Research

JAMA Psychiatry | Original Investigation

Attention-Deficit/Hyperactivity Disorder Medications

and Long-Term Risk of Cardiovascular Diseases
Le Zhang, PhD; Lin Li, PhD; Pontus Andell, MD, PhD; Miguel Garcia-Argibay, PhD; Patrick D. Quinn, PhD;
Brian M. D’Onofrio, PhD; Isabell Brikell, PhD; Ralf Kuja-Halkola, PhD; Paul Lichtenstein, PhD;
Kristina Johnell, PhD; Henrik Larsson, PhD; Zheng Chang, PhD

Editorial page 123

IMPORTANCE Use of attention-deficit/hyperactivity disorder (ADHD) medications has Supplemental content
increased substantially over the past decades. However, the potential risk of cardiovascular
disease (CVD) associated with long-term ADHD medication use remains unclear.

OBJECTIVE To assess the association between long-term use of ADHD medication and the risk
of CVD.

DESIGN, SETTING, AND PARTICIPANTS This case-control study included individuals in Sweden
aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication
dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD
diagnoses and ADHD medication dispensation were obtained from the Swedish National
Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included
individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases,
cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease,
arterial disease, and other forms of heart disease). Incidence density sampling was used to
match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases
and controls had the same duration of follow-up.

EXPOSURE Cumulative duration of ADHD medication use up to 14 years.

MAIN OUTCOMES AND MEASURES The primary outcome was incident CVD. The association
between CVD and cumulative duration of ADHD medication use was measured using
adjusted odds ratios (AORs) with 95% CIs.

RESULTS Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were
identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with
51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601
males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer
cumulative duration of ADHD medication use was associated with an increased risk of CVD
compared with nonuse (0 to ⱕ1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ⱕ2 years: AOR,
1.09 [95% CI, 1.01-1.18]; 2 to ⱕ3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ⱕ5 years: AOR, 1.27
[95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD
medication use was associated with an increased risk of hypertension (eg, 3 to ⱕ5 years:
AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease
(eg, 3 to ⱕ5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]).
Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated
with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk
in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the
remaining follow-up. Similar patterns were observed in children and youth (aged <25 years)
and adults (aged ⱖ25 years).

CONCLUSIONS AND RELEVANCE This case-control study found that long-term exposure to
ADHD medications was associated with an increased risk of CVDs, especially hypertension
and arterial disease. These findings highlight the importance of carefully weighing potential Author Affiliations: Author
affiliations are listed at the end of this
benefits and risks when making treatment decisions about long-term ADHD medication use.
article.
Clinicians should regularly and consistently monitor cardiovascular signs and symptoms
Corresponding Authors: Zheng
throughout the course of treatment. Chang, PhD ([email protected]) and
Le Zhang, PhD ([email protected]),
Department of Medical Epidemiology
and Biostatistics, Karolinska
JAMA Psychiatry. 2024;81(2):178-187. doi:10.1001/jamapsychiatry.2023.4294 Institutet, Nobels väg 12A, 171 65
Published online November 22, 2023. Stockholm, Sweden.

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 ADHD Medications and Long-Term Risk of Cardiovascular Diseases Original Investigation Research

A
ttention-deficit/hyperactivity disorder (ADHD) is a com-
mon psychiatric disorder characterized by develop- Key Points
mentally inappropriate inattentiveness, impulsivity,
Question Is long-term use of attention-deficit/hyperactivity
and hyperactivity.1,2 Pharmacological therapy, including both disorder (ADHD) medication associated with an increased risk of
stimulants and nonstimulants, is recommended as the first- cardiovascular disease (CVD)?
line treatment for ADHD in many countries.1,3 The use of ADHD
Findings In this case-control study of 278 027 individuals in
medication has increased greatly in both children and adults
Sweden aged 6 to 64 years who had an incident ADHD diagnosis
during the past decades.4 Although the effectiveness of ADHD or ADHD medication dispensation, longer cumulative duration of
medications has been demonstrated in randomized clinical ADHD medication use was associated with an increased risk of
trials (RCTs) and other studies,5,6 concerns remain regarding CVD, particularly hypertension and arterial disease, compared with
their potential cardiovascular safety.7 Meta-analyses of RCTs nonuse.
have reported increases in heart rate and blood pressure as- Meaning Findings of this study suggest that long-term exposure
sociated with both stimulant and nonstimulant ADHD to ADHD medications was associated with an increased risk of
medications.5,7-9 CVD; therefore, the potential risks and benefits of long-term
As RCTs typically evaluate short-term effects (average ADHD medication use should be carefully weighed.
treatment duration of 75 days),7 it remains uncertain whether
and to what extent the increases in blood pressure and heart
rate associated with ADHD medication lead to clinically
significant cardiovascular disease (CVD) over time. Longitu- Methods
dinal observational studies10-12 examining the association be-
tween ADHD medication use and serious cardiovascular out- Data Sources
comes have emerged in recent years, but the findings have been We used data from several Swedish nationwide registers linked
mixed. A meta-analysis13 of observational studies found no sta- through unique personal identification numbers.18 Diagnoses
tistically significant association between ADHD medication were obtained from the National Inpatient Register,19 which con-
and risk of CVD. However, the possibility of a modest risk tains data on inpatient diagnoses since 1973 and outpatient di-
increase cannot be ruled out due to several methodological agnoses since 2001. Information on prescribed medications was
limitations in these studies, including confounding by indi- retrieved from the Swedish Prescribed Drug Register, which con-
cation, immortal time bias, and prevalent user bias. Addi- tains all dispensed medications in Sweden since July 2005 and
tionally, most of these studies had an average follow-up includes information on drug identity based on the Anatomi-
time of no more than 2 years.13,14 Thus, evidence regarding cal Therapeutic Chemical (ATC) classification,20 dispensing
the long-term cardiovascular risk of ADHD medication use dates, and free-text medication prescriptions. Socioeconomic
is still lacking. factors were obtained from the Longitudinal Integrated Data-
Examining the long-term cardiovascular risk associated base for Health Insurance and Labour Market studies.21 Infor-
with ADHD medicine use is clinically important given that in- mation on death was retrieved from the Swedish Cause of Death
dividuals with a diagnosis of ADHD, regardless of whether they Register,22 which contains information on all deaths since 1952.
receive treatment, face an elevated risk of CVD.15 Addition- The study was approved by the Swedish Ethical Review Author-
ally, a substantial proportion of young individuals with ADHD ity. Informed patient consent is not required for register-based
continues to have impairing symptoms in adulthood,16 neces- studies in Sweden. The study followed the Reporting of Stud-
sitating prolonged use of ADHD medication. Notably, studies ies Conducted Using Observational Routinely Collected Health
have indicated a rising trend in the long-term use of ADHD Data–Pharmacoepidemiological Research (RECORD-PE)
medications, with approximately half of individuals using guideline.23
ADHD medication for over 5 years.17 Furthermore, evidence
is lacking regarding how cardiovascular risk may vary based Study Design
on factors such as type of CVD, type of ADHD medication, age, We conducted a nested case-control study of all individuals
and sex.13 Therefore, there is a need for long-term follow-up residing in Sweden aged 6 to 64 years who received an inci-
studies to address these knowledge gaps and provide a more dent diagnosis of ADHD or ADHD medication dispensation15
comprehensive understanding of the cardiovascular risks as- between January 1, 2007, and December 31, 2020. The diag-
sociated with ADHD medication use. This information is also nosis of ADHD (International Statistical Classification of Dis-
crucial from a public health perspective, particularly due to the eases and Related Health Problems, Tenth Revision [ICD-10] code
increasing number of individuals receiving ADHD medica- F90) was identified from the National Inpatient Register. In-
tions worldwide.4 cident ADHD medication dispensation was identified from the
This study aimed to assess the association between cu- Swedish Prescribed Drug Register and was defined as a dis-
mulative use of ADHD medication up to 14 years and the risk pensation after at least 18 months without any ADHD medi-
of CVD by using nationwide health registers in Sweden. We hy- cation dispensation.24 Baseline (ie, cohort entry) was defined
pothesized that longer cumulative use of ADHD medication as the date of incident ADHD diagnosis or ADHD medication
would be associated with increased CVD risk. In addition, we dispensation, whichever came first. Individuals with ADHD
aimed to examine whether the associations differ across types medication prescriptions for indications other than ADHD25
of ADHD medication, types of CVD, sex, and age groups. and individuals who emigrated, died, or had a history of CVD

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 Research Original Investigation ADHD Medications and Long-Term Risk of Cardiovascular Diseases

Sweden during the study period, including stimulants (meth-

Figure 1. Selection of Cases and Matched Controls
ylphenidate [ATC code N06BA04], amphetamine [ATC code
N06BA01], dexamphetamine [ATC code N06BA02], and lis-
278 027 Individuals aged 6-64 y with incident diagnosis of
ADHD or ADHD medication dispensation, 2007-2020 dexamfetamine [ATC code N06BA12]) as well as nonstimu-
lants (atomoxetine [ATC code N06BA09] and guanfacine [ATC
19 192 Excluded code C02AC02]). Duration of ADHD medication use was de-
7097 With previous CVD diagnosis
9111 Emigrated before baseline rived from a validated algorithm that estimates treatment du-
2976 Used ADHD medication for ration from free text in prescription records.25 The cumula-
other indication
8 Died on day of or before tive duration of ADHD medication use was calculated by
baseline summing all days covered by ADHD medication between
baseline and 3 months prior to the index date. The last 3
258 835 Met inclusion criteria
months before the index date were excluded to reduce
reverse causation, as clinicians’ perception of potential car-
10 842 With CVD diagnosis diovascular risks may influence ADHD medication prescrip-
tion. This time window was chosen because routine psychiat-
448 With follow-up ≤3 mo excluded ric practice in Sweden limits a prescription to a maximum 3
months at a time.27 Individuals with follow-up of less than 3
10 394 With CVD without Controlsa matched 5:1 to cases months were excluded.
emigration records

6 Without any matched control Statistical Analysis

We conducted conditional logistic regression analyses to
10 388 With CVD (cases) analyzed 51 672 Without CVD (controls) estimate odds ratios (ORs) for the associations between cu-
mulative durations of ADHD medication use and incident
ADHD indicates attention-deficit/hyperactivity disorder; CVD, cardiovascular CVD. Crude ORs were adjusted for all matching variables (age,
disease. sex, and calendar time) by design. Adjusted ORs (AORs) were
a
Controls were derived from the same base cohort as the cases; thus, a case additionally controlled for country of birth (Sweden vs other),
with a later date of CVD diagnosis could potentially serve as a control for highest educational level (primary or lower secondary, upper
another case in the study.
secondary, postsecondary or postgraduate, or unknown; in-
dividuals aged <16 years were included as a separate cat-
before baseline were excluded from the study. The cohort was egory), and diagnoses of somatic (type 2 diabetes, obesity, dys-
followed until the case index date (ie, the date of CVD diag- lipidemia, and sleep disorders) and psychiatric comorbidities
nosis), death, migration, or the study end date (December 31, (anxiety disorders, autism spectrum disorder, bipolar disor-
2020), whichever came first. der, conduct disorder, depressive disorder, eating disorders,
intellectual disability, personality disorders, schizophrenia, and
Identification of Cases and Controls substance use disorders; eTable 1 in Supplement 1) before base-
Within the study cohort, we identified cases as individuals with line. The association between cumulative ADHD medication
an incident diagnosis of any CVD (including ischemic heart dis- use and incident CVD was assessed using both continuous and
eases, cerebrovascular diseases, hypertension, heart failure, categorical measures (no ADHD medication use, 0 to ≤1, 1 to
arrhythmias, thromboembolic disease, arterial disease, and ≤2, 2 to ≤3, 3 to ≤5, and >5 years). To capture potential non-
other forms of heart disease; eTable 1 in Supplement 1) dur- linear associations, we used restricted cubic splines to exam-
ing follow-up. For each case, the date of their CVD diagnosis ine ADHD medication use as a continuous measure through-
was assigned as the index date. Using incidence density out follow-up.28 The associations were examined in the full
sampling,26 up to 5 controls without CVD were randomly se- sample and stratified by age at baseline, that is, children or
lected for each case from the base cohort of individuals with youth (<25 years old) and adults (≥25 years old). Further-
ADHD. The matching criteria included age, sex, and calendar more, to evaluate the association with dosage of ADHD medi-
time, ensuring that cases and controls had the same duration cation, we estimated the risk of CVD associated with each 1-year
of follow-up from baseline to index date. Controls were eli- increase in use of ADHD medication across different dosage
gible for inclusion if they were alive, living in Sweden, and free groups categorized by the average defined daily dose (DDD;
of CVD at the time when their matched case received a diag- for instance, 1 DDD of methylphenidate equals 30 mg) during
nosis of CVD, with the index date set as the date of CVD diag- follow-up.29
nosis of the matched case (Figure 1). Controls were derived from In subgroup analyses, we examined the associations be-
the same base cohort as the cases. Thus, a case with a later date tween ADHD medication use and specific CVDs, including ar-
of CVD diagnosis could potentially serve as a control for an- rhythmias, arterial disease, cerebrovascular disease, heart fail-
other case in the study.26 ure, hypertension, ischemic heart disease, and thromboembolic
disease (eTable 1 in Supplement 1). Additionally, we investi-
Exposures gated the associations with CVD risk for the most commonly
The main exposure was cumulative duration of ADHD medi- prescribed ADHD medications in Sweden, ie, methylpheni-
cation use, which included all ADHD medications approved in date, lisdexamfetamine, and atomoxetine, while adjusting for

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 ADHD Medications and Long-Term Risk of Cardiovascular Diseases Original Investigation Research

Table 1. Characteristics of Cases and Matched Controls

Full sample, No. (%) Age <25 y, No. (%) Age ≥25 y, No. (%)
Controls Cases Controls Cases
Baseline characteristic Cases (n = 10 388) (n = 51 672) (n = 3406) (n = 17 027) (n = 6982) Controls (n = 34 645)
Age, median (IQR), y 34.6 (20.0-45.7) 34.6 15.8 15.8 42.2 42.1 (34.4-49.1)
(19.8-45.6) (12.3-19.6) (12.3-19.6) (34.4-49.3)
Follow-up, median (IQR), y 4.1 (1.9-6.8) 4.1 (1.9-6.8) 4.2 (1.9-7.0) 4.2 (1.9-6.9) 4.0 (1.9-6.8) 4.0 (1.9-6.8)
Sex
Female 4234 (40.8) 21 071 (40.8) 1322 (38.8) 6607 (38.8) 2912 (41.7) 14 464 (41.7)
Male 6154 (59.2) 30 601 (59.2) 2084 (61.2) 10 420 (61.2) 4070 (58.3) 20 181 (58.3)
Country of birth
Sweden 9520 (91.6) 46 805 (90.6) 3208 (94.2) 15 935 (93.6) 6312 (90.4) 30 870 (89.1)
Other 868 (8.4) 4867 (9.4) 198 (5.8) 1092 (6.4) 670 (9.6) 3775 (10.9)
Educational level
Primary or lower secondary 3081 (29.7) 13 741 (26.6) 1182 (34.7) 5626 (33.0) 1899 (27.2) 8115 (23.4)
Upper secondary 4062 (39.1) 19 942 (38.6) 410 (12.0) 2313 (13.6) 3652 (52.3) 17 629 (50.9)
Postsecondary or postgraduate 1449 (13.9) 9064 (17.5) 58 (1.7) 367 (2.2) 1391 (19.9) 8697 (25.1)
People aged <16 ya 1680 (16.2) 8374 (16.2) 1680 (49.3) 8374 (49.2) NA NA
Unknown 116 (1.1) 551 (1.1) 76 (2.2) 347 (2.0) 40 (0.6) 204 (0.6)
Psychiatric comorbidities
Anxiety disorders 3489 (33.6) 14 930 (28.9) 670 (19.7) 2811 (16.5) 2819 (40.4) 12 119 (35.0)
Autism spectrum disorder 803 (7.7) 4390 (8.5) 343 (10.1) 1853 (10.9) 460 (6.6) 2537 (7.3)
Bipolar disorder 830 (8.0) 3847 (7.4) 88 (2.6) 369 (2.2) 742 (10.6) 3478 (10.0)
Conduct disorder 189 (1.8) 799 (1.5) 139 (4.1) 634 (3.7) 50 (0.7) 165 (0.5)
Depressive disorder 3323 (32.0) 15 096 (29.2) 582 (17.1) 2574 (15.1) 2741 (39.3) 12 522 (36.1)
Eating disorders 363 (3.5) 1609 (3.1) 86 (2.5) 417 (2.4) 277 (4.0) 1192 (3.4)
Intellectual disability 276 (2.7) 1151 (2.2) 154 (4.5) 626 (3.7) 122 (1.7) 525 (1.5)
Personality disorders 1467 (14.1) 6137 (11.9) 167 (4.9) 640 (3.8) 1300 (18.6) 5497 (15.9)
Schizophrenia 516 (5.0) 2102 (4.1) 72 (2.1) 199 (1.2) 444 (6.4) 1903 (5.5)
Substance use disorders 3332 (32.1) 12 693 (24.6) 500 (14.7) 1638 (9.6) 2832 (40.6) 11 055 (31.9)
Somatic comorbidities
Obesity 699 (6.7) 2186 (4.2) 217 (6.4) 563 (3.3) 482 (6.9) 1623 (4.7)
Type 2 diabetes 287 (2.8) 657 (1.3) 22 (0.6) 30 (0.2) 265 (3.8) 627 (1.8)
Dyslipidemia 81 (0.8) 404 (0.8) 6 (0.2) 12 (0.1) 75 (1.1) 392 (1.1)
Sleep disorders 642 (6.2) 2507 (4.9) 128 (3.8) 456 (2.7) 514 (7.4) 2051 (5.9)

Abbreviation: NA, not applicable.

a
The highest educational level is not relevant for individuals younger than 16 years.

other ADHD medication use. We also examined sex-specific

associations. Results
To further examine the robustness of our findings, we
conducted 4 sensitivity analyses. First, we restricted the The study cohort consisted of 278 027 individuals with ADHD
sample to ever users of ADHD medication to reduce unmea- aged 6 to 64 years. The incidence rate of CVD was 7.34 per 1000
sured confounding between ADHD medication users and person-years. After applying exclusion criteria and matching,
nonusers. Second, we assessed ADHD medication exposure the analysis included 10 388 cases (median [IQR] age at base-
over the entire follow-up period without excluding the 3 line, 34.6 (20.0-45.7) years; 6154 males [59.2%] and 4234 fe-
months prior to the index date. Third, to capture fatal cardio- males [40.8%]) and 51 672 matched controls (median [IQR] age
vascular events, we additionally included death by CVD in at baseline, 34.6 [19.8-45.6] years; 30 601 males [59.2%] and
the outcome definition. Finally, we constructed a conditional 21 071 females [40.8%]) (Figure 1 and Table 1). Median (IQR)
logistic regression model that adjusted for propensity scores follow-up in both groups was 4.1 (1.9-6.8) years. Among the
of ADHD medication use. Data management was performed controls, 3363 had received a CVD diagnosis after their index
using SAS, version 9.4 (SAS Institute Inc) and all analyses dates. The most common types of CVD in cases were hyper-
were performed using R, version 4.2.3 (R Foundation for Sta- tension (4210 cases [40.5%]) and arrhythmias (1310 cases
tistical Computing). [12.6%]; eTable 2 in Supplement 1). Table 1 presents the socio-

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 Research Original Investigation ADHD Medications and Long-Term Risk of Cardiovascular Diseases

Figure 2. Risk of Cardiovascular Disease (CVD) Associated With Cumulative Duration of Attention-Deficit/Hyperactivity Disorder
(ADHD) Medication Use

Cumulative
duration of ADHD Cases, Controls, Crude OR AOR Lower odds Higher odds
medication, y No. (%) No. (%) (95% CI) (95% CI) of CVD of CVD
Full sample 10 388 51 672
0 1675 (16.1) 8520 (16.5) 1 [Reference] 1 [Reference]
0 to ≤1 3363 (32.4) 18 052 (34.9) 0.94 (0.88-1.01) 0.99 (0.93-1.06)
1 to ≤2 1699 (16.4) 8417 (16.3) 1.04 (0.97-1.13) 1.09 (1.01-1.18)
2 to ≤3 1083 (10.4) 5216 (10.1) 1.10 (1.01-1.20) 1.15 (1.05-1.25)
3 to ≤5 1400 (13.5) 6165 (11.9) 1.23 (1.13-1.33) 1.27 (1.17-1.39)
>5 1168 (11.2) 5302 (10.3) 1.20 (1.09-1.31) 1.23 (1.12-1.36)
Group aged <25 y 3406 17 027
0 491 (14.4) 2551 (15.0) 1 [Reference] 1 [Reference]
0 to ≤1 1123 (33.0) 6021 (35.4) 0.96 (0.86-1.08) 1.00 (0.89-1.13)
1 to ≤2 592 (17.4) 2995 (17.6) 1.05 (0.92-1.20) 1.08 (0.94-1.25)
2 to ≤3 385 (11.3) 1782 (10.5) 1.18 (1.01-1.38) 1.21 (1.03-1.42)
3 to ≤5 455 (13.4) 2083 (12.2) 1.22 (1.05-1.42) 1.25 (1.07-1.47)
>5 360 (10.6) 1595 (9.4) 1.30 (1.10-1.55) 1.35 (1.13-1.62)
Group aged ≥25 y 6 982 34 645
0 1184 (17.0) 5969 (17.2) 1 [Reference] 1 [Reference]
0 to ≤1 2240 (32.1) 12 031 (34.7) 0.94 (0.87-1.01) 0.99 (0.91-1.08)
1 to ≤2 1107 (15.9) 5422 (15.7) 1.05 (0.95-1.15) 1.10 (1.00-1.21)
2 to ≤3 698 (10.0) 3434 (9.9) 1.06 (0.95-1.18) 1.12 (1.00-1.25)
3 to ≤5 945 (13.5) 4082 (11.8) 1.23 (1.12-1.36) 1.29 (1.16-1.43)
>5 808 (11.6) 3707 (10.7) 1.16 (1.04-1.29) 1.19 (1.07-1.34)

0.8 1.0 1.2 1.4 1.6 1.8

AOR (95% CI)

Crude odds ratios (ORs) were based on cases and controls matched on age, sex, and sleep disorders), and psychiatric comorbidities (anxiety disorders, autism
and calendar time. Adjusted ORs (AORs) were based on cases and controls spectrum disorder, bipolar disorder, conduct disorder, depressive disorder,
matched on age, sex, and calendar time and adjusted for country of birth, eating disorders, intellectual disability, personality disorders, schizophrenia, and
educational level, somatic comorbidities (type 2 diabetes, obesity, dyslipidemia, substance use disorders).

demographic information and somatic and psychiatric comor- Supplement 1). The dosage analysis showed that the risk of CVD
bidities in cases and controls. In general, cases had higher rates associated with each 1 year of ADHD medication use in-
of somatic and psychiatric comorbidities and a lower level of creased with higher average DDDs. The risk was found to be
educational attainment compared with controls. statistically significant only among individuals with a mean
A similar proportion of cases (83.9%) and controls (83.5%) dose of at least 1.5 times the DDD (eTable 3 in Supplement 1).
used ADHD medication during follow-up, with methylpheni- For example, among individuals with a mean DDD of 1.5 to 2
date being the most commonly dispensed type, followed by or less (eg, for methylphenidate, 45 to ≤60 mg), each 1-year
atomoxetine and lisdexamfetamine. Longer cumulative increase in ADHD medication use was associated with a 4%
duration of ADHD medication use was associated with an increased risk of CVD (AOR, 1.04 [95% CI, 1.02-1.05]).
increased risk of CVD compared with nonuse (0 to ≤1 year: Among individuals with a mean DDD >2 (eg, for methylphe-
AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% nidate >60 mg), each 1-year increase in ADHD medication
CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to use was associated with 5% increased risk of CVD (AOR, 1.05
≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.03-1.06]).
[95% CI, 1.12-1.36]) (Figure 2). The restricted cubic spline model When examining the risk for specific CVDs, we found that
suggested a nonlinear association, with the AORs increasing long-term use of ADHD medication (compared with no use)
rapidly for the first 3 cumulative years of ADHD medication was associated with an increased risk of hypertension (AOR,
use and then becoming stable thereafter (Figure 3). Through- 1.72 [95% CI, 1.51-1.97] for 3 to ≤5 years; AOR, 1.80 [95% CI
out the entire follow-up, each 1-year increase in the use of 1.55-2.08] for >5 years) (Table 2), as well as arterial disease
ADHD medication was associated with a 4% increased risk of (AOR, 1.65 [95% CI, 1.11-2.45] for 3 to ≤5 years; AOR, 1.49 [95%
CVD (AOR, 1.04 [95% CI, 1.03-1.05]), and the corresponding in- CI 0.96-2.32] for >5 years). However, we did not observe any
crease for the first 3 years was 8% (AOR, 1.08 [95% CI, 1.04- statistically significant increased risk for arrhythmias, heart
1.11]). We observed similar results when examining children failure, ischemic heart disease, thromboembolic disease, or
or youth and adults separately (Figure 2). The restricted cu- cerebrovascular disease (Table 2). Furthermore, long-term use
bic spline model suggested a similar nonlinear association, with of methylphenidate (compared with no use) was associated
higher AORs in children or youth than in adults, but the 95% with an increased risk of CVD (AOR, 1.20 [95% CI, 1.10-1.31] for
CIs largely overlapped (Figure 3). Furthermore, similar asso- 3 to ≤5 years; AOR, 1.19 [95% CI, 1.08-1.31]) for >5 years;
ciations were observed for females and males (eFigure in eTable 4 in Supplement 1). Compared with no use, lisdexam-

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 ADHD Medications and Long-Term Risk of Cardiovascular Diseases Original Investigation Research

Figure 3. Association Between Cumulative Attention-Deficit/Hyperactivity Disorder Medication (ADHD)

Use and Risk of Cardiovascular Disease

A Overall

2.2

2.0

1.8

1.6
AOR

1.4

1.2

1.0

0.8
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Cumulative ADHD medication use, y
No. of individuals exposed to ADHD medication
Cases 1675 3363 1699 1083 801 599 387 292 198 127 88 48 22 6 <5
Controls 8520 18 052 8417 5216 3578 2587 1825 1323 829 588 392 199 109 33 <5

B By age
2.2

6-24 y
2.0
25-64 y

1.8

1.6
AOR

1.4

1.2

1.0

0.8
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Cumulative ADHD medication use, y
No. of individuals exposed to ADHD medication
Age <25 y The solid lines represent the adjusted
Cases 491 1123 592 385 256 199 131 88 55 42 26 8 9 <5 <5
odds ratios, and the shaded areas
Controls 2551 6021 2995 1782 1206 877 554 417 228 186 119 58 27 5 <5
Age ≥25 y
represent the 95% CIs. In restricted
Cases 1184 2240 1107 698 545 400 256 204 143 85 62 40 13 5 <5 cubic splines analysis, knots were
Controls 5969 12 031 5422 3434 2372 1710 1271 906 601 402 273 141 82 28 <5 placed at the 10th, 50th, and 90th
percentiles of ADHD medication use.

fetamine was also associated with an elevated risk of CVD scores of ADHD medication use, the findings remained consis-
(AOR, 1.23 [95% CI, 1.05-1.44] for 2 to ≤3 years; AOR, 1.17 [95% tent (eTable 5 in Supplement 1).
CI, 0.98-1.40] for >3 years), while the AOR for atomoxetine
use was significant only for the first year of use (1.07 [95% CI
1.01-1.13]; eTable 4 in Supplement 1).
In sensitivity analyses, we observed a similar pattern of es-
Discussion
timates when the analysis was restricted to ever users of ADHD This large, nested case-control study found an increased risk
medications. Significantly increased risk of CVD was found when of incident CVD associated with long-term ADHD medication
comparing ADHD medication use for 1 year or less with use for use, and the risk increased with increasing duration of ADHD
3 to 5 or less years (AOR, 1.28 (95% CI, 1.18-1.38) or for use for medication use. This association was statistically significant
more than 5 years (AOR, 1.24 [95% CI, 1.13-1.36]) (eTable 5 in both for children and youth and for adults, as well as for fe-
Supplement 1). When assessing ADHD medication use across the males and males. The primary contributors to the association
entire follow-up period, and compared with no use, the pattern between long-term ADHD medication use and CVD risk was
of estimates was similar to the main analysis (3 to ≤5 years: AOR, an increased risk of hypertension and arterial disease. In-
1.28 [95% CI, 1.18-1.39]; >5 years: AOR, 1.25 [95% CI, 1.14-1.37]) creased risk was also associated with stimulant medication use.
(eTable 5 in Supplement 1). The analysis that included cardio- We found individuals with long-term ADHD medication
vascular death as a combined outcome also had results similar use had an increased risk of incident CVD in a dose-response
to the main analysis. Moreover, when adjusting for propensity manner in the first 3 years of cumulative ADHD medication use.

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 Research Original Investigation ADHD Medications and Long-Term Risk of Cardiovascular Diseases

Table 2. Risk of Cardiovascular Disease (CVD) Associated With Cumulative Duration of Attention-Deficit/
Hyperactivity Disorder (ADHD) Medication Use, Stratified by Type of CVD Event
CVD event and
cumulative duration of
ADHD medication use, y Cases, No. (%)a Controls, No. (%) Crude OR (95% CI)b Adjusted OR (95% CI)c
Arrhythmias 1310 6499 NA NA
0 233 (17.8) 1074 (16.5) 1 [Reference] 1 [Reference]
0 to ≤1 460 (35.1) 2396 (36.9) 0.89 (0.75-1.06) 0.91 (0.76-1.10)
1 to ≤2 236 (18.0) 1084 (16.7) 1.02 (0.83-1.26) 1.04 (0.84-1.28)
2 to ≤3 120 (9.2) 624 (9.6) 0.90 (0.70-1.16) 0.92 (0.70-1.19)
3 to ≤5 143 (10.9) 696 (10.7) 0.95 (0.75-1.22) 0.95 (0.74-1.23)
>5 118 (9.0) 625 (9.6) 0.85 (0.64-1.11) 0.87 (0.66-1.16)
Arterial disease 580 2890 NA NA
0 66 (11.4) 450 (15.6) 1 [Reference] 1 [Reference]
0 to ≤1 203 (35.0) 1029 (35.6) 1.31 (0.98-1.77) 1.42 (1.04-1.93)
1 to ≤2 104 (17.9) 471 (16.3) 1.54 (1.10-2.17) 1.63 (1.15-2.32)
2 to ≤3 74 (12.8) 323 (11.2) 1.65 (1.13-2.40) 1.72 (1.17-2.53)
3 to ≤5 78 (13.4) 352 (12.2) 1.61 (1.10-2.36) 1.65 (1.11-2.45)
>5 55 (9.5) 265 (9.2) 1.44 (0.93-2.21) 1.49 (0.96-2.32)
Hypertension 4210 20 924 NA NA
0 624 (14.8) 3478 (16.6) 1 [Reference] 1 [Reference]
0 to ≤1 1227 (29.1) 7123 (34.0) 0.94 (0.85-1.05) 1.06 (0.95-1.18)
1 to ≤2 699 (16.6) 3291 (15.7) 1.22 (1.08-1.38) 1.34 (1.18-1.52)
2 to ≤3 426 (10.1) 2132 (10.2) 1.19 (1.04-1.37) 1.30 (1.12-1.50)
3 to ≤5 650 (15.4) 2598 (12.4) 1.57 (1.38-1.79) 1.72 (1.51-1.97)
>5 584 (13.9) 2302 (11.0) 1.67 (1.45-1.92) 1.80 (1.55-2.08)
Cerebrovascular disease 705 3511 NA NA
0 131 (18.6) 629 (17.9) 1 [Reference] 1 [Reference]
0 to ≤1 230 (32.6) 1152 (32.8) 0.96 (0.75-1.21) 0.93 (0.72-1.20)
1 to ≤2 121 (17.2) 590 (16.8) 0.99 (0.75-1.30) 0.97 (0.73-1.31)
2 to ≤3 58 (8.2) 314 (8.9) 0.89 (0.63-1.26) 0.85 (0.60-1.22)
3 to ≤5 101 (14.3) 432 (12.3) 1.12 (0.82-1.52) 1.10 (0.80-1.52)
>5 64 (9.1) 394 (11.2) 0.74 (0.52-1.05) 0.74 (0.51-1.07)
Heart failure 370 1833 NA NA
0 64 (17.3) 299 (16.3) 1 [Reference] 1 [Reference]
Abbreviation: OR, odds ratio.
0 to ≤1 120 (32.4) 584 (31.9) 0.95 (0.68-1.34) 1.04 (0.72-1.51) a
Multiple incident diagnoses can be
1 to ≤2 41 (11.1) 298 (16.3) 0.63 (0.41-0.98) 0.68 (0.43-1.08) assigned simultaneously on the
2 to ≤3 47 (12.7) 192 (10.5) 1.14 (0.73-1.77) 1.22 (0.76-1.95) same day as incident CVD. As a
result, the percentages of individual
3 to ≤5 49 (13.2) 248 (13.5) 0.93 (0.60-1.44) 1.05 (0.66-1.66)
diagnoses may add up to more than
>5 49 (13.2) 212 (11.6) 1.14 (0.72-1.81) 1.23 (0.76-1.99) 100%.
b
Ischemic heart disease 493 2437 NA NA Crude ORs are based on cases and
0 83 (16.8) 380 (15.6) 1 [Reference] 1 [Reference] controls matched on age, sex, and
calendar time.
0 to ≤1 164 (33.3) 838 (34.4) 0.89 (0.67-1.19) 0.94 (0.69-1.28) c
Adjusted ORs are based on cases
1 to ≤2 60 (12.2) 384 (15.8) 0.70 (0.48-1.02) 0.72 (0.49-1.06) and controls matched on age, sex,
2 to ≤3 55 (11.2) 256 (10.5) 1.00 (0.67-1.47) 1.09 (0.73-1.65) and calendar time and adjusted for
country of birth, highest
3 to ≤5 68 (13.8) 285 (11.7) 1.14 (0.78-1.64) 1.20 (0.82-1.77)
educational level, somatic
>5 63 (12.8) 294 (12.1) 0.98 (0.66-1.45) 1.06 (0.70-1.60) comorbidities (type 2 diabetes,
Thromboembolic disease 1254 6237 NA NA obesity, dyslipidemia, and sleep
disorders), and psychiatric
0 216 (17.2) 1048 (16.8) 1 [Reference] 1 [Reference] comorbidities (anxiety disorders,
0 to ≤1 428 (34.1) 2150 (34.5) 0.98 (0.82-1.17) 0.97 (0.80-1.18) autism spectrum disorder, bipolar
1 to ≤2 202 (16.1) 1057 (16.9) 0.94 (0.76-1.17) 0.93 (0.74-1.17) disorder, conduct disorder,
depressive disorder, eating
2 to ≤3 131 (10.4) 624 (10.0) 1.03 (0.81-1.32) 1.07 (0.82-1.38) disorders, intellectual disability,
3 to ≤5 163 (13.0) 731 (11.7) 1.11 (0.87-1.41) 1.08 (0.84-1.39) personality disorders,
schizophrenia, and substance use
>5 114 (9.1) 627 (10.1) 0.88 (0.67-1.15) 0.84 (0.63-1.12)
disorders).

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 ADHD Medications and Long-Term Risk of Cardiovascular Diseases Original Investigation Research

To our knowledge, few previous studies have investigated Regarding types of ADHD medication, findings of the
the association between long-term ADHD medication use present study suggest that increasing cumulative durations
and the risk of CVD with follow-up of more than 2 years.13 of methylphenidate and lisdexamfetamine use were associ-
The only 2 prior studies with long-term follow-up (median, ated with incident CVD, while the associations for atom-
9.5 and 7.9 years30,31) found an average 2-fold and 3-fold oxetine were statistically significant only for the first year of
increased risk of CVD with ADHD medication use compared use. Previous RCTs have reported increased blood pressure
with nonuse during the study period, yet 1 of the studies30 and heart rate with methylphenidate, lisdexamfetamine,
included only children, and participants in the other study31 and atomoxetine,5,35,36 but the mechanisms behind these
were not the general population of individuals with ADHD adverse effects are still a topic of debate; there might be dif-
(including those with ADHD and long QT syndrome). Fur- ferences in cardiovascular adverse effects in stimulants vs
thermore, both studies were subject to prevalent user bias. nonstimulants.37
Results from the current study suggest that the CVD risk We found that the association between cumulative dura-
associated with ADHD medication use (23% increased risk for tion of ADHD medication use and CVD was similar in females
>5 years of ADHD medication use compared with nonuse) is and males. Previous investigations exploring sex-specific as-
lower than previously reported. 3 0,3 1 Furthermore, we sociation found higher point estimates in females, although
observed that the increased risk stabilized after the first sev- the differences were not statistically significant.13 Research has
eral years of medication use and persisted throughout the indicated that females diagnosed with ADHD may demon-
14-year follow-up period. strate different comorbidity patterns and potentially have dif-
The association between ADHD medication use and CVD ferent responses to stimulant medications compared with
was significant for hypertension and arterial disease, while no males.38-40 Therefore, additional studies are needed to ex-
significant association was observed with other types of car- plore and better understand the potential sex-specific differ-
diovascular events. To our knowledge, only 1 previous study12 ences in cardiovascular responses to ADHD medications.
has examined the association between ADHD medication use
and clinically diagnosed hypertension, and it found an in- Strengths and Limitations
creased risk, although the increase was not statistically sig- A strength of this study is that data on ADHD medication pre-
nificant. Furthermore, increased blood pressure associated scriptions and CVD diagnoses were recorded prospectively, so
with ADHD medication use has been well documented.7,9 One the results were not affected by recall bias. The findings should,
study32 found that blood pressure was mainly elevated dur- however, be interpreted in the context of several limitations.
ing the daytime, suggesting that the cardiovascular system may First, our approach for identification of patients with CVD was
recover at night. However, the cross-sectional nature of that based on recorded diagnoses and there could be under ascer-
study cannot preclude a long-term risk of clinically diag- tainment of cardiovascular diagnoses in the registers used. This
nosed hypertension associated with ADHD medication use. We means that some controls may have had undiagnosed CVD that
also identified an increased risk for arterial disease. To date, did not yet require medical care, which would tend to under-
no previous study has explored the association between ADHD estimate associations between ADHD medication use and
medication use and arterial disease. A few studies have re- CVD. Second, exposure misclassification may have occurred
ported that ADHD medication may be associated with changes if patients did not take their medication as prescribed. This mis-
in serum lipid profiles, but the results were not consistent.33,34 classification, if nondifferential, would tend to reduce ORs such
Further research is needed on the potential implications of that the estimates we observed were conservative. Third, while
ADHD medications for individuals’ lipid profiles. We did not we accounted for a wide range of potential confounding
observe any association between ADHD medication use and variables, considering the observational nature of the study
the risk of arrhythmias. A recent systematic review of obser- and the possibility of residual confounding, we could not
vational studies of ADHD medication use reported an el- prove causality. It is possible that the association observed
evated risk of arrhythmias, but the finding was not statisti- might have been affected by time-varying confounders. For
cally significant.13 A review of RCTs also found that the use of example, other psychotropic medications and lifestyle fac-
stimulants was associated with an average increase in heart tors could have affected both ADHD medication use and the
rate of 5.7 beats/min,9 but no evidence of prolonged QT inter- occurrence of cardiovascular events.41,42 Confounding by
val or tachycardia was found based on electrocardiograms.7 ADHD severity is also a potential factor to consider, as indi-
Additionally, it is worth noting that some individuals receiv- viduals with more severe ADHD symptoms may have more
ing ADHD medications might be prescribed antiarrhythmic comorbidities and a less healthy lifestyle, which could affect
β-blockers to alleviate palpitation symptoms, thus poten- the risk of CVD. Fourth, the study did not examine the risk
tially attenuating an association between ADHD medications of CVD among individuals with preexisting CVD. Individuals
and arrhythmias. Nevertheless, the absence of an association with preexisting CVD represent a distinct clinical group that
between ADHD medication use and clinically diagnosed ar- requires careful monitoring; thus, evaluating the risk among
rhythmias in the present study does not rule out an increased them necessitates a different study design that carefully
risk for mild arrhythmias or subclinical symptoms, as palpi- considers the potential impact of prior knowledge and peri-
tations and sinus tachycardia are not routinely coded as ar- odic monitoring. Finally, the results by type of ADHD medi-
rhythmia diagnoses. Further research is necessary to repli- cation and type of CVD need to be replicated by studies with
cate our findings. larger sample sizes.

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 Research Original Investigation ADHD Medications and Long-Term Risk of Cardiovascular Diseases

light the importance of carefully weighing potential benefits

Conclusions and risks when making treatment decisions on long-term
ADHD medication use. Clinicians should be vigilant in moni-
The results of this population-based case-control study with toring patients, particularly among those receiving higher
a longitudinal follow-up of 14 years suggested that long-term doses, and consistently assess signs and symptoms of CVD
use of ADHD medication was associated with an increased risk throughout the course of treatment. Monitoring becomes even
of CVD, especially hypertension and arterial disease, and the more crucial considering the increasing number of individu-
risk was higher for stimulant medications. These findings high- als engaging in long-term use of ADHD medication.

ARTICLE INFORMATION Data Sharing Statement: See Supplement 2. 2011;306(24):2673-2683. doi:10.1001/jama.

Accepted for Publication: August 29, 2023. 2011.1830
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