured at 45 min) or repeated injection
of 5.0 mg/kg, twice a day for 10 days (measured after 2 hr)
increased dopamine levels in the caudate. Recently, micro-
dialysis of in vivo extracellular dopamine release showed
a dose-dependent increase, in the striatum of rats, in
response to 0.5, 1.0, 2.5, and 5.0 mg/kg, with a peak con-
centration at 20 to 40 min after drug administration at all
doses (Kuczenski & Segal, 1989).
Taken together, these results indicate that, in rats, stri-
atal dopamine release produced by acute low-dose
AMPH does not produce long-lasting effects as doses
and duration increase up to 15 to 20 mg/kg/day for sev-
eral days. Further increases above this threshold are
associated with substantial dopamine depletion and
degeneration of dopamine nerve terminals.
There is empirical evidence for such a threshold with
respect to METH (ODell et al., 1991). In those studies,
rats were given a 4 mg/kg METH injection every 2 hr for a
total of either three or four injections. Microdialysis results
12 Journal of Attention Disorders
showed that the first two injections increased extracellular
dopamine concentration, which remained at 200% to
600% of basal values after the third injection. But the
fourth injection produced much larger elevations, up to
3,600% of basal values, and the dopamine efflux remained
elevated for 16 hr afterward. When measured 1 week after
this treatment, there were significant depletions of
dopamine in both striatum (51% depletion) and nucleus
accumbens (43% depletion) after four but not three METH
injections. The fourth injection was critical for producing
long-term dopamine depletion and neurotoxicity.
Chronic Amphetamine in Animal
Models of ADHD: Primates
Recently, however, new data from Ricaurte et al.
(2005) indicate that primates may be much more suscep-
tible than rats to AMPH-induced neurotoxicity. They
examined the effect of the drug in adult baboons and
squirrel monkeys, as clinically used to treat ADHD. In
the first two studies, baboons were trained to orally self-
administer a mixture of AMPH salts (a 3:1 ratio of dex-
tro [S(+)] and levo [R(-)] AMPH, which simulated a
common formulation for ADHD treatment). AMPH was
administered twice daily for approximately 4 weeks at
escalating doses of 2.5 to 20 mg (0.67 to 1.00 mg/kg).
During the second study, plasma AMPH concentrations
were determined at the end of each week. In the third
study, AMPH was administered by orogastric gavage to
squirrel monkeys and doses were adjusted (to 0.58-0.68
mg/kg) so that for approximately the last 3 weeks plasma
drug concentrations were comparable to those reported
in clinical populations of children receiving chronic
AMPH treatment-100 to 150 ng/ml (McGough et al.,
2003). Measurements in all three investigations were
taken 2 to 4 weeks after drug treatment.
Results from the first two studies showed significant
reductions in striatal dopamine concentration, dopamine
transporter density, and vesicular monoamine transporter
sites. Plasma AMPH concentration at the end of the 4
week treatment period was 168 25 ng/ml. In squirrel
monkeys, brain dopamine concentrations and vesicular
transporter sites were also significantly reduced although
dopamine transporter decreases were not statistically
significant.
These results raise obvious concerns about clinical drug
treatment of ADHD, although extrapolation to human
populations may be premature until possible species dif-
ferences in mechanism of action, developmental variables,
or metabolism are determined. Ricaurte et al. (2005)
noted there is no consistent evidence of dopaminergic
neurotoxicity in patients with ADHD who have been treated
with AMPH. But they pointed out that overt impairment,
such as parkinsonism, may not be evident until dopamine
function is reduced by 80% to 90%. Furthermore, if ADHD
symptoms themselves are related to abnormalities in
dopaminergic function, it might be difficult to detect deficits
because of underlying disease rather than amphetamine
neurotoxicity. Because most neuroimaging studies of
ADHD have been conducted with medication-naive indi-
viduals the absence of, or inconsistencies in, evidence for
dopaminergic neurotoxicity in ADHD patients does not rule
out the possibility that it might occur.
Chronic Amphetamine in Animal
Models of ADHD: Rodents
Although the evidence from Ricaurte and colleagues
(2005) may have disturbing implications for AMPH treat-
ment of ADHD, their observations seem dramatically at
odds with the results of a series of articles by Kolb and
colleagues (Heijtz, Kolb, & Forssberg, 2003; Robinson &
Kolb, 1997, 1999). The rationale for these experiments is
derived from the behavioral phenomenon of sensitization,
in which repeated administration of (usually) addictive
drugs leads to an increase in their activating or rewarding
effects, as opposed to the decrease that defines tolerance.
By considering sensitization to be an example of experience-
dependent plasticity, they reasoned that its development
would, like other forms of behavioral plasticity, be
mediated by structural changes in neural connections.
Because behaviors that are sensitized by AMPH are
believed to be mediated by the effect of the drug in the
nucleus accumbens and the prefrontal cortex (rather than
the striatum), they examined those sites.
In the first study, rats received two intraperitoneal
injections a day, 8 hr apart, for 5 consecutive days, fol-
lowed by 2 drug-free days, for a total of 5 weeks. The
first dose of 1 mg/kg was gradually increased to 8 mg/kg
(16/mg/kg/day) for the last 4 days of treatment. The ani-
mals were left alone for 38 days, and then their brains
were removed for morphological examination. In a sec-
ond study, the AMPH dose was reduced to a single daily
IP injection of 3 mg/kg for 5 days, followed by 2 drug-
free days repeated for a total of 4 consecutive weeks.
In the third study, they modified the drug injection
protocol to simulate ADHD treatment. Male juvenile
rats were injected SC on postnatal days 22 through 34
(approximately preadolescence in humans), with 0.5
mg/kg of AMPH, followed by a second injection 6 hr
later. This schedule was chosen to compensate for the
short half-life of AMPH in juvenile rats (about 1 hr)

compared with children (about 6 to 7 hr). No other treat-
ment was given until postnatal days 48 to 50, when the
brains were removed and prepared for analysis.
The results of these three investigations were essen-
tially the same. In the first study, dendritic length, spine
density and the number of branched spines were signifi-
cantly greater in the nucleus accumbens of the AMPH
treated group than in the saline control group, and in
some instances, dendritic segments appeared to be thicker.
Dendritic length and spine density were also increased in
some areas of the prefrontal cortex. In the second study,
AMPH (and cocaine) significantly increased the number
of dendritic branches and the density of dendritic spines
on specific neurons of the nucleus accumbens and the
prefrontal cortex. And in the third study, in which the low-
est dose was administered to immature rats, there were
increases in dendritic length and branches of pyramidal
neurons of the medial prefrontal cortex but not the nucleus
accumbens. Furthermore, there was a 30% increase in the
expression of calcium/calmodulin-dependent protein
kinase (CaMKII) in the prefrontal cortex of adult rats,
treated with AMPH as juveniles. This protein has been
implicated in many types of behavioral plasticity, and has
been considered to have trophic benefits for synaptic
organization.
As discussed by the authors, the observation of long-
lasting morphological changes in the brain after low-dose
AMPH in adult and juvenile animals has many implications
in regard to human behavioral development and pharmaco-
logical therapy for ADHD. First, it would be useful to know
if methylphenidate, or any other ADHD drug treatment,
also produced such effects, and second, if the observed
synaptic changes are limited to the nucleus accumbens and
prefrontal cortex. Third, although AMPH treatment is asso-
ciated with behavioral sensitization in adult rats, sensiti-
zation is not seen with stimulant treatment of children
(Solanto, 2000) or juvenile rats (Robinson & Kolb, 1999,
1997). Will therapeutic treatment of human adults with
ADHD produce sensitization? This is important because
sensitization has been suggested to promote the develop-
ment of substance abuse. Although an increased likelihood
of drug abuse has been found in adults who were diagnosed
with ADHD as children and not treated with stimulants
(Molina & Pelham, 2003), stimulant treatment of ADHD in
childhood has been reported to reduce drug abuse when
such children become adults (Barkley et al., 2003; Wilens
et al., 2003). If such a protective effect is mediated by the
neuroanatomical changes reported by Kolb and colleagues,
what consequences might be expected by extending, or ini-
tiating, treatment in adulthood?
Fourth, it has been appreciated that a significant pro-
portion of children diagnosed with ADHD may outgrow
Advokat / Treatment of ADHD 13
this disorder during adolescence (Wilens et al., 2004). The
results of Kolb and colleagues raise the possibility that
such developmental changes may have a neuroanatomi-
cal basis.1 If developmental improvement is mediated
by synaptic reorganization, then such neuroanatomical
changes, or processes they initiate, would presumably be
permanent. Fifth, to the extent that stimulant treatment of
ADHD improves academic performance (and the long-
term effect of these drugs on academic achievement is
not clear-cut (Swanson, Cantwell, Lerner, McBurnett, &
Hana, 1991), would such cognitive benefits be related to
the morphological evidence of changes in synaptic orga-
nization? If so, would such changes in brain develop-
ment also be produced in individuals without the disorder?
Finally, concerns about stimulant treatment in adults
with ADHD are not limited to those individuals with the
diagnosis but may also have implications for their children.
Recent evidence shows that when pregnant rats are injected
with AMPH their offspring exhibit an abnormal increase in
sensitivity to and less inhibition of, startle stimulation
and greater amphetamine-induced stereotypy (Tan, 2003).
Offspring of mice that had been treated with the stimulant
fenproporex during pregnancy tended to be more active
than controls although in this case stereotyped behavior
was reduced (Moreira, Faria, & Moreira, 2005).
Implications for ADHD
At present, the reason for the apparent contradiction
between results in primates, showing neurotoxic effects
of low-dose AMPH, and those in rats, showing neu-
rotrophic effects, is not apparent. However, recent neu-
roimaging studies in ADHD-diagnosed humans may
be relevant. Several reviews have described an elevation
of the striatal dopamine transporter (DAT) availability
in children and adults with ADHD (Madras, Miller, &
Fischman, 2005; Spencer et al., 2005; Volkow, Wang,
Fowler, & Ding, 2005). Moreover, after methylphenidate
treatment DAT availability is lowered in both children
and adults (Krause, la Fougere, Krause, Ackenheil, &
Dresel, 2005 and references therein; Madras et al., 2005;
Spencer et al., 2005). Relationships between DAT den-
sity and treatment response to MPH have also been
observed. Decreased DAT binding has been associated
with a positive treatment response, whereas low DAT
availability did not seem to respond to therapy with
MPH (Krause et al., 2005). Unfortunately, such results
may be confounded by the fact that, depending on the
time between stimulant administration and the neu-
roimaging procedure, a portion of the decreased binding
could be because of MPH occupation of DAT sites rather
14 Journal of Attention Disorders
than DAT downregulation. It must also be kept in mind
that primate and rodent models do not have ADHD.
Nevertheless, comparisons of individuals treated with
MPH or AMPH as children, with those who were not
given stimulants, might be informative. Somewhat sur-
prisingly, the effects of repeated therapeutic doses of
amphetamine on DAT density in living human brain are
unknown (Madras et al., 2005, p. 1403).
In summary, recent pharmacological developments, of
long-acting AMPH formulations coupled with clinical
developments in the diagnosis of ADHD, raise new ques-
tions about the neurobiological effects of stimulant ther-
apy. Answers to these questions may not only be relevant
for understanding the etiology, therapy, and treatment of
ADHD but could also have broad implications for our
concepts of the general processes that mediate behav-
ioral and intellectual development.
Note
1. I thank Benjamin Hill for this suggestion.
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Claire Advokat is a professor of biological psychology in the
Psychology Department of Louisiana State University. Her
primary focus of research is the psychopharmacology of drugs
used in the treatment of psychiatric and behavioral disorders.
Her ongoing research concerns the effectiveness of the newer
antipsychotics and antidepressants in psychiatric inpatients
and the use of these drugs in the forensic population.