Long-Term Stimulant Use: Cardiovascular and Growth Effects
Long-term stimulant use (methylphenidate and amphetamines) is associated with sustained but modest cardiovascular effects—including small increases in blood pressure (2-8 mmHg systolic) and heart rate (3-11 bpm)—and statistically significant reductions in height and weight gain, though these effects are generally minor on a group level but require consistent monitoring as they may be clinically relevant in individual patients, particularly those with preexisting cardiovascular disease. 1, 2
Cardiovascular Effects
Blood Pressure and Heart Rate Changes
Both methylphenidate and amphetamines produce small but statistically significant increases in blood pressure and heart rate that persist with long-term use. 1, 3
Blood pressure increases by approximately 2-8 mmHg systolic and 2-14 mmHg diastolic on average across all age groups, with sustained effects over time. 1
Heart rate increases by 3-11 beats per minute with therapeutic dosing, and these effects are dose-related and similar for both methylphenidate and amphetamine preparations. 1, 2
In a long-term study of adults treated with mixed amphetamine salts for up to 24 months, mean changes in diastolic blood pressure (1.3 mm Hg), systolic blood pressure (2.3 mm Hg), and pulse (2.1 bpm) were small and not clinically significant. 4
Greater cumulative stimulant exposure is associated with higher heart rate even after years of treatment—in the MTA study, this adrenergic effect persisted at years 3 and 8. 5
Risk of Serious Cardiovascular Events
The risk for serious cardiovascular adverse events, including sudden cardiac death, associated with stimulants prescribed for ADHD is extremely low. 3
Large retrospective, population-based cohort studies did not show evidence that methylphenidate was associated with an increase in risk of myocardial infarction, sudden cardiac death, or stroke in the short to mid-term. 5
However, a 2024 Swedish case-control study found that longer cumulative duration of ADHD medication use was associated with increased risk of cardiovascular disease compared with nonuse, particularly after 2 years of continuous use. 6
Specifically, cumulative use of 3-5 years showed an adjusted odds ratio of 1.27 (95% CI, 1.17-1.39), and use >5 years showed an AOR of 1.23 (95% CI, 1.12-1.36) for any cardiovascular disease. 6
Each 1-year increase of ADHD medication use was associated with a 4% increased risk of cardiovascular disease (AOR 1.04), with a larger increase in risk in the first 3 years of cumulative use (AOR 1.08) and stable risk over remaining follow-up. 6
Longer cumulative ADHD medication use was particularly associated with increased risk of hypertension (3-5 years: AOR 1.72; >5 years: AOR 1.80) and arterial disease (3-5 years: AOR 1.65). 6
Clinical Significance and Individual Variability
While group-level cardiovascular effects are minor, they may be clinically relevant for individual patients, especially those with preexisting cardiovascular disease. 2, 1
The 1998 NIH Consensus Development Conference cautioned that extremely high doses of stimulants might cause central nervous system damage, cardiovascular damage, and hypertension, though these effects relate to conditions of severe toxic overdose rather than standard practice. 2
Few subjects with normal baseline vital signs exhibited clinically significant abnormalities at endpoint, but several subjects with borderline baseline values exhibited shifts to abnormal values during stimulant therapy. 4
Growth Effects
Height and Weight Impact
Findings from longitudinal studies indicate that treatment with psychostimulants is associated with statistically significant reductions in height and weight gain. 2
These effects are usually minor but can be clinically relevant in subgroups and generally require careful monitoring. 2
The effects are dose-related and similar for both methylphenidate and amphetamine. 2
In the MTA study, ADHD children treated with chronic stimulants showed significant decrements in rates of weight acquisition compared with ADHD children randomized to nonmedication treatment. 2
Changes in rates of height acquisition in the MTA study differed only minimally between groups during the 14-month treatment period and did not reach clinical significance. 2
To date, it remains unclear whether effects on height should be considered reversible. 2
Prospective follow-up into adult life has revealed no significant impairment of final height attained. 2
Reduced appetite, as a highly frequent side effect of stimulant treatment, certainly plays a major role in growth effects, though other possible mechanisms such as hormonal dysregulation require further investigation. 2
Long-Term Efficacy Considerations
Duration of Benefit
Short-term trials of stimulants (most often 3 months or less) have reported robust efficacy with 70% response rate, but only 22 of more than 160 controlled studies lasted more than 3 months. 2
Prospective, longer-duration randomized controlled trials lasting 12-24 months, including the MTA study, showed that stimulants lead to stable improvements in ADHD symptoms as long as the drug continues to be taken. 2
Follow-up observations from the MTA study suggest that children with ADHD who continued psychostimulants for more than 10 years fared no better in terms of symptom reduction than those who had discontinued their medication, raising questions about whether long-term treatment continues to be beneficial. 2
In a seven-week randomized placebo-controlled methylphenidate-(dis)continuation study of children treated for more than 2 years, there was significant between-group difference in favor of the group that continued methylphenidate treatment. 2
Tolerance Development
Overall, there has been little evidence of the development of tolerance to the stimulant effects on symptoms of ADHD and little evidence of a need to increase the dose to get the same response. 2
Children most often continue to respond to the same dose of stimulant medication. 2
More recent pharmacodynamic studies suggest that stimulant blood levels need to increase throughout the day to maintain constant efficacy, because short-term tolerance to methylphenidate develops by the second dose given in the same day. 2
Toxicology and Abuse Potential
Animal Studies and Human Relevance
Animal toxicity studies using high doses of stimulants have reported abnormal findings not found in humans, which may be a result of differences of species, dose, route of administration, and end point selected. 2
Hepatic tumors increased only in mice (a strain known to have genetic diathesis for liver tumors), whereas rats had a decreased rate (similar to human data) when treated with high oral doses of methylphenidate. 2
Abuse and Dependence
Methylphenidate has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction. 7
Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation. 7
Methylphenidate may produce physical dependence, with withdrawal signs and symptoms after abrupt discontinuation including dysphoric mood, depression, fatigue, vivid unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation. 7
Methylphenidate may produce tolerance, characterized by a reduced response to a drug after repeated administration. 7
An uncontrolled follow-up study suggested that long-term treatment with methylphenidate might predispose children with ADHD to abuse of nicotine and possibly cocaine, based on the process of sensitization, though this speculation is difficult to extrapolate from animal findings to clinical use. 2
Monitoring Requirements
Baseline and Ongoing Assessment
Clinical guidelines recommend baseline blood pressure and heart rate measurement before initiating stimulants. 1
Clinical guidelines recommend periodic monitoring of pulse and blood pressure during treatment. 1, 2
Measure baseline blood pressure and heart rate before initiating psychostimulants, and monitor at each follow-up visit during treatment. 1
Adjust dose or discontinue if blood pressure increases >10-15 mmHg or heart rate >20 bpm from baseline. 1
Patients should be periodically assessed, potentially including a medication-free interval, to determine whether there is a continued need for psychostimulant treatment. 2
Contraindications
Both methylphenidate and amphetamines should be avoided in patients with uncontrolled hypertension, underlying coronary artery disease, and tachyarrhythmias. 1
Great caution is advised when considering stimulant medications for patients of any age with a personal or family history or other known risk factors for cardiovascular disease. 3
Common Pitfalls
Do not assume that small group-level cardiovascular effects mean individual patients are not at risk—patients with preexisting cardiovascular disease, personal or family history of cardiac conditions, or uncontrolled hypertension may experience clinically significant cardiovascular changes. 1, 3
Do not neglect growth monitoring—while average effects are small, individual children may experience clinically meaningful growth suppression requiring intervention. 2
Do not continue stimulants indefinitely without periodic reassessment—the long-term benefit beyond several years remains uncertain, and medication-free intervals should be considered to determine ongoing need. 2
Do not ignore the most recent large-scale evidence showing increased cardiovascular risk with cumulative use beyond 2 years, particularly for hypertension and arterial disease. 6