SPECIAL SECTION

Effects of Stimulant Medication on Growth Rates

Across 3 Years in the MTA Follow-up
JAMES M. SWANSON, PH.D., GLEN R. ELLIOTT, PH.D., M.D.,
LAURENCE L. GREENHILL, M.D., TIMOTHY WIGAL, PH.D., L. EUGENE ARNOLD, M.D.,
BENEDETTO VITIELLO, M.D., LILY HECHTMAN, M.D., JEFFERY N. EPSTEIN, PH.D.,
WILLIAM E. PELHAM, PH.D., HOWARD B. ABIKOFF, PH.D., JEFFREY H. NEWCORN, M.D.,
BROOKE S.G. MOLINA, PH.D., STEPHEN P. HINSHAW, PH.D., KAREN C. WELLS, PH.D.,
BETSY HOZA, PH.D., PETER S. JENSEN, M.D., ROBERT D. GIBBONS, PH.D.,
KWAN HUR, PH.D., ANNAMARIE STEHLI, M.P.H., MARK DAVIES, M.S.,
JOHN S. MARCH, M.D., M.P.H., C. KEITH CONNERS, PH.D., MARK CARON, PH.D.,
AND NORA D. VOLKOW, M.D.

ABSTRACT
Objective: To evaluate the hypothesis of stimulant medication effect on physical growth in the follow-up phase of the
Multimodal Treatment Study of Children With ADHD. Method: Naturalistic subgroups were established based on patterns of
treatment with stimulant medication at baseline, 14-, 24-, and 36-month assessments: not medicated (n = 65), newly
medicated (n = 88), consistently medicated (n = 70), and inconsistently medicated (n = 147). Analysis of variance was used to
evaluate effects of subgroup and assessment time on measures of relative size (z scores) obtained from growth norms.
Results: The subgroup  assessment time interaction was significant for z height (p < .005) and z weight (p < .0001), due
primarily to divergence of the newly medicated and the not medicated subgroups. These initially stimulant-naı̈ve subgroups
had z scores significantly 90 at baseline. The newly medicated subgroup showed decreases in relative size that reached
asymptotes by the 36-month assessment, when this group showed average growth of 2.0 cm and 2.7 kg less than the not
medicated subgroup, which showed slight increases in relative size. Conclusions: Stimulant-naı̈ve school-age children with
Combined type attention-deficit/hyperactivity disorder were, as a group, larger than expected from norms before treatment but
show stimulant-related decreases in growth rates after initiation of treatment, which appeared to reach asymptotes within 3
years without evidence of growth rebound. J. Am. Acad. Child Adolesc. Psychiatry, 2007;46(8):1015Y1027. Key Words:
attention-deficit/hyperactivity disorder, growth, methylphenidate, side effects, long-term outcome.

The use of stimulant medications (see American

Accepted January 8, 2007.
Please see end of text for author affiliations.
Academy of Child and Adolescent Psychiatry, 2002)
The work reported was supported by cooperative agreement grants and contracts to treat children with attention-deficit/hyperactivity
from the National Institute of Mental Health to the following: University of disorder (ADHD) has increased dramatically since
California, Berkeley: U01 MH50461 and N01MH12009; Duke University: 1990 (Olfson et al., 2002; Swanson et al., 1995),
U01 MH50477 and N01MH12012; University of California, Irvine: U01
MH50440 and N01MH 12011; Research Foundation for Mental Hygiene despite limited information on long-term effects
(New York State Psychiatric Institute/Columbia University): U01 MH50467. (Charach et al., 2004; Gillberg et al., 1997). The
The opinions and assertions contained in this report are the private views of Multimodal Treatment Study of Children With
the authors and are not to be construed as official or as reflecting the views of the
National Institute of Mental Health, the National Institutes of Health, or the
ADHD (MTA) was intended to fill this gap (see
Department of Health and Human Services. Arnold et al., 1997). The primary reports of outcome in
Correspondence to Dr. James M. Swanson, UCI Child Development Center, the MTA focused on efficacy, with assessment of
19722 MacArthur Blvd., Irvine, CA 92612; e-mail: [email protected].
outcome at the end of the initial 14-month treatment
8567/07/4608-1015Ó2007 by the American Academy of Child and
Adolescent Psychiatry. phase (MTA Cooperative Group, 1999) and at the first
DOI:10.1097/chi.0b013e3180686d7e follow-up 10 months later, 24 months after initiation

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:8, AUGUST 2007 1015

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SWANSON ET AL.

of treatment (MTA Cooperative Group, 2004a). adulthood was not affected by childhood treatment
The companion reports in this special section (Jensen with stimulants. Klein and Mannuzza (1988) followed
et al., 2007; Molina et al., 2007; Swanson et al., 2007) the Mattes and Gittelman (1983) sample into adult-
focus on efficacy and changes in effectiveness at the end hood and compared their average size to a nonclinical
of the second follow-up phase, 36 months after control group. No difference in height or weight was
initiation of treatment. The secondary analyses reported observed. Kramer et al. (2000) followed the Loney et al.
here focus on a possible side effect of stimulant (1981) sample into adulthood and compared height
medication on growth rates of school-age children and weight to control groups drawn from family
with ADHD. members (unmedicated brothers and fathers), the
The hypothesis of a stimulant-related decrease in community (randomly selected classmates), and clinical
physical growth rates (a slowing in the gain of height groups (individuals with clinical problems but never
and weight) was proposed by Safer et al. (1972). medicated). No differences in self-reported height or
Consensus reviews and statements decades apart (see weight were documented. Because ultimate height
NIH Consensus Committee, 1998; Roche et al., 1979) appeared not to be compromised in adults who had
discounted the clinical significance of this hypothesis, shown growth slowing during treatment as children, the
based on prevailing views that short-term growth implication of these studies was that growth rebound
suppression may occur but does not result in long- must have occurred. However, growth rebound was not
term effects on ultimate size. Two hypotheses that offer measured directly in these influential studies.
explanations for this discrepancy of short- and long- Spencer et al. (1996) proposed that maturational lag
term effects on growth and relative size are the growth characterized the clinical condition of ADHD, which
rebound hypothesis (Safer et al., 1975) and the delayed produced a reduction in growth rate that was correlated
maturation hypothesis (Spencer et al., 1996). with but not necessarily a result of treatment with
The evidence of growth rebound is inconsistent and stimulant medication. This hypothesis was based on
mostly circumstantial. Safer et al. (1975) reported that data from a 4-year follow-up of a longitudinal study of
when children were treated with stimulant medications a group of 124 boys with ADHD, all but 10 with a
(D-amphetamine or methylphenidate) during the school lifetime history of treatment with medication, com-
year, then growth rates for both height and weight were pared to a control group of 109 boys without ADHD.
less than expected based on norms, but if medication was However, growth measures were obtained only at one
discontinued during the summer, growth rates then point in time in the longitudinal study, providing only
appeared to be greater than expected, suggesting growth cross-sectional evaluation of size. The key findings of
rebound. Satterfield et al. (1979) reported that growth the study were that height and weight deficits were
suppression was manifested in the first year of treatment evident in the younger but not the older adolescent
but was followed by growth rebound (greater than children with ADHD and that there was no association
expected growth) whether or not stimulant medication between height deficits and treatment with various drug
was discontinued in the summer. However, multiple classes (stimulant or other), various dose regimens
studies have not replicated this effect of growth rebound (robust or mild), and duration of treatment. Based on
during continued treatment with stimulant medication. this, they proposed that slow growth in ADHD
Mattes and Gittelman (1983) evaluated groups of children was due primarily to early but temporary
children with continuous treatment for 1 to 4 years and manifestations of the ADHD itself and may be disorder
documented stimulant-related growth deficit that accu- related rather than treatment related. Using the same
mulated with the duration of treatment. It was still design, Biederman et al. (2003) described the growth of
present during the final year of observation in the group a group of 140 girls with ADHD, most (70%) with a
treated for 4 years with methylphenidate, suggesting that lifetime history of treatment with medication, com-
growth slowing did not abate during continuous pared with a control group of 122 non-ADHD girls.
treatment. They reported a similar pattern as Spencer et al. (1996)
Apparently, the growth rebound hypothesis gained reported for boys: the group of preadolescent but not
prominence and acceptance based on long-term follow- adolescent girls was shorter than the control group, but
up studies that suggested that ultimate height in this difference was not significant for relative size

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 EFFECTS OF STIMULANT MEDICATION ON GROWTH

adjusted for age and was not related to medication included in the initial report of the effects of treatment.
history. Comparisons of the two samples showed no The first evaluation of growth in the MTA was part of a
significant effect of sex. Based on this, they concluded report of outcome at the first follow-up 2 years after
that treatment with stimulant medication does not have initiation of treatment (MTA Cooperative Group,
an adverse impact on growth of children with ADHD. 2004b). In this report the intent-to-treat evaluation of
In recent studies of possible effects of stimulant assigned treatment revealed that at 14 months the two
medication on growth, the findings are inconsistent. groups assigned to systematic stimulant medication
Two recent chart-review studies of children treated with showed an initial reduction in growth rate for height
stimulant medication in clinical practices in the United (j1.23 cm/year) and weight (j2.48 kg/year), which
States (Lisska and Rivkees, 2003) and Australia dissipated by the 24-month assessment. However, this
(Poulton and Cowell, 2003) have shown reductions dissipation was apparently due to differences between
in growth rates for up to 3 years without evidence of assigned and actual treatment. Changes in height and
growth rebound. In two other recent chart-review weight in naturalistic subgroups defined by consistent
studies, no evidence was found to support the treatment (i.e., with stimulant medication at both the
hypothesis that clinical treatment with stimulant 14- and 24-month assessments or no treatment at either
medications reduced the growth rates of children with assessment) revealed continued stimulant-related reduc-
ADHD (Pliszka et al., 2006; Spencer et al., 2006). tions in annual growth rates in the second year for height
However, in both of these studies, the treatment (j1.04 cm/year) and weight (j1.22 kg/year).
regimens allowed for medication holidays, so they did However, in the 24-month evaluation of growth in
not evaluate the effects of continuous treatment. A the MTA, we did not evaluate growth in terms of
recent prospective study of the initiation of methyl- normed relative size (z scores) or the effect of previous
phenidate treatment in preschool children, the Pre- treatment with stimulant medication on initial size
school ADHD Treatment Study, did evaluate effects of upon entry into the MTA. Here we focus on the
stimulant medication on growth when treatment was evaluation of the hypothesis of long-term growth
monitored frequently and was maintained for the initial slowing, this time with more rigorous methods and a
period of 1 year, and under these conditions, significant longer follow-up period than in the previous report
reductions in growth rates were documented for both (MTA Cooperative Group, 2004b).
height and weight (Swanson et al., 2006).
When the MTA was initiated (see Arnold et al., METHOD
1997) and when the initial analyses were performed (see The characteristics of the clinical sample and the general methods
MTA Cooperative Group, 1999), there was a strong of the MTA are described in previous publications (MTA
consensus (NIH Consensus Committee, 1998; Roche Cooperative Group, 1999, 2004a) and in one of the companion
papers in this issue (Jensen et al., 2007), so only a brief description is
et al., 1979) that growth suppression either was provided here. For the MTA, 579 children between 7.0 and 9.9
clinically insignificant (due to a temporary effect of years of age (80% males, 61% white, 20% African American, and
initial treatment with stimulant medication followed by 8% Hispanic) with confirmed diagnosis of ADHD Combined type
growth rebound) or was an artifact of a characteristic of were recruited from a variety of sources at seven sites in North
America and randomly assigned to one of four treatment
the clinical condition that resulted in slow growth that conditions: medication management (MedMgt), behavior therapy
was correlated with the use of stimulants but not a (Beh), the combination of these two modalities (Comb), and usual
consequence of this treatment. Based on this consensus, community care (CC). The MTA Medication Algorithm was used
to manage stimulant medications for most of the participants in the
the possible risk of stimulant-related growth suppres- MedMgt and Comb groups over the initial 14-month treatment
sion was not a consideration (e.g., it was not mentioned phase (Greenhill et al., 2001; Vitiello et al., 2001), and some
in the consent forms for the MTA), and a test of the participants in the CC (67%) and Beh (26%) received stimulant
medication from clinicians in the community. Compliance with
hypothesis of stimulant-related growth suppression was initial randomly assigned treatment conditions was not perfect
not addressed as a specific aim of the MTA. during the treatment phase, and adherence to these conditions
It is not surprising, then, that the initial evaluations of waned during the follow-up phases of the MTA, which made the
outcome emphasized characterization of long-term evaluation of actual as well as assigned treatment advisable (MTA
Cooperative Group, 2004b). A record of actual treatment was
efficacy (MTA Cooperative Group, 1999) and that the provided by parental reports on the Services for Children and
evaluation of the measures of height and weight were not AdolescentsYParent Interview (SCA-PI; Hoagwood et al., 2004;

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SWANSON ET AL.

TABLE 1
Naturalistic Subgroups Based on SCA-PI Reports of Use of Stimulant Medication
Previous 14 Mo 24 Mo 36 Mo
Not (n = 65) No Med No Med No Med No Med
Newly (n = 88)a No Med Med Med Med
Consistently (n = 70)b Med Med Med Med
Inconsistently (n = 147) 58:89 80:67 68:79 74:73
(n = 13) Med No Med No Med No Med
(n = 18) No Med Med No Med No Med
(n = 2) No Med No Med Med No Med
(n = 9) No Med No Med No Med Med
(n = 23)b No Med No Med Med Med
(n = 6)b Med Med No Med No Med
(n = 5) Med No Med Med No Med
(n = 6)b Med No Med No Med Med
(n = 18) No Med Med Med Med
(n = 19) No Med Med No Med Med
(n = 11) Med Med Med No Med
(n = 8) Med Med No Med Med
(n = 9) Med No Med Med Med
Note: SCAPI = Services for Children and Adolescents-Parent Interview.
a
One missing value for weight at baseline assessment.
b
One missing value for weight at 36-mo assessment.

Jensen et al., 2004) at each assessment, which provided information points, there are 24 patterns of medication use that define 16
to estimate how many days stimulant medication was used since the possible naturalistic subgroups at the 36-month assessment.
previous assessment and the doses administered, which were The most recent growth norms provided by the U.S. Centers for
expressed in methylphenidate equivalents for amphetamine ( 2) Disease Control and Prevention (Kuczmarski et al., 2000) were used
and pemoline ( 5), which were the other stimulants that were to transform the raw scores (centimeters and kilograms) into
available and in use during this trial. From this record, we standard scores (z height and z weight). Based on an assumption of
determined the total number of days treated and total cumulative normal size at entry to the MTA, the baseline z scores are expected
dose consumed during the study, as well as whether medication was to be near zero, and based on the assumption of normal growth rates
administered during the 30 days before each assessment. In all three during the MTA implementation of the MTA protocol, the z scores
subgroups treated with medication, the primary drug used was for height and weight are expected to remain constant over time. A
methylphenidate at all assessment points, with the percentage two-way analysis of variance, with a significance level of p < .05, was
ranging from 95.4% to 73.5%. At the baseline and 14-, 24-, and 36- used to evaluate the effects of the between group factor (naturalistic
month assessment points, respectively, the percentages of medicated subgroups), the within group factor (assessment time), and the
children taking methylphenidate were the following: consistently interaction on measures of z height and z weight.
(85.4%, 79.7%, 76.8%, and 73.5%; newly (not available, 95.4%,
93.0%, and 85.9%), and inconsistently (94.9%, 93.1%, 92.4%,
and 85.1%). RESULTS
In other publications on the MTA outcomes, two definitions of
positive medication status have been used. In the secondary analysis Complete information was obtained at each time
of changes in effectiveness and growth at the 24-month assessment, point for 370 of the 485 children in the MTA follow-
medication use during the previous 30 days (MTA Cooperative up (Jensen et al., 2007). These cases were spread across
Group, 2004b) was the criterion for positive medication status. In
the assessment of effectiveness at the 36-month assessment, the 16 possible naturalistic subgroups defined by the
medication use more than 50% of the days since the previous patterns of medication status (Med or No Med) across
assessment was the criterion for positive medication use (Jensen the four assessment points (Table 1), but were
et al., 2007; Swanson et al., 2007). To maintain consistency with
the previous article on growth (MTA Cooperative Group, 2004b),
concentrated in three of these subgroups that repre-
here we used the 30-day definition; therefore, if medication was sented consistent patterns over time: not medicated
used within a 30-day period before the assessment medication status (65 stimulant-naı̈ve children at entry who were not
was positive (Med) and otherwise negative (No Med). If an receiving stimulant medication at any assessment
individual_s medication status changed at any assessment point,
then they were placed in the inconsistently medicated group. For point), newly medicated (88 children stimulant naı̈ve
this binary designation of medication status at four assessment at entry who started stimulant medication in the MTA

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 EFFECTS OF STIMULANT MEDICATION ON GROWTH

and were receiving medication at each assessment point symptoms, sex, expected adult size (mid-parent size),
after baseline), and consistently medicated (70 children welfare status, or maternal smoking (Table 2).
receiving stimulant medication during the 30-day The analyses of variance of our measures of physical
period before entry, although the length of the previous size produced significant interactions of naturalistic
treatment was not determined, and at each assessment subgroup  assessment time (Fig. 1 and Table 3) for z
point). The other subgroups were collapsed into a single height (F 9,1083 = 3.88; p < .005) and z weight (F 9,1,068 =
group to form a fourth subgroup who were incon- 8.88; p < .0001). The overall interaction was
sistently medicated (147 children, with reports of decomposed into two orthogonal components to
medication at some but not all of the assessment points, evaluate the impact of starting medication (the not
with ratios of Med to No Med of 58:89, 80:67, 68:79, medicated versus the newly medicated subgroups) and
and 74:73, respectively, across the four assessment consistency of medication (the consistently medicated
points). At the 24-month and 36-month assessment versus the inconsistently medicated subgroups). To
points, we also obtained height and weight measures complete the set of three orthogonal comparisons, the
from 213 of the 279 classmates of the ADHD cases who third was derived from a combination of the conditions
were recruited from the local normative comparison (Not + Newly vs. Consistently + Inconsistently). This
group (LNCG), which became part of the MTA follow- decomposition of variance into nonoverlapping com-
up at the 24-month assessment point. ponents revealed that the overall interaction was due
Both randomization and self-selection operated to primarily to the starting medication component,
form these naturalistic subgroups. To check whether which accounted for 92% of the interaction for height
they differed on some relevant factors at baseline, we (F3,441 = 11.77; p < .0001) and 72.8% for weight
used the MTA database to obtain information on 26 (F3,438 = 21.76; p < .0001). The profiles shown by
child, parent, pregnancy, birth, and infant variables. dashed lines in Figure 1A (for height) and B (for
We used one-way analysis of variance to compare the weight) suggest that this effect was due to the sig-
four naturalistic subgroups on each of these variables. nificant divergence of the unmedicated clinical control
As would be expected by chance for 26 F tests, each group (the not medicated subgroup) and prospectively
with 3 and 366 df and an unadjusted significance level of medicated group (the newly medicated subgroup).
p < .05, 1 (pregnancy length) showed a small but The consistency of medication contrast was also
statistically significant between-group difference. After significant, but this was due to a main effect of group
adjustment for multiple tests (0.05/26 = 0.002), none of without an interaction with assessment time. At the
these tests were statistically significant. It is notable that baseline assessment, the consistently medicated sub-
the four subgroups did not differ on initial size at birth group was smaller than the inconsistently medicated
(birth weight), age, parent or teacher ratings of ADHD subgroup, and this difference was maintained over time,

TABLE 2
Baseline Demographic and Clinical Variables Across the Four Naturalistic Medication Subgroups
ANOVA With 3 df (Group) and 369 df (Error) Not Newly Inconsistently Consistently p
Child variables
Birth weight, kg 3.42 3.35 3.30 3.46 .0990
Age at baseline, y 7.94 7.75 7.91 8.04 .8449
SNAP parent compositea 1.91 1.92 2.00 2.04 .5060
SNAP teacher compositea 1.87 1.89 1.91 2.08 .4840
Sex, % male 74 74 78 90 .0580
Parent variables
Parent average height z score 0.17 0.28 0.20 0.24 .6155
% Welfare 15.38 13.64 17.81 8.57 .3426
% Mother smoked during pregnancy 18.52 32.10 33.33 16.05 .2362
Note: ANOVA = analysis of variance; SNAP = Swanson, Nolan, and Pelham.
a
SNAP composites were ratings in unmedicated state of 18 DSM-IV attention-deficit/hyperactivity disorder symptoms on 0Y3 metric.

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SWANSON ET AL.

as shown by the parallel profiles for these two subgroups Using information from the SCAPI, we estimated
for both height and weight (see solid lines in Fig. 1A, B). the number of days treated with stimulant medication
In Figure 1C the average SNAP scores for the four and the ending milligrams/kilogram dose of stimulant
naturalistic subgroups are presented to provide infor- medication (in methylphenidate equivalents) for each
mation on the effectiveness of treatment along with the child. Regression analyses were used to relate these
information on effects related to growth presented in measures to relative size at the 36-month assessment.
Figure 1A (for height) and B (for weight). In the The fitted equations had negative slopes indicating sig-
companion articles (Jensen et al., 2007; Swanson et al., nificant exposure-related reduction in relative height
2007), the effects of actual as well as assigned (z height 0.589 Y 0.218[years of treatment], F1,369 =
medication status over time were addressed in detail, 19.18; p 9 .0001) and relative weight (z weight 0.776 Y
with different methods (e.g., time-varying covariates), 0.183[years of treatment], F1,365 = 12.68; p < .0004)
and at the 36-month assessment, there were no group and significant dose-related reduction in relative
differences apparent. The analysis of this measure of height (z height 0.493 j 0.0117[mg/kg], F1,365 =
effectiveness for the naturalistic subgroups confirms the 11.04; p .0010) but not relative weight (z weight
results reported in the companion articles. 0.547 j 0.0045[mg/kg], F1,365 = 1.34; p 9 .2486).

Fig. 1 Profiles for the naturalistic subgroup  assessment time interaction, showing standardized measures of size (z height [A] and z weight [B]) and efficacy
(average SNAP ratings [C]) for the four subgroups formed on the basis of history of medication use before entry into the MTA (baseline), at the end of the MTA
treatment phase (14 months), at the first follow-up (24 months) and at the second follow-up (36 months). LNCG = local normative comparison group; SNAP =
Swanson, Nolan, and Pelham.

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 EFFECTS OF STIMULANT MEDICATION ON GROWTH

TABLE 3
Means, SDs, and SEs for the Naturalistic Subgroups
Base 14 Mo 24 Mo 36 Mo
No. Mean SD SE Mean SD SE Mean SD SE Mean SD SE
Height z score
Not med 65 0.357 0.892 0.111 0.415 0.870 0.108 0.491 0.913 0.113 0.541 0.894 0.111
Newly 88 0.178 1.12 0.119 0.072 1.08 0.115 0.0435 1.11 0.118 0.0725 1.09 0.116
Incons 147 0.239 1.02 0.084 0.248 1.02 0.084 0.282 1.12 0.092 0.310 1.05 0.087
Consis 70 j0.140 0.905 0.108 0.165 0.905 0.108 j0.159 1.04 0.124 j0.12 0.894 0.107
LNCG 260 0.229 0.945 0.014 0.234 0.924 0.015
Weight z score
Not med 65 0.617 0.915 0.113 0.621 0.954 0.118 0.652 0.975 0.121 0.756 1.01 0.125
Newly 88 0.616 0.999 0.106 0.113 1.14 0.122 0.181 1.09 0.116 0.293 1.15 0.123
Incons 147 0.430 1.05 0.087 0.311 1.16 0.096 0.35 1.21 0.100 0.519 1.25 0.103
Consis 70 0.312 0.999 0.119 0.037 1.05 0.125 0.071 1.03 0.123 0.156 1.200 0.143
LNCG 259 0.427 1.04 0.026 0.425 1.07 0.026
SNAP
Not med 39 1.66 0.406 0.050 1.04 0.565 0.070 1.08 0.508 0.063 1.01 0.545 0.068
Newly 63 1.87 0.424 0.045 0.811 0.509 0.054 1.02 0.521 0.056 1.12 0.555 0.059
Incons 106 1.76 0.398 0.033 1.10 0.524 0.043 1.16 0.497 0.041 1.09 0.516 0.043
Consis 55 1.92 0.405 0.048 1.04 0.410 0.049 1.19 0.427 0.051 1.10 0.382 0.046
LNCG 251 0.444 0.945 0.028 0.38 0.924 0.024

Note: Not med = not medicated; LNCG = local normative comparison group; Newly = newly medicated; Incons = inconsistently medicated;
Consis = consistently medicated; SNAP = Swanson, Nolan, and Pelham Rating Scale.

At the 36-month assessment, the average relative size 529 mg), inconsistently medicated (603 days and
(z height and z weight) of the naturalistic subgroups 16,183 mg), newly medicated (983 days and 31,797 mg),
were negatively related to the average cumulative and consistently medicated (1,022 days and 33,576 mg).
exposure to stimulant medication. As shown in Figure The stimulant-untreated clinical control group was
2 the totals for the naturalistic subgroups, which were taller and heavier than average (not medicated: z height
formed using the 30-day criteria at each assessment 0.541 and z weight 0.765), whereas the two groups
point, varied as expected: not medicated (28 days and that were medicated for about 1,000 days and received

Fig. 2 Size (z height and z weight) at the 36-month assessment time point for the four naturalistic subgroups that differed in exposure (total milligrams and total
number of days) to stimulant medication in the MTA. LNCG = local normative comparison group.

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:8, AUGUST 2007 1021

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SWANSON ET AL.

930,000 mg methylphenidate over the 3 years of the in terms of growth velocity after initiating medication
MTA follow-up were just slightly above or below revealed the time course of stimulant-related reduction
expected relative size based on norms (newly medi- in annual growth rate, which was maximal in the first
cated: z height 0.073 and z weight 0.293; consistently year, decreased in the second year, and absent in the
medicated: z height j0.120 and z weight 0.156) and third year of treatment.
well below the average relative height and weight of We did not document a decrease in relative size in
the LNCG. the group of participants with a history of treatment
The average population SDs for 7- to 12-year-old before entry into the MTA protocol during subsequent
children, 6.5 cm for height and 5.5 kg for weight, treatment with stimulant medication over the 3 years.
were used to transform the average z scores at the 36- However, this group (the consistently medicated
month assessment into absolute units (centimeters naturalistic subgroup) was smaller than the stimulant-
and kilograms) for comparisons to the stimulant- naı̈ve group (the newly medicated naturalistic sub-
untreated clinical control group as well as the group) at entry, suggesting that early treatment of
classmate nonclinical control group. These compar- children (before the ages of 7Y9 years) with stimulant
isons revealed that the newly medicated subgroup medication may have produced a reduction of growth
(which had been only 1.1 cm shorter than the not rate before entry into the MTA protocol. Of course,
medicated group at baseline) was at 36 months 3.04 other possibilities exist, such as selective early treatment
cm shorter and 2.71 kg lighter than the not of individuals who are smaller than normal. Similarly,
medicated subgroup and 1.1 cm shorter and 0.7 kg the participants without continuous treatment with
lighter than the LNCG. The consistently medicated stimulant medication (the inconsistently medicated
subgroup was 2.3 cm shorter and 1.5 kg lighter than subgroup) did not manifest a decrease in relative size
the LNCG and 4.21 cm shorter and 3.51 kg lighter during the MTA protocol but was slightly smaller at
than the not medicated subgroup. baseline and did not increase in relative size as much as
the not medicated group over the 3-year follow-up. By
the 36-month assessment, this subgroup was signifi-
DISCUSSION
cantly smaller than the stimulant-untreated clinical
The MTA provides an excellent opportunity to control group (not medicated), even though it was
address two key methodological issues in the literature nominally larger than the LNCG. The definition of
that were identified by Spencer et al. (1996), who inconsistent treatment here was not based on a
recommended Bto differentiate disorder from treatment- systematic variation of planned medication holidays
related growth effects, studies must compare treated on the weekend or in summer as in some previous
children with ADHD with untreated children, and not studies (Gittelman-Klein et al., 1988; Safer et al., 1975;
with unaffected control subjects,[ and that this Bshould Satterfield et al., 1979).
be evaluated in future longitudinal studies.[ Our findings do not support the hypothesis of
In this prospective longitudinal study of school-age growth rebound when treatment is continued, as
children with diagnoses of ADHD Combined type, one suggested by Satterfield et al. (1979). The newly
of the naturalistic self-selected subgroups (derived medicated subgroup manifested a slight increase in
largely from those randomly assigned to Beh) provided relative size from the 24- to 36-month assessment. This
a stimulant-untreated clinical control group. Compared suggests an increase in growth rate to a level that is
to this not medicated subgroup, we documented a greater than expected based on population norms,
significant stimulant-related decrease in growth rate in which may be interpreted as growth rebound. However,
the newly medicated subgroup consisting of initially the stimulant-untreated clinical control (the not
stimulant-naı̈ve individuals (at least for 30 days before medicated subgroup) also showed a similar increase in
entering the study) for whom treatment was initiated relative size across this time frame. To support the
and maintained for 3 years of the MTA protocol. These hypothesis of growth rebound, the growth rates of the
subgroups did not differ in severity of ADHD stimulant-treated groups would have to exceed that of
symptoms or initial relative size at the baseline the stimulant-untreated clinical control group, which
assessment. The comparison of these two subgroups did not occur in this study. We did not include a

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 EFFECTS OF STIMULANT MEDICATION ON GROWTH

randomized withdrawal of medication, which would evaluated here. Instead, these naturalistic subgroups
have provided a test of the growth rebound hypothesis were formed partially by the assignment to the initial
(greater than normal growth velocity for a time after treatment conditions provided in the MTA protocol
medication is stopped) that was suggested by Safer et al. with (MedMgt and Comb) and without (Beh)
(1975). stimulant medication, and then by choices over time
Similarly, our findings do not support the hypothesis to start, stop, or continue the use of stimulant
of delayed maturation in children with ADHD. At medication. These decisions depended on the assigned
entry into the MTA, the height and weight of treatment group. Unless the assignment to a condition
stimulant-naı̈ve 7.0- to 9.9-year-old children were that included medication was refused, the only way to
greater than expected (rather than smaller as would be be in the Bnever medicated[ group was to enter
predicted by delayed maturation). For those left stimulant naı̈ve and be assigned to Beh or be in the
untreated with stimulant medication, the growth rate minority of CC children who were not medicated.
over the next 3 years was greater as opposed to less than Thus, the never-medicated group was determined more
that of the LNCG (the classmate control group) or the by original randomization than the other three
population norms. This is an important new finding naturalistic groups, which were compatible with assign-
from the MTA, suggesting a disorder-related acceler- ment to any of the four groups (Comb, MedMgt, CC,
ated rather than delayed maturation. even Beh if nonprotocol medication was taken before
Basic science research collaborators with expertise 14 months). Self-selection for the never medicated
in the neurotransmitter dopamine in multiple group was passive, amounting to not starting medica-
pathways at multiple levels of analysis (Bosse et al., tion, whereas for the other three groups, self-selection
1997; Posner and Raichle, 1994; Volkow et al., would require taking action by continuing, starting, or
2002) suggested how the mechanism of action of stopping medication. Furthermore, the self-selection to
stimulant medications may affect growth. Studies stay not medicated was based largely on satisfactory
using positron emission tomography show that results with the assigned behavioral treatment, whereas
clinical doses of methylphenidate in adults (Volkow decisions to continue or start medication were not
et al., 2002) and adolescents (Neto et al., 2002) necessarily based on satisfaction with treatment results.
increased (rather than decreased, as proposed by At 14 months 26% of Beh subjects had found it
some theories) extrasynaptic levels of dopamine in necessary to add nonprotocol medication because Beh
the striatum due to potent blockade of dopamine alone was not sufficient treatment, and more than half
transporters, but with a time course that minimized of those had taken medication 950% of the time from
the reinforcing (euphoric) effects accompanying baseline. These subjects were counted in a medicated
intravenous doses (Volkow et al., 1999). Studies of group for purpose of the analyses presented here, which
mice (Bosse et al., 1997) that lack the dopamine may have weeded out the worst treatment responders
transporter show that high levels of dopamine occur and more serious cases from the never-medicated
in the hypothalamus as well as the striatum. The group. Thus, it is possible that the never-medicated
excess dopamine is dispersed by blood flow, reaches group was pared down to good responders and the
the pituitary, and retards growth in these animals. medicated groups enriched with poor Beh responders.
Caron (2004) summarized this converging informa- These limitations of the naturalistic medication groups
tion from basic science studies and speculated that a must be kept in mind when attempting to interpret
common synaptic mechanism (dopamine transporter Figure 1c, which suggests lack of effectiveness for
blockade and increased dopamine levels) in different stimulant medication at the 36-month assessment in
brain regions (hypothalamus and striatum) may the presence of lingering but significant stimulant-
mediate side effects (reduction in growth rate) as related reduction in growth rate.
well as efficacy (symptom reduction). Another serious limitation is the length of the follow-
up reported here, which covered only 3 years after the
Limitations
initiation of treatment in the MTA protocol. Because
The most important limitation of this study is the the participants in the study entered between the ages
lack of random assignment to the subgroups that were of 7 and 9 years, they were between the ages of 10 to

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SWANSON ET AL.

12 years when the 36-month assessments were classifications by medication have been considered as
performed. Subsequent reports of the continued well, as in the naturalistic subgroups described here and
follow-up of the MTA sample will provide assessment in previous publications on the findings of the MTA
after puberty, in adolescence, and eventually in follow-up. Also, other definitions are possible and some
adulthood. These assessments will allow evaluation of have been considered here (i.e., total exposure in terms
the impact of childhood treatment on ultimate size, of milligrams consumed or days treated), but the specific
which is not addressed in this report. contributions of dose or consistency of medication use
A third major limitation of this study is that only one have not been adequately evaluated.
stimulant medication (methylphenidate) and one A fifth limitation was the lack of evaluation of
formulation (immediate release) of stimulant medica- planned medication holidays on the weekends or
tion were systematically evaluated. The MTA imple- during the summer, as some guidelines have proposed.
mented state-of-the-art treatment in the early 1990s For example, the use of summer (or periodic) holidays,
and used an immediate-release formulation of methyl- which represent relatively long intervals of nontreat-
phenidate (Ritalin, which then was prescribed for most ment interspersed within blocks of medication use in
cases when stimulant medication was used to treat clinical practice, has been proposed as a strategy to
children with ADHD (Arnold et al., 1997; Greenhill mitigate stimulant-related reductions in growth rates
et al., 2001; MTA Cooperative Group, 2004b). (Safer et al., 1975), but this was not evaluated in the
However, in 1998, 4 years after the initiation of present analyses. In two recent studies (Pliszka et al.,
the MTA, another stimulant, the 75:25 ratio of 2006; Spencer et al., 2006) in which drug holidays were
D,L - amphetamine (once used for weight control allowed but were not systematically varied, stimulant-
[Obetrol]) was renamed Adderall and was evaluated related reductions in growth rates were not documen-
for the treatment of ADHD. Adderall was shown to be ted. This and other unspecified factors still must be
effective in a double-blind study (Swanson et al., 1998) considered to understand the effects of stimulant
and soon after became widely used in clinical practice. medication on growth rates.
Because Adderall was not available when the MTA was
initiated, its effect was not evaluated and thus could not Clinical Implications
be reported here. Also, after 2000, controlled-release for-
mulations of both methylphenidate (Concerta: Swanson The practice parameter of the American Academy of
et al., 1999, 2000, 2003; Wolraich et al., 2001; Metadate Child and Adolescent Psychiatry (2002) regarding the
CD: Greenhill et al., 2002; Swanson et al., 2004; Wigal use of stimulant medication (presently under revision)
et al., 2003; Ritalin LA: Biederman et al., 2003) and suggests that height and weight be measured before
amphetamine (Adderall SR; Greenhill et al., 2001; initiating treatment (p 28S), and for the management
McCracken et al., 2003) were developed and became of possible treatment-related side effects recommends
widely used in clinical practice, rapidly replacing the the regular assessment of weight (but not height) as a
prescription of multiple daily doses of immediate- Bclinical guideline[ but not as a Bminimal standard[
release stimulant medications for the treatment of (p 29S). During the first two stages of treatment to
ADHD. Because these controlled-release formulations titrate dose and select among alternative stimulants,
were not available or used when the MTA was initiated weekly to monthly monitoring of both height and
or during the initial two follow-up phases, they were weight is suggested (Table 2, p 38S), but recommenda-
not evaluated and could not be reported here. Thus, the tions for long-term monitoring are not explicitly
findings here strictly apply to the immediate-release provided. In the section on Bcomplications and side
formulation of methylphenidate. effects[ (p 44S), the prevailing view is stated, indicating
A fourth limitation was the definition of medication that the literature supports short-term decrements in
use based on information from the SCA-PI. Two rate of weight acquisition but not height acquisition,
different definitions of medication use have been and no long-term effect on ultimate height.
considered for the MTA analyses of efficacy (i.e., within The findings reported here from the prospective
30 days before an assessment and 50% of the days since MTA follow-up suggest that short-term (up to 2 years)
the previous assessment), and consistency of these effects on height as well as weight may occur when

1024 J. AM. ACAD. CH ILD ADOLESC. PSYCHIAT RY, 46:8, AUGUST 2007

Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
 EFFECTS OF STIMULANT MEDICATION ON GROWTH

initiating treatment in stimulant-naı̈ve school-age University), Jeffrey H. Newcorn, M.D. (Mount Sinai School of
Medicine), Mark Davies (New York State Psychiatric Institute);
children with ADHD Combined type. This conclusion University of Pittsburgh: William E. Pelham, Ph.D. (currently at
is based on two opposing patterns of growth in the State University of New York, Buffalo), Betsy Hoza, Ph.D.
MTA: greater than expected annual growth rates in the (currently at University of Vermont, Burlington), Brooke Molina,
Ph.D. Original statistical and trial design consultant: Helena C.
subgroup of ADHD children who were not treated with Kraemer, Ph.D. (Stanford University). Follow-up phase statistical
stimulant medication and smaller than expected annual collaborators: Robert D. Gibbons, Ph.D. (University of Illinois,
growth rates in the subgroup of ADHD children who Chicago), Sue Marcus, Ph.D. (Mount Sinai School of Medicine),
Kwan Hur, Ph.D. (University of Illinois, Chicago). Collaborator
were continuously treated. This difference in annual from the Office of Special Education Programs/U.S. Department of
growth rates may be present for up to 3 years of Education: Thomas Hanley, Ed.D. Collaborator from Office
treatment and accumulate to result in a difference of of Juvenile Justice and Delinquency Prevention/Department of
Justice: Karen Stern, Ph.D. Non-MTA collaborators were Marc
about 2.0 cm in height and about 2.0 kg in weight. Caron, Ph.D. (Duke University), and Nora D. Volkow (National
The finding of a reduction in growth rate in height that Institute of Drug Abuse and Brookhaven National Laboratory).
extends up to 3 years is consistent with two recent
retrospective reviews of clinical charts (Lisska and
Disclosure: During the course of the MTA, since 1992: Dr. Swanson has
Rivkees, 2003; Poulton and Cowell, 2003), but not received research support from Alza, Richwood, Shire, Celgene,
with two others (Pliszka et al., 2006; Spencer et al., Novartis, Celltech, Gliatech, Cephalon, Watson, CIBA, Janssen, and
2006). Despite this inconsistency across chart-review McNeil; has been on the advisory board of Alza, Richwood, Shire,
Celgene, Novartis, Celltech, UCB, Gliatech, Cephalon, McNeil, and
studies, the finding from the prospective study of school- Eli Lilly; has been on the speakers_ bureaus of Alza, Shire, Novartis,
age children reported here as well as in a prospective study Celltech, UCB, Cephalon, CIBA, Janssen, and McNeil; and has
of preschool children (Swanson et al., 2006) may provide consulted to Alza, Richwood, Shire, Celgene, Novartis, Celltech, UCB,
enough evidence to consider revision of clinical practice Gliatech, Cephalon, Watson, CIBA, Janssen, McNeil, and Eli Lilly.
Dr. Elliott has received research funding from Cephalon, McNeil,
parameters to acknowledge the possibility of stimulant- Shire, Sigma Tau, and Novartis; has consulted to Cephalon and
related slowing in the usual developmental gains in height McNeil; and has been on the speakers_ bureaus of Janssen, Eli Lilly, and
as well as weight during the course of treatment of McNeil. Dr. Greenhill has received research funding or has been on the
speakers_ bureaus of Eli Lilly, Alza, Shire, Cephalon, McNeil, Celltech,
prepubertal children with ADHD. Novartis, Sanofi Aventis, Otsuka, and Janssen. Dr. Wigal has received
research funding from Eli Lilly, Shire, Novartis, and McNeil, and has
been on the speakers_ bureaus of McNeil and Shire. Dr. Arnold has
The Multimodal Treatment Study of Children with ADHD (MTA) received research funding from Celgene, Shire, Noven, Eli Lilly,
was a National Institute of Mental health (NIMH) cooperative Targacept, Sigma Tau, and Novartis; has consulted to Shire, Noven,
agreement randomized clinical trial involving six clinical sites. Sigma Tau, Ross, and Organon; and has been on the speakers_ bureaus
Collaborators from the National Institute of Mental Health: Peter S. of Abbott, Shire, McNeil, and Novartis. Dr. Vitiello has consulted to
Jensen, M.D. (currently at Columbia University, New York), L. Richwood Pharmaceuticals. Dr. Hechtman has received research
Eugene Arnold, M.D., M.Ed. (currently at Ohio State University), funding from the National Institute of Mental Health, Eli Lilly,
Joanne B. Severe, M.S. (Clinical Trials Operations and Biostatistics GlaxoSmithKline, Janssen-Ortho, Purdue Pharma, and Shire; has been
Unit, Division of Services and Intervention Research), Benedetto on the speakers_ bureaus of the National Institute of Mental Health, Eli
Vitiello, M.D. (Child and Adolescent Treatment and Preventive Lilly, Janssen-Ortho, and Shire; and has been on the advisory boards of
Interventions Research Branch), Kimberly Hoagwood, Ph.D. Eli Lilly, Janssen-Ortho, Purdue Pharma, and Shire. Dr. Epstein has
(currently at Columbia University); previous contributors from received research funding from McNeil, Shire, Eli Lilly, and Novartis;
NIMH to the early phase: John Richters, Ph.D. (currently at has been on the advisory board of Shire; and has been on the speakers_
National Institute of Nursing Research); Donald Vereen, M.D. bureaus of Shire and McNeil. Dr. Pelham has received research funding
(currently at National Institute on Drug Abuse). Clinical sites and from Alza, Shire, Noven, Eli Lilly, and Cephalon; has served on
principal investigators and co-investigators are University of advisory boards or has consulted to Alza/McNeil Richwood/Shire,
California, Berkeley/San Francisco: Stephen P. Hinshaw, Ph.D. Noven, Eli Lilly, Cephalon, Novartis, Celgene, and Abbott; and has
(Berkeley), Glen R. Elliott, M.D., Ph.D. (San Francisco); Duke been on the speakers_ bureaus of Shire, and McNeil. Dr. Abikoff has
University: C. Keith Conners, Ph.D., Karen C. Wells, Ph.D., John received research funding from McNeil, Shire, Eli Lilly, and Bristol-
March, M.D., M.P.H., Jeffrey Epstein, Ph.D.; University of Myers Squibb; has consulted to McNeil, Shire, Eli Lilly, Pfizer,
California, Irvine/Los Angeles: James Swanson, Ph.D. (Irvine), Celltech, Cephalon, and Novartis; and has been on the speakers_
Dennis P. Cantwell, M.D. (deceased, Los Angeles), Timothy Wigal, bureaus of McNeil, Shire, and Celltech. Dr. Newcorn has received
Ph.D. (Irvine), Annamarie Stehli, M.P.H. (Irvine); Long Island research funding from or has been on the speakers_ bureaus of Eli Lilly,
Jewish Medical Center/Montreal Children_s Hospital: Howard B. Alza, Shire, Celgene, McNeil, Celltech/UCB, Novartis, Sanofi Aventis,
Abikoff, Ph.D. (currently at New York University School of Janssen, and Bristol-Myers Squibb. Dr. Hinshaw has consulted to
Medicine), Lily Hechtman, M.D. (McGill University, Montreal); Noven and Sigma Tau and has been on the speakers_ bureau of McNeil.
New York State Psychiatric Institute/Columbia University/Mount Dr. Hoza has received research funding from MediaBalance, Inc., and
Sinai Medical Center: Laurence L. Greenhill, M.D. (Columbia has received support for educational conferences from Abbott

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:8, AUGUST 2007 1025

Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
SWANSON ET AL.

Laboratories. Dr. Jensen has received research funding from McNeil Kramer JR, Loney J, Ponto LB, Roberts MA, Grossman S (2000), Predictors
and unrestricted grants from Pfizer; has consulted to Best Practice, Inc., of adult height and weight in boys treated with methylphenidate for
Shire, Janssen, Novartis, and UCB; and has been on the speakers_ childhood behavior problems. J Am Acad Child Adolesc Psychiatry 39:
bureaus of Janssen-Ortho, Alza, McNeil, UCB, CME Outfitters, and 517Y524
Kuczmarski RJ, Ogden CL, Grummer-Steawn LM et al. (2000), Advance
the Neuroscience Education Institute. Dr. March has been a consultant data 314,1Y27. Available at: http://www.cdc.gov/growthcharts
or scientific advisor to or received research funding from Eli Lilly, Lisska MC, Rivkees SA (2003), Daily methylphenidate use slows the growth
Pfizer, Wyeth, Jazz, MedAvante, Shire, Cephalon, Organon, McNeil, of children in a community sample. J Pediatr Endocrinol Metab 16:
and AstraZeneca; serves on a DSMB for Organon, Johnson & Johnson, 711Y718
and AstraZeneca; and holds stock in MedAvante. Dr. Conners has Loney J, Kramer J, Milich R (1981), The hyperactive child grows up:
received research funding from Celgene, Shire, Noven, Eli Lilly, predictors of symptoms, delinquency, and achievement at follow-up. In:
Targacept, and Novartis; has consulted to Celgene, Shire, Novartis, Psychosocial Aspects of Drug Treatment for Hyperactivity, Gadow K,
Alza, and Noven; is on the Eli Lilly Advisory Committee, and has been Loney J, eds. Boulder, CO: Westview, pp 381Y415
on the speakers_ bureaus of Shire, McNeil, and Novartis. Dr. Caron has Mattes JA, Gittelman R (1983), Growth of hyperactive children on main-
tenance regimen of methylphenidate. Arch Gen Psychiatry 40:317Y321
received research funding from and has consulted to Lundbeck, has been
McCracken JT, Biederman J, Greenhill LL et al. (2003), Analog classroom
on the Scientific Advisory Board of Acadia Pharmaceutical, and has assessment of a once-daily mixed amphetamine formulation, SLI381
had an unrestricted grant from Bristol-Myers Squibb. Dr. Volkow has (Adderall XR), in children with ADHD. J Am Acad Child Adolesc
received research funding from GlaxoSmithKline. The other authors Psychiatry 42:673Y683
have no financial relationships to disclose. Molina B, Flory K, Hinshaw SP et al. (2007), Delinquent behavior and
emerging substance use in the MTA at 36 months: prevalence, course,
and treatment effects for the MTA Cooperative group. J Am Acad Child
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