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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


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

8
Advokat / Treatment of ADHD 9

The difference in neurotoxicity between MPH and newly diagnosed adults. As a result, extended coverage of
AMPH has been attributed to the difference in their respec- symptoms throughout the day has become common (and
tive mechanisms of action. MPH blocks the synaptic reup- presumably throughout the summer months), with some
take transporters for the monoamines, particularly for evidence that adults may require higher doses, 0.9
dopamine. AMPH also prevents monoamine reuptake, but mg/kg/day, for maximal benefit (Conner & Steingard,
unlike MPH, AMPH crosses the cell membrane into the 2004; Wilens, 2003; Wilens, Faraone, & Biederman, 2004).
terminal and also interacts with the transporters that are Second, in parallel with these new treatment goals, the
responsible for vesicular storage of dopamine. As a result, need for longer-lasting formulations to provide coverage
AMPH displaces dopamine from vesicles, which increases throughout the day was recognized (Greenhill et al., 2003)
its cytoplasmic concentration, causing it to be released and accommodated, with the recent development of four
from the terminal in a process termed reverse transport. long-acting compounds. One of these, Adderall XRTM,
Importantly, this release does not require the nerve cell to which is an extended release capsule of mixed AMPH salts
be stimulated and occurs even during periods of inactivity. (approved in October of 2001), appears to have a longer
Finally, AMPH also acts inside the terminal to block duration of action than the other commercial long-acting
monoamine oxidase, the enzyme that normally breaks AMPH formulation, Dexedrine SpansulesTM improving
down dopamine and norepinephrine, allowing the trans- symptoms for up to 12 hr postadministration. However, to
mitters to remain active longer. These differences produce date, no direct clinical comparisons of these two com-
a more rapid and greater increase in synaptic monoamines pounds have been published.
with AMPH compared with MPH (Schiffer et al., 2006) These developments of extended long-term treatment
particularly after oral administration (Fone & Nutt, and newer long-lasting formulations have raised concern
2005), which may account for its greater toxicity. about illicit diversion of AMPH prescribed for ADHD.
Amphetamine (AMPH) is therefore, unusual among the Adults have control of their prescribed medications,
psychostimulants (and most psychoactive agents) in that it including drugs with a high abuse potential. There are
is a drug of abuse with neurotoxic potential, and a primary now numerous anecdotal reports and several published
medication (Robinson & Becker, 1986). Approximately articles describing the illegal use of stimulant drugs by
40% of children with the diagnosis of ADHD respond college students, who may obtain them with fraudulent
equally well to both MPH and AMPH, although 35% prescriptions or buy them from those who have a legiti-
respond better to AMPH (Conner & Steingard, 2004). mate prescription (McCabe, Knight, Teter, & Wechsler,
However, like METH, AMPH has consistently been found 2005; Teter, McCabe, Cranford, Boyd, & Guthrie, 2005).
neurotoxic in nonhuman models of stimulant abuse. In Although much of this use is stated to be for academic
many cases these studies involved continuous, systemic purposesas a means of improving concentration or to
administration of high doses (>15 mg/kg) that increased stay awake while studying, recreational use is also
blood, and presumably brain concentration for several acknowledged.
days, followed by abrupt drug termination and eventual Given that the half-life of AMPH is 2 to 3 times longer
assay of the brain several days or weeks later. Such proce- in adults than in children (Brown, Hunt, Ebert, Bunney, &
dures were used to mimic human abuse patterns, and the Kopin, 1979), that more adults are being prescribed these
subsequent neurotoxicity was presumed to be predictive of drugs, and that there is reportedly an increase in illicit use
possible brain damage in stimulant addicts. among college students (who may not only take the drug
In contrast, the standard AMPH treatment for core orally but also dissolve and inject it), it is understandable
ADHD symptoms has, in the past, consisted of oral that a recent review acknowledged an urgent need to
administration of low doses, 0.1 to 0.5 mg/kg, often twice better understand their potential long-term adverse
a day during school hours, as immediate-release prepara- effects (Fone & Nutt, 2005, p. 88). The purpose of this
tions in children aged 6 to 12 years (Conner & Steingard, review is to summarize the evidence specifically describ-
2004). Therapeutic effects begin within 30 min, peak at ing AMPH-induced neurotoxicity and to discuss the
about 2 hr and last about 5 hr (Solanto, 2000). implications of this literature for the treatment of ADHD.
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 Chronic High-Dose Amphetamine:
adverse occupational, academic, and interpersonal conse- Neurochemical Toxicity
quences. This has meant acceptance of continued treatment
for children with the diagnosis as they mature and start col- Like METH, early studies were designed to evaluate the
lege or careers and families, and initiation of treatment for neurotoxic effects of AMPH in the context of substance
10 Journal of Attention Disorders

abuse. Several procedures were used to produce continu- levels, 1 week after injection of the combination dopamine
ous prolonged AMPH exposure in nonhuman subjects. concentration was reduced by 31% in the cerebral hemi-
One early method was by gradual escalation of AMPH in spheres and striata (Fuller & Hemrick-Luecke, 1980).
the drinking water of rats for 14 days followed by with- Subsequent studies showed that a single injection of 6.9
drawal for up to 7 days (Lynch, Kenny, & Leonard, 1977). mg/kg or 9.2 mg/kg of d-amphetamine to iprindole-treated
A more common approach was subcutaneous (SC) implan- rats produced significant decreases in striatal dopamine
tation of pellets or Alzet Osmotic Minipumps containing and dopaminergic metabolites DOPAC and HVA, 1 week
d-amphetamine base or sulfate, to mice or rats, which later (Steranka, 1981). Similar results were obtained with 5
provided continuous exposure to the drug for 3 to 7 days, mg/kg fluoxetine, a 5HT reuptake blocker, which also
at doses that varied from 0.6 mg/day (25 g/hr) to about increased the depletion of dopamine measured 2 weeks
4 or more mg/day. Animals were killed either while the after a series of 5 AMPH injections (15 mg/kg) spaced 6 hr
pellets or pumps were still implanted or from 1 to several apart. Although fluoxetine alone didnt change the
days or weeks after removal of the drug delivery system dopamine (or serotonin) concentration, it increased
(Ellison, Eison, Huberman, & Daniel, 1978; Ellison & dopamine depletion from 32% to 65%. This treatment also
Ratan, 1982; Jonsson & Nwanze, 1982; Nwanze & increased brain levels of amphetamine, suggesting that flu-
Jonsson, 1981; Ricaurte, Seiden, & Schuster, 1984; Ryan, oxetine was acting like iprindole (Ricaurte, Fuller, Perry,
Martone, Linder, & Groves, 1988; Steranka & Sanders- Seiden, & Schuster, 1983). These results were confirmed
Bush, 1980). and extended, by demonstrations that dopamine depletion
Results have generally been consistent in showing that did not occur when dopamine uptake was prevented, or
during drug administration, and for about 2 weeks after when dopamine synthesis was blocked (Fuller & Hemrick-
drug removal, whole-brain dopamine and synaptosomal Luecke, 1982; Ricaurte, Guillery, Seiden, & Schuster,
dopamine uptake were decreased by about 40 to 50%, 1984). Together, these data were interpreted to mean that
and activity of the biosynthetic enzyme, tyrosine hydrox- adequate levels of dopamine were required for ampheta-
ylase was reduced. Weeks to months after drug removal, mine-induced dopaminergic toxicity, manifested as a
there was usually some, incomplete, recovery of decrease in dopamine concentration, dopamine uptake
dopamine content (Jonsson & Nwanze, 1982). By com- capacity, and tyrosine hydroxylase activity.
bining the injection of a priming dose (15 mg/kg) with a Although most studies have been done in rodents,
16 hr minipump-infusion (1.36 mg/hr), a steady-state vervet monkeys appear to be even more susceptible to
brain AMPH concentration of 12 to 25 g/g was pro- amphetamine-induced neurotoxicity (Owen, Baker, Ridley,
duced during 0.5 to 16 hr. This resulted in marked Cross, & Crow, 1981). In one early report (Ridley, Baker,
decreases in striatal dopamine, [and the metabolites] Owen, Cross, & Crow, 1982), five animals were adminis-
DOPAC [3,4-dihydroxyphenylacetic acid] and HVA tered 4 mg/kg/day of d-amphetamine sulfate for 11 days.
[homovanillic acid] and the synaptosomal uptake of This dose was increased to 6 mg/kg for 9 days, then to 8
dopamine (Steranka, 1983, p. 162) which lasted for mg/kg for 7 days, 10 mg/kg for 5, and 12 mg/kg for 3. The
at least 12 weeks. By 24 weeks, DOPAC, HVA, and drug was given in flavored drinking water that was con-
synaptosomal uptake had recovered to control levels, but sumed in small quantities throughout the day. On the
the dopamine decrease persisted (Steranka, 1983). morning following the last drug administration, brains were
Results of these studies were consistent in showing that removed for biochemical analysis. Results showed dramatic
the effects were stereoselective for d-amphetamine reductions in the concentration of dopamine (75% to 93%)
(Steranka, 1981), predominantly selective for dopamine and its metabolites, especially DOPAC (~ 60% to 85%) and
(although sometimes affecting norepinephrine as well) tyrosine hydroxylase activity (~60% to 70%) in the corpus
and for the striatum. striatum and nucleus accumbens.
Although daily injections of high doses (25 mg/kg 2 Similar results were obtained by Melega and col-
per day, for 30 days) also depleted dopamine and leagues (Melega et al., 1996; Melega, Raleigh, Stout,
dopamine uptake in the caudate (Wagner et al., 1980), it Hung et al., 1997; Melega, Raleigh, Stout, Lacan, et al.,
was soon realized that even a single dose of AMPH could 1997) when they injected d-amphetamine sulfate intra-
become toxic to rats if it was prevented from being metab- muscularly once a day to each of five vervet monkeys,
olized and persisted in the brain for an extended period of starting from 4 mg/kg and increasing to 18 mg/kg on
time. This was shown when a dose of 18.4 mg/kg was the 9th and 10th days. By conducting PET scans using
given in conjunction with iprindole, a drug that blocked 6-[ 18F]fluoro-L-DOPA (FDOPA) and biochemical
AMPH metabolism and increased its half-life from 1 to analyses, they found decreases in both dopamine syn-
about 4 hr. Although, neither drug alone affected dopamine thesis and striatal concentration. Dopamine synthesis
Advokat / Treatment of ADHD 11

was initially reduced to approximately 30% of control are less than about 15 to 20 mg/kg/day, or if the exposure
and, after 2 years, had recovered to only 53% of pre- lasts for 3 days or less (Ryan et al., 1988). In mice, infu-
drug values. Likewise, dopamine content was approxi- sion of about 17 g/hr (0.408 mg/day) for 7 days did not
mately 95% depleted throughout the caudate and change dopamine concentration, although 25 g/hr for 7
putamen at 1 to 2 weeks but had recovered to 80% and days caused a 50% reduction in the striatum (Jonsson &
then baseline, at 1 and 2 years, respectively. Nwanze, 1982). Numerous studies found no change in
The sensitivity of vervet monkeys to AMPH-induced striatal dopamine content or tyrosine hydroxylase activ-
neurotoxicity was replicated in a second study in which ity, in rats, after single, multiple, or even escalating doses
two IM injections of 2 mg/kg each, were given 4 hr apart of AMPH. This was the case for Seiden and colleagues
in a single day. Analyses showed a decrease of 45% to 67% (Pearl & Seiden, 1979) after either a single or daily
in the index of striatal dopamine synthesis capacity at 3 to repeated administration of 2.5 mg/kg of d-AMPH for
6 weeks with recovery to about a 16% decrease at 32 more than 30 days, and with Ellison et al. (1978) after 7
weeks. Striatal dopamine concentrations were decreased daily injections of 3.7 mg/day, or 30 daily injections of
by 75% at 3 to 4 weeks and were still only 55% of baseline 3.2 mg/kg/day. Striatal dopamine levels, determined 2
10 to 12 weeks later. days after treatment, were unchanged when AMPH was
Recent observations in aged rats suggest developmental injected either 3 times a day, at doses that escalated from
factors may also influence the severity of amphetamine- 1 mg/kg up to 12 mg/kg, or the drug was given daily at
induced neurotoxicity even in nonprimate populations 3 mg/kg for 6 days (Kuczenski & Leith, 1981). Robinson
(Bowyer et al., 1998). and Camp (1987) administered two daily injections, 8 to
10 hr apart, for 5 days a week for 6 weeks. The doses
Chronic High-Dose Amphetamine: increased from 1 to 10 mg/kg (20 mg/kg/day) for the last
4 days. When the brains were removed 12 days later,
Neurological Toxicity
there was no change in dopamine concentration in the
striatum, nucleus accumbens, or medial frontal cortex.
In early studies of neurotoxicity produced by chronic
(One exception is a report of a significant decrease in
high-dose amphetamine, histological indices indirectly
caudate dopamine levels after only a single 4.0 mg/kg
indicated that dopamine terminals in the caudate nucleus
injection [Ellison & Ratan, 1982].)
had been damaged (Ellison et al., 1978; Jonsson &
These data are consistent with the conclusion that low
Nwanze, 1982; Nwanze & Jonsson, 1981). Direct evi-
daily AMPH doses, even when gradually increased to a
dence of neuroanatomical damage in rats was soon
total of 20 mg/kg/day, do not produce long-term dopamine
confirmed with the Fink-Heimer method of selective silver-
depletion in rats, although such treatment does acutely
impregnation of degenerating nerve fibers. This was
cause dopamine release. For example, Karoum, Speciale,
shown after administration by subcutaneous minipump or
Chuang, and Wyatt (1982) showed that both a single dose
iprindole treatment (Fuller & Hemrick-Luecke, 1980,
of 2.5 mg/day (measured at 45 min) or repeated injection
1982; Ricaurte, Guillery, Seiden, & Schuster, 1984). Ryan
of 5.0 mg/kg, twice a day for 10 days (measured after 2 hr)
and colleagues (Ryan, Linder, Martone, & Groves, 1990)
increased dopamine levels in the caudate. Recently, micro-
describe extensive ultrastructural damage produced by
dialysis of in vivo extracellular dopamine release showed
20 to 60 mg/kg /day administered for 3 days, by SC
a dose-dependent increase, in the striatum of rats, in
minipumps. Degeneration was reported for various corti-
response to 0.5, 1.0, 2.5, and 5.0 mg/kg, with a peak con-
cal structures, such as the somatosensory neocortex and in
centration at 20 to 40 min after drug administration at all
some frontal motor areas, depending on the particular
doses (Kuczenski & Segal, 1989).
strain of rat. Cases where dopamine levels recovered for
Taken together, these results indicate that, in rats, stri-
several months after AMPH exposure were suggested to
atal dopamine release produced by acute low-dose
indicate regeneration of dopamine nerve terminals, or col-
AMPH does not produce long-lasting effects as doses
lateral sprouting of dopamine fibers.
and duration increase up to 15 to 20 mg/kg/day for sev-
eral days. Further increases above this threshold are
Chronic Low-Dose Amphetamine: associated with substantial dopamine depletion and
Neurochemical Effects degeneration of dopamine nerve terminals.
There is empirical evidence for such a threshold with
Neurotoxicity is not usually seen in rats after admin- respect to METH (ODell et al., 1991). In those studies,
istration of lower amounts, either by continuous expo- rats were given a 4 mg/kg METH injection every 2 hr for a
sure via SC minipump, or repeated injection, if the doses total of either three or four injections. Microdialysis results
12 Journal of Attention Disorders

showed that the first two injections increased extracellular neurotoxicity in patients with ADHD who have been treated
dopamine concentration, which remained at 200% to with AMPH. But they pointed out that overt impairment,
600% of basal values after the third injection. But the such as parkinsonism, may not be evident until dopamine
fourth injection produced much larger elevations, up to function is reduced by 80% to 90%. Furthermore, if ADHD
3,600% of basal values, and the dopamine efflux remained symptoms themselves are related to abnormalities in
elevated for 16 hr afterward. When measured 1 week after dopaminergic function, it might be difficult to detect deficits
this treatment, there were significant depletions of because of underlying disease rather than amphetamine
dopamine in both striatum (51% depletion) and nucleus neurotoxicity. Because most neuroimaging studies of
accumbens (43% depletion) after four but not three METH ADHD have been conducted with medication-naive indi-
injections. The fourth injection was critical for producing viduals the absence of, or inconsistencies in, evidence for
long-term dopamine depletion and neurotoxicity. dopaminergic neurotoxicity in ADHD patients does not rule
out the possibility that it might occur.

Chronic Amphetamine in Animal


Models of ADHD: Primates Chronic Amphetamine in Animal
Models of ADHD: Rodents
Recently, however, new data from Ricaurte et al.
(2005) indicate that primates may be much more suscep- Although the evidence from Ricaurte and colleagues
tible than rats to AMPH-induced neurotoxicity. They (2005) may have disturbing implications for AMPH treat-
examined the effect of the drug in adult baboons and ment of ADHD, their observations seem dramatically at
squirrel monkeys, as clinically used to treat ADHD. In odds with the results of a series of articles by Kolb and
the first two studies, baboons were trained to orally self- colleagues (Heijtz, Kolb, & Forssberg, 2003; Robinson &
administer a mixture of AMPH salts (a 3:1 ratio of dex- Kolb, 1997, 1999). The rationale for these experiments is
tro [S(+)] and levo [R(-)] AMPH, which simulated a derived from the behavioral phenomenon of sensitization,
common formulation for ADHD treatment). AMPH was in which repeated administration of (usually) addictive
administered twice daily for approximately 4 weeks at drugs leads to an increase in their activating or rewarding
escalating doses of 2.5 to 20 mg (0.67 to 1.00 mg/kg). effects, as opposed to the decrease that defines tolerance.
During the second study, plasma AMPH concentrations By considering sensitization to be an example of experience-
were determined at the end of each week. In the third dependent plasticity, they reasoned that its development
study, AMPH was administered by orogastric gavage to would, like other forms of behavioral plasticity, be
squirrel monkeys and doses were adjusted (to 0.58-0.68 mediated by structural changes in neural connections.
mg/kg) so that for approximately the last 3 weeks plasma Because behaviors that are sensitized by AMPH are
drug concentrations were comparable to those reported believed to be mediated by the effect of the drug in the
in clinical populations of children receiving chronic nucleus accumbens and the prefrontal cortex (rather than
AMPH treatment-100 to 150 ng/ml (McGough et al., the striatum), they examined those sites.
2003). Measurements in all three investigations were In the first study, rats received two intraperitoneal
taken 2 to 4 weeks after drug treatment. injections a day, 8 hr apart, for 5 consecutive days, fol-
Results from the first two studies showed significant lowed by 2 drug-free days, for a total of 5 weeks. The
reductions in striatal dopamine concentration, dopamine first dose of 1 mg/kg was gradually increased to 8 mg/kg
transporter density, and vesicular monoamine transporter (16/mg/kg/day) for the last 4 days of treatment. The ani-
sites. Plasma AMPH concentration at the end of the 4 mals were left alone for 38 days, and then their brains
week treatment period was 168 25 ng/ml. In squirrel were removed for morphological examination. In a sec-
monkeys, brain dopamine concentrations and vesicular ond study, the AMPH dose was reduced to a single daily
transporter sites were also significantly reduced although IP injection of 3 mg/kg for 5 days, followed by 2 drug-
dopamine transporter decreases were not statistically free days repeated for a total of 4 consecutive weeks.
significant. In the third study, they modified the drug injection
These results raise obvious concerns about clinical drug protocol to simulate ADHD treatment. Male juvenile
treatment of ADHD, although extrapolation to human rats were injected SC on postnatal days 22 through 34
populations may be premature until possible species dif- (approximately preadolescence in humans), with 0.5
ferences in mechanism of action, developmental variables, mg/kg of AMPH, followed by a second injection 6 hr
or metabolism are determined. Ricaurte et al. (2005) later. This schedule was chosen to compensate for the
noted there is no consistent evidence of dopaminergic short half-life of AMPH in juvenile rats (about 1 hr)
Advokat / Treatment of ADHD 13

compared with children (about 6 to 7 hr). No other treat- this disorder during adolescence (Wilens et al., 2004). The
ment was given until postnatal days 48 to 50, when the results of Kolb and colleagues raise the possibility that
brains were removed and prepared for analysis. such developmental changes may have a neuroanatomi-
The results of these three investigations were essen- cal basis.1 If developmental improvement is mediated
tially the same. In the first study, dendritic length, spine by synaptic reorganization, then such neuroanatomical
density and the number of branched spines were signifi- changes, or processes they initiate, would presumably be
cantly greater in the nucleus accumbens of the AMPH permanent. Fifth, to the extent that stimulant treatment of
treated group than in the saline control group, and in ADHD improves academic performance (and the long-
some instances, dendritic segments appeared to be thicker. term effect of these drugs on academic achievement is
Dendritic length and spine density were also increased in not clear-cut (Swanson, Cantwell, Lerner, McBurnett, &
some areas of the prefrontal cortex. In the second study, Hana, 1991), would such cognitive benefits be related to
AMPH (and cocaine) significantly increased the number the morphological evidence of changes in synaptic orga-
of dendritic branches and the density of dendritic spines nization? If so, would such changes in brain develop-
on specific neurons of the nucleus accumbens and the ment also be produced in individuals without the disorder?
prefrontal cortex. And in the third study, in which the low- Finally, concerns about stimulant treatment in adults
est dose was administered to immature rats, there were with ADHD are not limited to those individuals with the
increases in dendritic length and branches of pyramidal diagnosis but may also have implications for their children.
neurons of the medial prefrontal cortex but not the nucleus Recent evidence shows that when pregnant rats are injected
accumbens. Furthermore, there was a 30% increase in the with AMPH their offspring exhibit an abnormal increase in
expression of calcium/calmodulin-dependent protein sensitivity to and less inhibition of, startle stimulation
kinase (CaMKII) in the prefrontal cortex of adult rats, and greater amphetamine-induced stereotypy (Tan, 2003).
treated with AMPH as juveniles. This protein has been Offspring of mice that had been treated with the stimulant
implicated in many types of behavioral plasticity, and has fenproporex during pregnancy tended to be more active
been considered to have trophic benefits for synaptic than controls although in this case stereotyped behavior
organization. was reduced (Moreira, Faria, & Moreira, 2005).
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 Implications for ADHD
in regard to human behavioral development and pharmaco-
logical therapy for ADHD. First, it would be useful to know At present, the reason for the apparent contradiction
if methylphenidate, or any other ADHD drug treatment, between results in primates, showing neurotoxic effects
also produced such effects, and second, if the observed of low-dose AMPH, and those in rats, showing neu-
synaptic changes are limited to the nucleus accumbens and rotrophic effects, is not apparent. However, recent neu-
prefrontal cortex. Third, although AMPH treatment is asso- roimaging studies in ADHD-diagnosed humans may
ciated with behavioral sensitization in adult rats, sensiti- be relevant. Several reviews have described an elevation
zation is not seen with stimulant treatment of children of the striatal dopamine transporter (DAT) availability
(Solanto, 2000) or juvenile rats (Robinson & Kolb, 1999, in children and adults with ADHD (Madras, Miller, &
1997). Will therapeutic treatment of human adults with Fischman, 2005; Spencer et al., 2005; Volkow, Wang,
ADHD produce sensitization? This is important because Fowler, & Ding, 2005). Moreover, after methylphenidate
sensitization has been suggested to promote the develop- treatment DAT availability is lowered in both children
ment of substance abuse. Although an increased likelihood and adults (Krause, la Fougere, Krause, Ackenheil, &
of drug abuse has been found in adults who were diagnosed Dresel, 2005 and references therein; Madras et al., 2005;
with ADHD as children and not treated with stimulants Spencer et al., 2005). Relationships between DAT den-
(Molina & Pelham, 2003), stimulant treatment of ADHD in sity and treatment response to MPH have also been
childhood has been reported to reduce drug abuse when observed. Decreased DAT binding has been associated
such children become adults (Barkley et al., 2003; Wilens with a positive treatment response, whereas low DAT
et al., 2003). If such a protective effect is mediated by the availability did not seem to respond to therapy with
neuroanatomical changes reported by Kolb and colleagues, MPH (Krause et al., 2005). Unfortunately, such results
what consequences might be expected by extending, or ini- may be confounded by the fact that, depending on the
tiating, treatment in adulthood? time between stimulant administration and the neu-
Fourth, it has been appreciated that a significant pro- roimaging procedure, a portion of the decreased binding
portion of children diagnosed with ADHD may outgrow 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 Fuller, R. W., & Hemrick-Luecke, S. (1980). Long-lasting depletion
that primate and rodent models do not have ADHD. of striatal dopamine by a single injection of amphetamine in
iprindole-treated rats. Science, 209, 305-307.
Nevertheless, comparisons of individuals treated with
Fuller, R. W., & Hemrick-Luecke, S. (1982). Further studies on the
MPH or AMPH as children, with those who were not long-term depletion of striatal dopamine in iprindole-treated rats
given stimulants, might be informative. Somewhat sur- by amphetamine. Neuropharmacology, 21, 433-438.
prisingly, the effects of repeated therapeutic doses of Gibb, J. W., Johnson, M., Elayan, I., Lim, H. K., Matsuda, L., &
amphetamine on DAT density in living human brain are Hanson, G. R. (1999). Neurotoxicity of amphetamines and their
unknown (Madras et al., 2005, p. 1403). metabolites. NIDA Research Monographs, 173, 128-145.
Greenhill, L. L., Swanson, J. M., Steinhoff, K., Fried, J., Posner, K.,
In summary, recent pharmacological developments, of Lerner, M., et al. (2003). A pharmacokinetic/pharmacodynamic
long-acting AMPH formulations coupled with clinical study comparing a single morning dose of Adderall to twice-daily
developments in the diagnosis of ADHD, raise new ques- dosing in children with ADHD. Journal of the American Academy
tions about the neurobiological effects of stimulant ther- of Child and Adolescent Psychiatry, 42, 1234-1241.
apy. Answers to these questions may not only be relevant Heijtz, R. D., Kolb, B., & Forssberg, H. (2003). Can a therapeutic
dose of amphetamine during pre-adolescence modify the pattern
for understanding the etiology, therapy, and treatment of
of synaptic organization in the brain? European Journal of
ADHD but could also have broad implications for our Neuroscience, 18, 3394-3399.
concepts of the general processes that mediate behav- Jonsson, G., & Nwanze, E. (1982). Selective (+)-amphetamine neu-
ioral and intellectual development. rotoxicity on striatal dopamine nerve terminals in the mouse.
British Journal of Pharmacology, 77, 335-345.
Note Karoum, F., Speciale, S. G. Jr., Chuang, L.-W., & Wyatt, R. J. (1982).
Selective effects of phenethylamine on central catecholamines: A
1. I thank Benjamin Hill for this suggestion. comparative study with amphetamines. Journal of Pharmacology
and Experimental Therapeutics, 223, 432-439.
Krause, J., la Fougere, C., Krause, K.-H., Ackenheil, M., & Dresel,
References S. H. (2005). Influence of striatal dopamine transporter availability
on the response to methylphenidate in adult patients with ADHD.
Barkley, R. A., Fletcher, K., Fischer, M., & Smallish, L. (2003). Does European Archives of Psychiatry and Clinical Neuroscience, 255,
the treatment of Attention Deficit/Hyperactivity Disorder with 428-431.
stimulants contribute to drug abuse? A 13-year prospective study. Kuczenski, R., & Leith, N. J. (1981). Chronic amphetamine: Is
Pediatrics, 111, 97-109. dopamine a link in or a mediator of the development of tolerance
Bowyer, J. F., Frame, L. T., Clausing, P., Nagamoto-Combs, K., and reverse tolerance? Pharmacology Biochemistry and Behavior,
Osterhout, C. A., Sterling, C. R., et al. (1998). Long-term effects 15, 405-413.
of amphetamine neurotoxicity on tyrosine hydroxylase mRNA Kuczenski, R., & Segal, D. (1989). Concomitant characterization of
and protein in aged rats. Journal of Pharmacology and behavioral and striatal neurotransmitter response to amphetamine
Experimental Therapeutics, 286, 1074-1085. using in vivo microdialysis. Journal of Neuroscience, 9, 2051-2065.
Bradley, C. (1937). The behavior of children receiving Benzedrine. Lynch, M., Kenny, M., & Leonard, B. E. (1977). The effect of chronic
American Journal of Psychiatry, 94, 577-585. administration of D-amphetamine on regional changes in cate-
Brown, G. L., Hunt, R. D., Ebert, M. H., Bunney, W. E. Jr., & Kopin, cholamines in the rat brain. Journal of Neuroscience Research, 3,
I. J. (1979). Plasma levels of d-amphetamine in hyperactive 295-300.
children. Psychopharmacology, 62, 133-140. Madras, B. K., Miller, G. M., & Fischman, A. J. (2005). The
Connor, D. F., & Steingard, R. J. (2004). New formulations of stimu- dopamine transporter and attention-deficit/hyperactivity disorder.
lants for attention-deficit hyperactivity disorder. CNS Drugs 18, Biological Psychiatry, 57, 1397-1409.
1011-1030. McCabe, S. E., Knight, J. R., Teter, C. J., & Wechsler, H. (2005).
Ellison, G., & Eison, M. S. (1983). Continuous amphetamine intoxi- Non-medical use of prescription stimulants among US college
cation: An animal model of the acute psychotic episode. students: Prevalence and correlates from a national survey.
Psychological Medicine, 13, 751-761. Addiction, 99, 96-106.
Ellison, G., Eison, M. S., Huberman, H. S., & Daniel, F. (1978). McCann, U. D., & Ricaurte, G. A. (2004). Amphetamine neurotoxic-
Long-term changes in dopaminergic innervation of caudate ity: Accomplishments and remaining challenges. Neuroscience
nucleus after continuous amphetamine administration. Science, and Biobehavioral Reviews, 27, 821-826.
201, 276-278. McCann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., Dannals,
Ellison, G., & Ratan, R. (1982). The late stage following continuous R. F., & Ricaurte, G. A. (1998). Reduced striatal dopamine trans-
amphetamine administration to rats is correlated with altered porter density in abstinent methamphetamine and methcathinone
dopamine but not serotonin metabolism. Life Sciences, 31, 771-777. users: Evidence from positron emission tomography studies with
Fone, K. C. F., & Nutt, D. J. (2005). Stimulants: Use and abuse in the [11C]WIN-35,482. Journal of Neuroscience, 18, 8417-8422.
treatment of attention deficit hyperactivity disorder. Current McGough, J. J., Biederman, J., Greenhill, L. L., McCracken, J. T.,
Opinion in Pharmacology, 5, 87-93. Spencer, T. J., Posner, K., et al. (2003). Pharmacokinetics of
Fuller, R. W. (1985). Persistent effects of amphetamine, p-chloroamphet- SLI381 (Adderall XR), an extended-release formulation of
amine, and related compounds on central dopamine and serotonin Adderall. Journal of the American Academy of Child and
neurons in rodents. Psychopharmacology Bulletin, 21, 528-532. Adolescent Psychiatry, 42, 684-691.
Advokat / Treatment of ADHD 15

Melega, W. P., Quintana, J., Raleigh, M. J., Stout, D. B., Yu, D.-C., review and evaluation of animal models of amphetamine psy-
Lin, K.-P., et al. (1996). 6-[18F]Fluoro-L-DOPA-PET studies show chosis. Brain Research Review, 11, 157-198.
partial reversibility of long-term effects of chronic amphetamine Robinson, T. E., & Camp, D. M. (1987). Long-lasting effects of escalat-
in monkeys. Synapse, 22, 63-69. ing doses of d-amphetamine on brain monoamines, amphetamine-
Melega, W. P., Raleigh, M. J., Stout, D. B., Huang, S.-C., & Phelps, induced stereotyped behavior and spontaneous nocturnal locomotion.
M. E. (1997). Ethological and 6-[18F]Fluoro-L-DOPA-PET pro- Pharmacology Biochemistry and Behavior, 26, 821-827.
files of long-term vulnerability to chronic amphetamine. Behavior Robinson, T. E., & Kolb, R. (1997). Persistent structural modifica-
and Brain Research, 84, 259-268. tions in nucleus accumbens and prefrontal cortex neurons pro-
Melega, W. P., Raleigh, M. J., Stout, D. B., Lacan, G., Huang, S.-C., duced by previous experience with amphetamine. Journal of
& Phelps, M. E. (1997). Recovery of striatal dopamine function Neuroscience, 17, 8491-8497.
after acute amphetamine- and methamphetamine-induced neuro- Robinson, T. E., & Kolb, B. (1999). Alterations in the morphology of
toxicity in the vervet monkey. Brain Research, 766, 113-120. dendrites and dendritic spines in the nucleus accumbens and pre-
Molina, B. S. G., & Pelham, W. E., Jr. (2003). Childhood predictors frontal cortex following repeated treatment with amphetamine or
of adolescent substance use in a longitudinal study of children cocaine. European Journal of Neuroscience, 11, 1598-1604.
with ADHD. Journal of Abnormal Psychology, 112, 497-507. Ryan, L. J., Linder, J. C., Martone, M. E., & Groves, P. M. (1990).
Moreira, C. Q., Faria, M. J. S. S., & Moreira, E. (2005). Behavioral neu- Histological and ultrastructural evidence that d-amphetamine
rotoxicity in adolescent and adult mice exposed to fenproporex dur- causes degeneration in neostriatum and frontal cortex of rats.
ing pregnancy. Human and Experimental Toxicology, 24, 403-408. Brain Research, 518, 67-77.
Nwanze, E., & Jonsson, G. (1981). Amphetamine neurotoxicity on Ryan, L. J., Martone, M. E., Linder, J. C., & Groves, P. M. (1988).
dopamine nerve terminals in the caudate nucleus of mice. Continuous amphetamine administration induces tyrosine hydrox-
Neuroscience Letters, 26, 163-168. ylase immunoreactive patches in the adult rat neostriatum. Brain
ODell, S. J., Weihmuller, F. B., & Marshall, J. F. (1991). Multiple Research Bulletin, 21, 133-137.
methamphetamine injections induce marked increases in extracel- Schiffer, W. K., Volkow, N. D., Fowler, J. S., Alexoff, D. L., Logan, J.,
lular striatal dopamine, which correlate with subsequent neuro- & Dewey, S. L. (2006). Therapeutic doses of amphetamine or
toxicity. Brain Research, 564, 256-260. methylphenidate differentially increase synaptic and extracellular
Owen, F., Baker, H. F., Ridley, R. M., Cross, A. J., & Crow, T. J. dopamine. Synapse, 59, 243-251.
(1981). Effects of chronic amphetamine administration on central Seiden, L. S., & Sabol, K. E. (1996). Methamphetamine and methyl-
dopaminergic mechanisms in the vervet. Psychopharmacology, enedioxymethamphetamine neurotoxicity: Possible mechanisms
74, 213-216. of cell destruction. NIDA Research Monograph, 163, 251-276.
Pearl, R. G., & Seiden, L. S. (1979). D-Amphetamine-induced Solanto, M. V. (2000). Clinical psychopharmacology of AD/HD:
increase in catecholamine synthesis in the corpus striatum of the Implications for animal models. Neuroscience and Biobehavioral
rat: Persistence of the effect after tolerance. Journal of Neural Reviews, 24, 27-30.
Transmission, 44, 21-38. Sonsalla, P. K., Jochnowitz, N. D., Zeevalk, G. D., Postveen, J. A., &
Ricaurte, G. A., Fuller, R. W., Perry, K. W., Seiden, L. S., & Schuster, Hall, E. D. (1996). Treatment of mice with methamphetamine pro-
C. R. (1983). Fluoxetine increases long-lasting neostriatal duces cell loss in the substantia nigra. Brain Research, 738, 172-175.
dopamine depletion after administration of d-methamphetamine Spencer, T. J., Biederman, J., Madras, B. K., Faraone, S. V., Dougherty,
and d-amphetamine. Neuropharmacology, 22, 1165-1169. D. D., Bonab, A. A., et al. (2005). In vivo neuroreceptor imaging in
Ricaurte, G. A., Guillery, R. W., Seiden, L. S., & Schuster, C. R. Attention-Deficit/Hyperactivity Disorder: A focus on the dopamine
(1984). Nerve terminal degeneration after a single injection of transporter. Biological Psychiatry, 57, 1293-1300.
d-amphetamine in iprindole-treated rats: Relation to selective long- Steranka, L. R. (1981). Stereospecific long-term effects of ampheta-
lasting dopamine depletion. Brain Research, 291, 378-382. mine on striatal dopamine neurons in rats. European Journal of
Ricaurte, G. A., Guillery, R. W., Seiden, L. S., Schuster, C. R., & Pharmacology, 76, 443-446.
Moore, R. Y. (1982). Dopamine nerve terminal degeneration pro- Steranka, L. R. (1983). Long-term effects of a priming dose and
duced by high doses of methylamphetamine in the rat brain. Brain short-term infusion of amphetamine on striatal dopamine neurons
Research, 235, 93-103. in rats. European Journal of Pharmacology, 96, 159-163.
Ricaurte, G. A., Seiden, L. S., & Schuster, C. R. (1984). Further evi- Steranka, L. R., & Sanders-Bush, E. (1980). Long-term effects of
dence that amphetamines produce long-lasting dopamine neuro- continuous exposure to amphetamine on brain dopamine concen-
chemical deficits by destroying dopamine nerve fibers. Brain tration and synaptosomal uptake in mice. European Journal of
Research, 303, 359-364. Pharmacology, 65, 439-443.
Ricaurte, G. A., Mechan, A. O., Yuan, J., Hatzidimitriou, G., Xie, T., Swanson, J. M., Cantwell, D., Lerner, M., McBurnett, K., & Hana, G.
Mayne, A. H., et al. (2005). Amphetamine treatment similar to (1991). Effects of stimulant medication on learning in children
that used in the treatment of adult Attention Deficit/Hyperactivity with ADHD. Journal of Learning Disorders, 24, 219-255.
Disorder damages dopaminergic nerve endings in the striatum of Tan, S. E. (2003). Prenatal amphetamine exposure alters behavioral
adult nonhuman primates. Journal of Pharmacology Experimental reactivity to amphetamine in rats. Neurotoxicology and
Therapeutics, 315, 91-98. Teratology, 25, 579-585.
Ridley, R. M., Baker, H. F., Owen, F., Cross, A. J., & Crow, T. J. Teter, C. J., McCabe, S. E., Cranford, J. A., Boyd, C. J., & Guthrie,
(1982). Behavioral and biochemical effects of chronic ampheta- S. K. (2005). Prevalence and motives for illicit use of prescription
mine treatment in the vervet monkey. Psychopharmacology, 78, stimulants in an undergraduate student sample. Journal of the
245-251. American College of Health, 53, 253-262.
Robinson, T. E., & Becker, J. B. (1986). Enduring changes in brain Thompson, P. M., Hayashi, K. M., Simon, S. L., Geaga, J. A., Hong,
and behavior produced by chronic amphetamine administration: A M. S., Sui, Y., et al. (2004). Structural abnormalities in the brains
16 Journal of Attention Disorders

of human subjects who use amphetamine. Journal of Neuroscience, Wilens, T. E. (2003). Drug therapy for adults with Attention-Deficit
24, 6028-6036. Hyperactivity Disorder. Drugs, 63, 2395-2411.
Villemagne, V., Yuan, J., Wong, D. F., Dannals, R. F., Hatzidimitriou, Wilens, T. E., Faraone, S. V., & Biederman, J. (2004). Attention-
G., Mathews, W. B. et al. (1998). Brain dopamine neurotoxicity in Deficit/Hyperactivity Disorder in adults. Journal of the American
baboons treated with doses of methamphetamine comparable to Medical Association, 292, 619-623.
those recreationally abused by humans: Evidence from [11C]WIN- Wilens, T. E., Faraone, S. V., Biederman, J., & Gunawardene, S.
35,428 positron emission tomography studies and direct in vitro (2003). Does stimulant therapy of Attention-Deficit/Hyperactivity
determinations. Journal of Neuroscience, 18, 419-427. Disorder beget later substance abuse? A meta-analytic review of
Vitiello, B. (2001). Long-term effects of stimulant medications on the the literature. Pediatrics, 111, 179-185.
brain: Possible relevance to the treatment of Attention Deficit Woolverton, W. L., Ricaurte, G. A., Forno, L. S., & Seiden, L. S.
Hyperactivity Disorder. Journal of Child and Adolescent (1989). Long-term effects of chronic methamphetamine adminis-
Psychopharmacology, 11, 25-34. tration in rhesus monkeys. Brain Research, 486, 73-78.
Volkow, N. D., Chang, L., Wang, G. -J., Fowler, J. S., Leonido-Yee, Yuan, J., McCann, U., & Ricaurte, G. (1997). Methylphenidate and
M., Franceschi, D. et al. (2001). Association of dopamine trans- brain dopamine neurotoxicity. Brain Research, 767, 172-175.
porter reduction with psychomotor impairment in methampheta- Zaczek, R., Battaglia, G., Contrera, J. F., Culp, S., & De Souza, E. B.
mine abusers. American Journal of Psychiatry, 158, 377-382. (1989). Methylphenidate and pemoline do not cause depletion of
Volkow, N. D., & Insel, T. R. (2003). What are the long-term effects of rat brain monoamine markers similar to that observed with
methylphenidate treatment? Biological Psychiatry, 54, 1307-1309. methamphetamine. Toxicology and Applied Pharmacology, 100,
Volkow, N. D., & Swanson, J. M. (2003). Variables that affect the 227-233.
clinical use and abuse of methylphenidate in the treatment of
ADHD. American Journal of Psychiatry, 160, 1909-1918.
Claire Advokat is a professor of biological psychology in the
Volkow, N. D., Wang, G.-J., Fowler, J. S., & Ding, Y. -S. (2005).
Imaging the effects of methylphenidate on brain dopamine: New
Psychology Department of Louisiana State University. Her
model on its therapeutic actions for Attention-Deficit/Hyperactivity primary focus of research is the psychopharmacology of drugs
Disorder. Biological Psychiatry, 57, 1410-1415. used in the treatment of psychiatric and behavioral disorders.
Wagner, G. C., Ricaurte, G. A., Johanson, C. E., Schuster, C. R., & Her ongoing research concerns the effectiveness of the newer
Seiden, L. S. (1980). Amphetamine induces depletion of dopamine antipsychotics and antidepressants in psychiatric inpatients
and loss of dopamine uptake sites in caudate. Neurology, 30, 547-550. and the use of these drugs in the forensic population.