Research

JAMA Neurology | Original Investigation

Effect of Dextroamphetamine on Poststroke Motor Recovery

A Randomized Clinical Trial
Larry B. Goldstein, MD; Laura Lennihan, MD; Meheroz J. Rabadi, MD; David C. Good, MD; Michael J. Reding, MD;
Alexander W. Dromerick, MD; Gregory P. Samsa, PhD; John Pura, MPH

Author Audio Interview

IMPORTANCE Data from animal models show that the administration of dextroamphetamine Supplemental content
combined with task-relevant training facilitates recovery after focal brain injury. Results of
clinical trials in patients with stroke have been inconsistent.

OBJECTIVES To collect data important for future studies evaluating the effect of
dextroamphetamine combined with physiotherapy for improving poststroke motor recovery
and to test the efficacy of the approach.

DESIGN, SETTING, PARTICIPANTS This pilot, double-blind, block-randomized clinical trial

included patients with cortical or subcortical ischemic stroke and moderate or severe motor
deficits from 5 rehabilitation hospitals or units. Participants were screened and enrolled from
March 2001 through March 2003. The primary outcome was assessed 3 months after stroke.
Study analysis was completed December 31, 2015. A total of 1665 potential participants were
screened and 64 were randomized. Participants had to begin treatment 10 to 30 days after
ischemic stroke. Data analysis was based on intention to treat.

INTERVENTIONS Participants were allocated to a regimen of 10 mg of dextroamphetamine (n

= 32) or placebo (n = 32) combined with a 1-hour physical therapy session beginning 1 hour
after drug or placebo administration every 4 days for 6 sessions in addition to standard
rehabilitation.

MAIN OUTCOMES AND MEASURES The primary outcome was the difference between groups
in change in Fugl-Meyer motor scores from baseline to 3 months after stroke (intention to
treat with dextroamphetamine). Secondary exploratory measures included the National
Institutes of Health Stroke Scale, Canadian Neurological Scale, Action Research Arm Test,
modified Rankin Scale score, Functional Independence Measure, Ambulation Speed and
Distance, Mini-Mental State Examination, Beck Depression Inventory, and Stroke Impact
Scale.

RESULTS Among the 64 patients randomized to dextroamphetamine vs placebo (55% men;

median age, 66 years; age range, 27-91 years), no overall treatment-associated difference in
the mean (SEM) change in Fugl-Meyer motor scores from baseline to 3 months after stroke
was noted (−18.65 [2.27] points with dextroamphetamine vs −20.83 [2.94] points with
placebo; P = .58). No overall treatment-associated differences in any of the study’s secondary
measures and no differences in subgroups based on stroke location or baseline severity were
found. No adverse events were attributed to study treatments.

CONCLUSIONS AND RELEVANCE Treatment with dextroamphetamine combined with physical

therapy did not improve recovery of motor function compared with placebo combined with
physical therapy as assessed 3 months after hemispheric ischemic stroke. The studied
treatment regimen was safe. Author Affiliations: Author
affiliations are listed at the end of this
article.
TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01905371
Corresponding Author: Larry B.
Goldstein, MD, Department of
Neurology, Kentucky Neuroscience
Institute, University of Kentucky, 740
S Limestone St, Room J401,
JAMA Neurol. doi:10.1001/jamaneurol.2018.2338 Lexington, KY 40536 (larry.goldstein
Published online August 27, 2018. @uky.edu).

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 Research Original Investigation
S
troke is the third leading cause of disability worldwide.1
More than 60% of Medicare beneficiaries in the United
States receive care in inpatient rehabilitation or skilled
nursing facilities after stroke.2 One study of 4-year survivors af-
ter stroke3 found 42% had ongoing disabilities, 28% could not
fully participate in activities, and 78% reported that they had not
completely recovered. Even after treatment with mechanical
thrombectomy, 49% to 88% of participants have some disabil-
ity after 90 days.4 These data highlight the need for additional
approaches intended to enhance poststroke recovery.
Laboratory experiments performed during several de-
cades in a variety of animal models show that systemic ad-
ministration of dextroamphetamine days or weeks after stroke
or other forms of injury to the cerebral cortex, when com-
bined with task-relevant training, can facilitate postinjury func-
tional recovery.5,6 Factors affecting efficacy include the fre-
quency, type, and intensity of therapy sessions. Therefore, the
results of variably designed clinical trials evaluating the ap-
proach, not surprisingly, have been inconsistent.7 Some stud-
ies suggest benefit,8,9 whereas others had negative findings.10-14
The Amphetamine-Enhanced Stroke Recovery Trial was an
exploratory, phase 2, double-blind, placebo-controlled, mul-
ticenter randomized clinical trial intended to refine the tar-
get patient population, gain information to permit an accu-
rate sample size calculation, determine appropriate outcome
measures, develop management procedures for a subse-
quent study, and collect preliminary efficacy data.
Methods
Participants
A copy of the trial protocol is found in Supplement 1. Partici-
pants were screened and enrolled at 5 rehabilitation hospi-
tals or units (Burke Rehabilitation Hospital, White Plains, New
York; Helen Hayes Hospital, West Haverstraw, New York; Wake
Forest University, Winston-Salem, North Carolina; Duke Uni-
versity, Durham, North Carolina; and Washington University
in St Louis, St Louis, Missouri) from March 2001 through March
2003. The study protocol was approved by each participating
center’s institutional review board, and all patients or their rep-
resentatives provided written informed consent.
The Amphetamine-Enhanced Stroke Recovery Trial en-
rolled potential participants if they (1) had a documented (in-
cluding neuroimaging) ischemic hemispheric stroke; (2) could
start treatment from 10 to 30 days after stroke; (3) were inde-
pendent before the index stroke (modified Rankin Scale score,
0 or 1 [range, 0-6, with 6 indicating death]); (4) had a moderate
or severe stroke-associated motor impairment; (5) were ca-
pable of giving informed consent (or had a legal representative
to do so); (6) would be available for the required follow-up evalu-
ations; and (7) were physically able to receive the study drug
or placebo. Potential participants were excluded if they had (1)
uncontrolled hypertension, defined as systolic blood pressure
of at least 160 mm Hg or diastolic blood pressure of at least 100
mm Hg at rest, determined by 3 readings during the 24 hours
before randomization; (2) an index or a remote intracerebral or
subarachnoid hemorrhage; (3) a history of active psychosis or
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Effect of Dextroamphetamine on Poststroke Motor Recovery
Key Points
Question Does the administration of dextroamphetamine
combined with physiotherapy improve poststroke motor
recovery?
Findings In this pilot randomized clinical trial of 64 patients with
ischemic stroke, no overall treatment-associated difference in the
change in Fugl-Meyer motor scores from baseline to 3 months
after treatment, no overall treatment-associated differences in any
of the study’s secondary measures, and no differences in any
subgroup based on stroke location or baseline severity were
found. No adverse events were attributed to study treatments.
Meaning This study found no evidence that dextroamphetamine
combined with physiotherapy improves poststroke motor
recovery.
bipolar disorder; (4) angina pectoris within the preceding 3
months; (5) a myocardial infarction within the preceding year;
(6) inducible myocardial ischemia based on results of an exer-
cise or pharmacologic stress test if performed within the prior
year; (7) clinically significant congestive heart failure, defined
as New York Heart Association classification III or IV; (8) atrial
or ventricular arrhythmias, including atrial fibrillation, atrial flut-
ter, ventricular tachycardia, ventricular fibrillation, and Wolff-
Parkinson-White syndrome by history or electrocardiographic
or Holter monitor findings; (9) a history of seizures or seizures
associated with the index ischemic stroke; (10) an allergy to am-
phetamine; (11) current treatment with levodopa, another dopa-
mine agonist, or a monoamine oxidase inhibitor; (12) glau-
coma; (13) a need for treatment with a drug or a class thought
to impair recovery based on laboratory and available clinical evi-
dence (α1-adrenergic receptor antagonist, α2-adrenergic recep-
tor agonist, benzodiazepine, dopamine receptor antagonist, phe-
nobarbital, or phenytoin); (14) hyperthyroidism; (15) current
pregnancy; (16) an expected rehabilitation stay of less than 3
weeks; (17) a mild stroke-associated motor impairment (ad-
justed Fugl-Meyer motor score ≥80 [range, 0-100, with higher
scores indicating better motor performance]); (18) participa-
tion in another investigational protocol; or (19) any condition
that in the view of the investigator would put the patient at risk
through participation in the study.
Screening and Randomization
All potential participants were screened for study eligibility
at the time of rehabilitation admission based on a standard
admission evaluation, including a comprehensive medical,
neurologic, and psychiatric history, review of medical rec-
ords, results of physical and neurologic examinations, review
of brain imaging reports, electrocardiographic findings, and
pregnancy test results in premenopausal women. Eligible
participants were invited to participate in the study. After
consent, baseline testing was performed and participants
were block randomized within each center based on stroke
severity at the beginning of rehabilitation (Fugl-Meyer motor
score, 0-35 for severe stroke and 36-79 for moderate stroke)15
and stroke subtype (subcortical vs cortical hemispheric ische-
mic stroke using the Oxfordshire criteria and neuroimaging
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 Effect of Dextroamphetamine on Poststroke Motor Recovery Original Investigation Research

data),16,17 resulting in 4 blocks with 1:1 randomization to dex-

Figure 1. Study Flowchart
troamphetamine or placebo within each block (severe corti-
cal, severe subcortical, moderate cortical, and moderate sub-
1665 Participants assessed for
cortical stroke). eligibility

1601 Excluded
Study Drug and Placebo 1544 Not meeting inclusion
Active and placebo capsules were prepared by the hospital criteria
56 Declined to participate
pharmacy on-site at each institution. The pharmacies were 1 Enrolled but developed
given a randomization scheme generated by the study statis- tachycardia before
treatment
tician (G.P.S.) at the coordinating center. Each patient’s study
medications were prepared as a unit-dose kit according to
64 Randomized
this predetermined randomization schedule. The on-site phar-
macies were not to reveal the randomization assignment to
other personnel except in the extraordinary circumstance that 32 Randomized to 32 Randomized to placebo plus
dextroamphetamine plus physiotherapy
the information would be required for a patient’s emergency physiotherapy
treatment.
Two 5-mg dextroamphetamine tablets obtained commer-
0 Lost to follow-up 5 Lost to follow-up
cially by each hospital pharmacy were split and placed in a
0 Discontinued 1 Death
single opaque blue gelatin capsule (Gallipot, Inc). The 5-mg tab- dextroamphetamine 1 Condition that poses risk to
patient when treated with
lets were cut with a pill splitter to allow them to fit into 1 size amphetamine
0 capsule (any fragmented pills were discarded). To prevent 3 Personal reasona
movement within the capsules, lactose monohydrate pow-
der (AMEND, Inc) was used as a filler. Identical placebo cap-
32 Included in analysis 32 Included in analysis
sules were filled with 0.65 g of powdered lactose monohy-
drate (the amount of lactose does not represent a significant a
Includes withdrew owing to depression and family’s desire to have patient
load and did not preclude those with lactose intolerance from closer to home (n = 1); early withdrawal owing to lack of transportation (n = 1);
participating in the study). The gelatin capsules dissolve in the and discharge home with family (n = 1).
stomach within 1 to 3 minutes and do not interfere with the
absorption of the dextroamphetamine tablets.
(10) any other condition that the investigator believed might
Treatment Regimen reasonably be associated with dextroamphetamine treat-
Based on the results of a small trial suggesting benefit,9 en- ment and present a risk to the patient.
rolled participants were randomized to double-blind treat-
ment with a regimen of 10 mg of dextroamphetamine or pla- Outcome Assessments
cebo combined with a 1-hour session of active physical therapy The primary, prespecified outcome was the change in Fugl-
directed at a primary motor impairment beginning 1 hour af- Meyer motor score18 (exclusive of sensation and reflexes) as-
ter drug or placebo administration and delivered every 4 days sessed 3 months after stroke. Secondary measures included the
for a total of 6 sessions. A target motor impairment for physi- National Institutes of Health Stroke Scale,19 Canadian Neuro-
cal therapy intervention was designated (usually gait, but in logical Scale,20 Action Research Arm Test,21 modified Rankin
some cases arm function). An outline indicating a range and Scale score,22 Functional Independence Measure,23 Ambula-
level of physical therapy interventions was provided to the tion Speed and Distance (6-minute walk test), 24,25 Mini-
therapists, and the level and target of therapy were recorded. Mental State Examination,26 Beck Depression Inventroy,27 and
Throughout the rehabilitation hospitalization (and including Stroke Impact Scale.28 Assessments were also performed at the
the 3-week study treatment phase), all participants also re- end of treatment.
ceived standard, comprehensive rehabilitation services.
Statistical Analysis
Protocol-Specified Criteria for Withdrawal Although the study was not primarily intended to determine
The protocol specified that participants would be withdrawn the efficacy of the intervention, we hypothesized that the
from the study if they experienced any of the following addition of treatment with dextroamphetamine to targeted
adverse events: (1) moderate or severely elevated blood pres- physical therapy would result in at least a 12.6-point differ-
sure (systolic blood pressure of ≥180 mm Hg or diastolic ence in improvement in the Fugl-Meyer motor score at 3
blood pressure of ≥110 mm Hg); (2) angina pectoris; (3) myo- months after stroke, which was anticipated to be a clinically
cardial infarction; (4) stroke or transient ischemic attack; (5) important effect. To detect a 12.6-point difference in Fugl-
New York Heart Association classification III or IV congestive Meyer motor scores between the groups with a 2-sided
heart failure or a cardiac arrhythmia (as listed in exclusion α = .05 and a power of 80%, a sample size of 25 participants
criteria 8); (6) psychosis; (7) hallucinations; (8) agitation per group for each regimen was calculated as adequate.
requiring treatment; (9) need for treatment with a drug Based on preliminary data, we anticipated that approxi-
thought to impair recovery (listed in exclusion criteria 13); or mately 24% of participants meeting exclusion criteria would

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 Research Original Investigation Effect of Dextroamphetamine on Poststroke Motor Recovery

Table 1. Characteristics of Participants at Baseline

Treatment Group
Dextroamphetamine
Characteristic (n = 32) Placebo (n = 32) P Value
Age, median (IQR) 67.5 (57.0-77.5) 65.5 (56.0-75.0) .69
Sex, No. (%)
Male 19 (59) 16 (50)
.45
Female 13 (41) 16 (50)
Race/ethnicity, No. (%)
White 26 (81) 23 (72)
Black 2 (6) 8 (25)
.11
Latino or Hispanic 2 (6) 0
Other 2 (6) 1 (3)
History, No. (%)
Stroke 4 (13) 4 (13) .96 Abbreviations: IQR, interquartile
Hypertension 23 (72) 23 (72) .84 range; MMSE, Mini-Mental State
Examination; SSRI, selective
Diabetes 7 (22) 12 (38) .15 serotonin reuptake inhibitor;
Smoking 8 (25) 9 (28) .78 TCA, tricyclic antidepressant.
a
Medication type, No. (%) Scores range from 0 to 100, with
Antihypertensive 13 (41) 14 (44) .97 higher scores indicating better
motor performance.
Antiplatelet 28 (88) 25 (78) .32 b
Scores range from 0 to 6, with 6
Benzodiazepine 1 (3) 1 (3) >.99 indicating death.
Statin 16 (50) 14 (44) .62 c
Scores range from 0 to 20, with
Antidepressant, No. (%) higher scores indicating greater
severity.
SSRI 2 (6) 3 (9)
.55 d
Scores range from 0 to 8, with
TCA 1 (3) 0
higher scores indicating less
Assessments severity.
Fugl-Meyer motor score, mean (SEM)a 23.2 (3.6) 24.5 (3.6) .75 e
Scores range from 7 to 126, with
Modified Rankin Scale score, median (IQR)b 4 (4-4) 4 (4-4) .09 higher scores indicating more
dependence.
National Institutes of Health Stroke Scale score, mean (SEM)c 13.1 (1.1) 13.2 (1.1) .86 f
Scores range from 0 to 57, with
Canadian Neurological Scale score, mean (SEM)d 5.75 (0.4) 5.84 (0.3) .91 higher scores indicating better
Functional Independence Measure score, mean (SEM)e 60 (4) 61 (3) .82 performance.
g
Ambulation Distance and Speed, mean (SEM) Scores range from 0 to 30, with
Distance, m 52.4 (18.3) 54.9 (5.9) .93 higher scores indicating better
cognition.
Speed, m/min 16.5 (8.2) 11.9 (3.4) .79 h
Scores range from 0 to 27, with
Action Research Arm Test, mean (SEM)f 62 (4) 63 (3) .38 higher scores indicating more
MMSE score, mean (SEM)g 18 (2) 22 (1) .27 depression.
i
Beck Depression Index score, mean (SEM)h 12 (1) 12 (2) .52 Scores range from 0 to 100, with
higher scores indicating better
Stroke Impact Scale score, mean (SEM)i 36 (2) 36 (2) .78
recovery.

be withdrawn because of complications normally occurring
during poststroke rehabilitation hospitalizations (eg, angina,
myocardial infarction, new cardiac arrhythmia, stroke, sei-
zure, psychosis, agitation, or transfer to an acute care hospi-
tal). Therefore, a total of 65 participants were to be enrolled
to allow for a 30% dropout rate.
The analysis of the primary end point was based on the in-
tention to treat with dextroamphetamine for participants who
received at least 1 dose of study drug. A 2-sample paired t test
was first used to compare the intervention and placebo groups
with respect to change in Fugl-Meyer motor scores. This analy-
sis was repeated for each of the secondary outcomes (the
Wilcoxon rank sum test was used for group comparisons for
ordinal data). The frequencies of serious adverse events were
compared with χ2 analyses. Because of the exploratory na-
ture of the analyses, P values were not adjusted for multiple
comparisons. P < .05 indicated significance.
Results
Study Population
A total of 1665 potential participants were screened, and 64 were
randomized (1544 did not meet inclusion criteria, 56 declined
to participate, and 1 was enrolled but excluded because of de-
velopment of tachycardia before any study procedures)
(Figure 1). Patients were most frequently excluded because they
had a mild stroke-related impairment (n = 536), an index brain
hemorrhage (n = 249), or an expected rehabilitation stay of less
than 3 weeks or were deemed by the investigator to be at high

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 Effect of Dextroamphetamine on Poststroke Motor Recovery Original Investigation Research

Table 2. Change in Fugl-Meyer Motor Scoresa

Mean (SEM) Fugl-Meyer Motor Score

3 mo After Difference, Baseline
Stroke Type by Treatment Baseline End of Treatment Treatment to 3 mo
Severe cortical
Dextroamphetamine 14.75 (3.52) 27.13 (5.61) 34.38 (6.75) 19.63 (3.64)
Placebo 13.78 (4.54) 26.50 (10.99) 19.75 (5.78) 13.50 (5.07)
P value .63 .44 .20 .35
Severe subcortical
Dextroamphetamine 13.75 (2.42) 24.09 (4.67) 28.09 (4.09) 14.55 (2.28)
Placebo 20.25 (4.34) 34.27 (5.75) 40.92 (5.95) 21.18 (4.55)
P value .23 .16 .15 .39
Moderate cortical
Dextroamphetamine 42.50 (11.13) 50.00 (11.56) 56.67 (12.27) 14.17 (1.96)
Placebo 36.75 (9.63) 59.75 (7.69) 71.50 (4.52) 34.75 (7.60)
P value .75 >.99 .39 .054
Moderate subcortical
Dextroamphetamine 34.17 (10.47) 53.50 (12.56) 63.50 (11.82) 29.3 (8.88)
Placebo 40.83 (10.65) 45.20 (13.72) 52.20 (12.71) 14.80 (3.92)
P value .63 .65 .58 .36
All
Dextroamphetamine 23.22 (3.63) 35.58 (4.41) 42.10 (4.61) 18.65 (2.27)
a
Placebo 24.48 (3.58) 38.50 (4.77) 44.68 (4.89) 20.83 (2.94) Fugl-Meyer motor score 0-35
indicates severe stroke and 36-79,
P value .75 .63 .70 .58
moderate stroke.

risk for complications of participation (n = 153). A total of 64 par-
ticipants (35 men [55%] and 29 women [45%]; median age, 66
years; age range, 27-91 years) were randomized (32 per treat-
ment group, dextroamphetamine vs placebo). The groups were
balanced according to the block randomization plan among se-
vere cortical, severe subcortical, moderate cortical, and mod-
erate subcortical strokes (eFigure in Supplement 2). Table 1 gives
the baseline characteristics of the participants by treatment
group (eTable 1 in Supplement 2 further gives baseline charac-
teristics of the participants by randomization block and treat-
ment group). Demographics, vascular risk factors, medica-
tions, and the results of baseline assessments were similar for
dextroamphetamine- and placebo-treated participants.
Outcomes
Table 2 gives the overall baseline, end of treatment, and 30-
day posttreatment findings and baseline to 30-day difference
for the primary outcome (Fugl-Meyer motor score) and by
randomization strata (intention to treat). The overall and within-
randomization strata differences between dextroamphet-
amine- and placebo-treated participants were not significant,
although participants with moderate cortical strokes tended to
have greater improvements with placebo (mean [SEM] differ-
ence, −34.75 [7.60] vs −14.17 [1.96]; P = .054).
Figure 2 gives the baseline, end of treatment, and 30-day
posttreatment results for the modified Rankin Scale score. The
difference in improvement between the groups from base-
line to 3 months was not significant (mean [SEM] difference,
0.71 [0.14] vs 0.92 [0.13] points; P = .29). eTables 2 to 9 in
Supplement 2 give the baseline, end of treatment, 3-month
poststroke, and baseline to 3-month differences by strata and
overall for the National Institutes of Health Stroke Scale (over-
all mean [SEM] difference for dextroamphetamine vs pla-
cebo groups, −4.84 [0.75] vs −4.96 [0.77] points; P = .97), Ca-
nadian Neurological Score (mean [SEM] difference, 1.95 [0.27]
vs 2.04 [0.33] points; P = .66), Functional Independence Mea-
sure (mean [SEM] difference, 38.29 [3.31] vs 34.46 [2.84] points;
P = .46), Ambulation Distance (mean [SEM] difference, 109.64
[21.36] vs 67.71 [19.55] m; P = .16), Ambulation Speed (mean
[SEM] difference, 9.41 [7.69] vs 9.49 [2.85] m/min; P = .21), Re-
search Action Arm Test (mean [SEM] difference, 7.24 [2.72] vs
12.83 [3.69] points; P = .08), Mini-Mental State Examination
(mean [SEM] difference, 4.90 [2.23] vs 17.58 [3.49] points; P =
.12), and Beck Depression Inventory (mean [SEM] difference,
−3.03 [1.16] vs −1.43 [1.66] points; P = .15). eTable 10 in
Supplement 2 gives the baseline, 3-month poststroke, and base-
line to 3-month differences by strata and overall for the Stroke
Impact Scale (mean [SEM] difference, 18.04 [7.69] vs 9.49 [2.85]
points; P = .21). We found no overall differences between the
groups for any measure. Those with severe subcortical strokes
had somewhat greater improvements with placebo on the
Action Research Arm test (mean [SEM] difference, 17.33 [5.42]
vs 2.27 [1.89] points; P = .01, uncorrected for multiple com-
parisons) (eTable 7 in Supplement 2).
Safety
Five participants (8%) did not complete the protocol through
the 3-month poststroke follow-up evaluation (Figure 1). None
were withdrawn owing to a protocol-specified cause and all
were allocated to the placebo group. One patient withdrew con-
sent, 1 moved away from the study site, and 1 transferred to a
rehabilitation facility closer to home. One participant with a

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 Research Original Investigation Effect of Dextroamphetamine on Poststroke Motor Recovery

ischemic stroke based on the Fugl-Meyer motor score.

Figure 2. Distribution of Modified Rankin Scale Scores at Baseline,
End of Treatment, and 3 Months After Stroke
Although only highly selected patients in whom amphet-
amine treatment was considered safe and who were thought
0 1 2 3 4 5
to most likely benefit from the intervention were included,
no difference in any of the trial’s secondary measures
A Baseline occurred.
3.1 12.5 84.4
A meta-analysis that included data from 9 trials (total of 114
Amphetamine
amphetamine-treated participants and 112 controls)29 found no
6.3 87.5 6.2
overall effect of treatment with dextroamphetamine on motor
Placebo
recovery (standard mean difference, −0.08; 95% CI, −0.34 to
0 20 40 60 80 100
0.19); in 4 trials, the meta-analysis found no effect on activi-
Participants, % ties of daily living (total of 58 amphetamine-treated partici-
pants and 55 controls; standard mean difference, 3.85; 95% CI,
B End of treatment −5.75 to 13.49) after stroke. More deaths occurred at the end of
3.2 6.5 41.9 48.4
follow-up among participants randomized to amphetamine
Amphetamine
(8.5% vs 2.2%; odds ratio, 2.8; 95% CI, 0.9-8.6), which may have
21.4 17.9 60.7 been owing to baseline imbalances between the groups, but the
Placebo difference was not significant. The trials, however, were small
and had important differences in patient populations, drug treat-
0 20 40 60 80 100
Participants, %
ment regimens, physiotherapy protocols, and outcome
measures.30 Although intended as a pilot, the present study
C 3-Month follow-up represents, to our knowledge, the second largest randomized
3.2 6.5 54.8 25.8 trial of dextroamphetamine conducted to date. Despite the
Amphetamine choice of a dosing and treatment regimen modeled after a prior
23.1 46.2 30.7 trial that suggested benefit in a smaller, single-site study that
Placebo also included careful linking of drug treatment with targeted
physiotherapy,9 the present study also failed to find a treat-
0 20 40 60 80 100
ment effect.
Participants, %
Preclinical laboratory studies of the effect of amphet-
Scores range from 0 (no deficit) to 6 (death). None of the participants died amine administration on recovery after brain injury were
during the study period. Numbers above the bars indicate the percentage of limited to experiments in which the lesion was restricted to
participants with each score at each point for those randomized to the cerebral cortex.31 Therefore, no preclinical data evaluated
dextroamphetamine (n = 32) or placebo (n = 32). The difference between the
the potential effects of treatment with dextroamphetamine
groups between baseline and 3 months is not significant (P = .29).
on recovery after injury to subcortical structures. Because
the present study was intended to be exploratory, partici-
remote history of a seizure disorder had a possible uncompli- pants with strokes affecting the cerebral cortex or subcortical
cated partial seizure. A fifth participant had bilateral lower- hemispheric structures resulting in motor deficits were
extremity deep vein thromboses, was transferred to an acute included. Although not powered for subgroup analyses, our
care hospital, and was then found to have colon cancer with participants were randomized according to stroke subtype
hepatic metastases. That patient was subsequently found to (cortical vs subcortical) and functional severity. Those par-
have a second stroke on magnetic resonance imaging with- ticipants with moderately severe cortical strokes tended to
out clinical manifestations and died of sepsis in the acute care have more benefit with placebo, with no differences in other
hospital. subgroups. As in our study, another trial14 found no effect of
Adverse events that did not prompt withdrawal from treatment in subgroups of participants with a cortically based
the study included 1 participant who had a second stroke 2 stroke.
months after completing treatment and after completing the We anticipated that 30% of enrolled participants would
last study assessment. An additional participant had a deep vein be withdrawn owing to expected complications during reha-
thrombosis that was treated with an inferior vena cava filter. bilitation. During the trial, only 5 participants (8%) did not
No treatment-associated serious adverse events occurred. complete the 3-month assessment, providing sufficient
power to evaluate the primary efficacy end point. None of
the adverse events that occurred during the trial were consid-
ered to have been associated with study treatments. This
Discussion finding is consistent with those of other studies that found no
The primary result of this pilot clinical trial was that inten- clinically important adverse events related to treatment with
tion to treat with dextroamphetamine combined with physi- dextroamphetamine during poststroke rehabilitation.14,32,33 As
cal therapy did not improve recovery of motor function in our study, these clinical trials carefully excluded partici-
compared with placebo combined with physical therapy in pants who might be at higher risk of amphetamine-related
similar participants as assessed 3 months after hemispheric complications.

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 Effect of Dextroamphetamine on Poststroke Motor Recovery Original Investigation Research

Limitations our study was conducted, acute thrombectomy has been

This study has several important limitations. Although pow-
ered to detect what was anticipated to be a clinically impor-
tant effect, this pilot trial included participants for whom there
was no preclinical evidence of treatment benefit. An alterna-
tive dosing regimen was not assessed. Although study-
related physiotherapy sessions followed a standard protocol,
other physiotherapy was permitted, which could obscure a
treatment effect. Whether subgroups of participants (eg, those
with a cortical stroke causing a moderate motor deficit) might
benefit cannot be assessed. Whether a different amphet-
amine dose or administration schedule (eg, more or less fre-
quent treatment or beginning sooner after the stroke) or a modi-
fied patient population (eg, more severely affected) might show
a benefit would need to be evaluated in other studies. Since
proven effective,34 and physiotherapeutic approaches may
have evolved,35 both of which might influence the effect of
drugs such as dextroamphetamine on the trajectory of func-
tional recovery after stroke.
Conclusions
Despite supportive preclinical data, we found no evidence that
treatment with dextroamphetamine combined with physio-
therapy leads to an important improvement in poststroke re-
covery. Future studies could assess other strategies for modu-
lating central neurotransmitters and other subgroups of
participants.

ARTICLE INFORMATION He did not receive compensation for his physiotherapy after stroke. Cerebrovasc Dis. 2001;
Accepted for Publication: June 14, 2018. contributions. 12(3):253-257. doi:10.1159/000047712

Published Online: August 27, 2018.
doi:10.1001/jamaneurol.2018.2338
Author Affiliations: Department of Neurology,
Kentucky Neuroscience Institute, University of
Kentucky, Lexington (Goldstein); Department of
Neurology, Columbia University, New York, New
York (Lennihan); Department of Neurology,
Department of Veterans Affairs Medical Center 127,
Oklahoma City, Oklahoma (Rabadi); Department of
Neurology, Penn State University, Hershey,
Pennsylvania (Good); Department of Neurology,
Burke Rehabilitation Hospital, Yonkers, New York
(Reding); MedStar National Rehabilitation Hospital,
Washington, DC (Dromerick); Department of
Rehabilitation Medicine, Georgetown University,
Washington, DC (Dromerick); Department of
Biostatistics and Bioinformatics, Duke University,
Durham, North Carolina (Samsa, Pura).
Author Contributions: Dr Goldstein had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Goldstein, Lennihan, Good,
Reding, Dromerick.
Acquisition, analysis, or interpretation of data: All
authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Samsa, Pura.
Obtained funding: Lennihan, Dromerick.
Administrative, technical, or material support:
Goldstein, Reding, Dromerick.
Supervision: Lennihan, Rabadi, Reding.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by
grant NS39934 from the National Institutes of
Health.
Role of the Funder/Sponsor: The sponsor had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: Fletcher McDowell, MD,
Burke Rehabilitation Hospital, White Plains, New
York, helped bring the research group together and
helped secure funding to collect preliminary data.
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