New Evidence That ADHD Medications Increase Cardiovascular Risk

Two recent observational studies support a long-held concern that use of central nervous system stimulant medications to treat attention deficit hyperactivity disorder (ADHD) increases the risk of cardiovascular disease, a risk that may persist even after patients discontinue the drug. These medications include methylphenidate (APTENSIO, CONCERTA, CONTEMPLA, DAYTRANA, JORNAY, METADATE, METHYLIN, QUILLICHEW, QUILLIVANT, RELEXXII, RITALIN and generics), atomoxetine (STRATTERA and generics) and lisdexamfetamine (VYVANSE and generics).

About stimulant medications to treat ADHD

Stimulant medications have long been used to treat ADHD symptoms in children, teenagers and adults. They have demonstrated limited, though uncertain, effectiveness, especially when they are used in conjunction with psychotherapy and other nonpharmacologic interventions, including training for parents and teachers of distracted and overactive children.[1],[2],[3],[4],[5]

Public Citizen’s Health Research Group classifies most ADHD medications as Limited Use or Do Not Use depending upon the active ingredients and the age of the patient (we recommend against using these drugs in preschoolers).[6] Because diagnosing ADHD is uncertain due to a lack of biomarkers for the disorder, we recommend that second opinions be obtained before starting medical treatment.

Stimulant drugs used to treat ADHD have numerous safety concerns. The prescribing information includes a boxed warning, the most serious of the warnings issued by the Food and Drug Administration. For most stimulants, these boxed warnings are for misuse, which can lead to substance use disorders (including addiction and overdose).[7],[8] For atomoxetine, a norepinephrine reuptake inhibitor, the boxed warning is for suicidal ideation in children and adolescents.[9]

Other common safety concerns (frequency of at least 5% in clinical trials and increased frequency compared with placebo) for widely used ADHD medications include upper abdominal pain, decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight loss, irritability, hyperhidrosis (excessive sweating), fatigue, constipation, erectile dysfunction and urinary hesitation.

Less common concerns include increases in blood pressure and heart rate, psychotic or manic symptoms, aggression, priapism (prolonged erections) and growth retardation. Because many of these adverse effects and precautions are associated with cardiovascular function, long-term follow-up studies are important; stimulant use for ADHD often begins in childhood and can extend well into adulthood.[10]

New observational studies

A 2024 study in JAMA Psychiatry considered whether ADHD medication use was associated with the development of cardiovascular disease, including ischemic heart disease (heart artery blockage), cerebrovascular disease (stroke), hypertension (high blood pressure), heart failure, arrythmias, thromboembolic disease and arterial disease.[11] The researchers used the national Swedish diagnostic and treatment databases to identify 278,027 individuals between the ages of 6 and 64 years who, sometime between 2007 and 2020, had a new ADHD diagnosis or prescription. With those databases, the researchers constructed a case-control study that compared 10,388 individuals who went on to develop a cardiovascular diagnosis (cases) with 51,672 matched individuals (by sex, age and time of first ADHD diagnosis) who did not develop such disease (controls).

The study found that one year or less of ADHD medication use was not associated with increases in cardiovascular disease risk, but additional time on such medications did significantly increase that risk. The increased risk was about 4% per year of medication use over the course of the 14-year follow-up and 8% per year in the first three exposure years. The analysis was adjusted for education level, medical conditions (such as diabetes), and psychiatric conditions (such as anxiety, depression and substance use disorders, including addiction to tobacco products).

The JAMA Psychiatry study further found that the increased cardiovascular risk was mainly driven by an increased risk of hypertension and arterial disease, not other cardiovascular diseases. Another noteworthy finding was that atomoxetine use was only associated with increased cardiovascular risk in the first year of use. Limits of this study are that it was an observational study, not a randomized trial, and thus could not establish cause and effect. It also did not correct for severity of ADHD or for diet, exercise and other lifestyle factors that influence cardiovascular disease risk.

A second 2024 study in the Journal of the American College of Cardiology[12] used data from a national registry of Danish adults (median age 31-33 years) who were new users of ADHD medications (mostly methylphenidate, atomoxetine and lisdexamfetamine) between 1998 and 2020. Those identified were divided into three drug-exposure groups: (1) prior users who only filled their stimulant prescriptions in the first six months (n=26,357), (2) those who filled prescriptions in months 6-12 with only one or fewer stimulant doses per day (n=31,211) and (3) those who used more than one dose per day during months 6-12 (n=15,696). A fourth comparison group of controls without ADHD or stimulant prescriptions were matched by sex and by birth month and year (n=145,456).

Outcomes assessed for up to 10 years (median follow-up period was 6.5 years) after treatment initiation were acute coronary syndrome (ischemic heart disease), stroke and heart failure. Increases in absolute risk (compared with controls) for any of the cardiovascular outcomes were highest in the highest-exposed group (more than one dose per day) at 3.9% and lowest in those who discontinued the drug within six months at 3.0%, although no significant differences were evident for acute coronary syndrome alone. When the analyses were extended up to five additional years, including consideration of the cumulative exposure to stimulants over time, these overall elevated and roughly dose-proportional cardiovascular risk patterns persisted.

An accompanying commentary that generally praised the Journal of the American College of Cardiology study noted that a randomized clinical trial to confirm the cardiovascular effects of stimulants is “unlikely to be conducted.” The commentary concluded that the harmful cardiovascular effects of such medications are real but difficult and expensive to detect in the context of a clinical trial and thus should be fully considered by individual patients and their clinicians before and during treatment with such drugs.

What You Can Do

If you have been treated with stimulant medications to cope with ADHD symptoms, be proactive to protect your cardiovascular health, including informing your clinicians about your complete stimulant use history. Cardiovascular health concerns should influence the initial decision to use stimulants to treat ADHD and may be of clinical importance for many years after stimulant use is discontinued.
 

References

[1] Boesen K, Paludan-Müller AS, Gøtzsche PC, Jørgensen KJ. Extended-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2022, Issue 2. Art. No.: CD012857.

[2] Lopez PL, Torrente FM, Ciapponi A, et al. Cognitive-behavioral interventions for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No.: CD010840.

[3] Castells X, Blanco-Silvente L, Cunill R. Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2018, Issue 8. Art. No.: CD007813.

[4] Cândido RCF, Menezes de Padua CA, Golder S, Junqueira DR. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database of Systematic Reviews 2021, Issue 1. Art. No.: CD013011.

[5] Storebø OJ, Pedersen N, Ramstad E, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non-randomised studies. Cochrane Database of Systematic Reviews 2018, Issue 5. Art. No.: CD012069.

[6] Worst Pills Best Pills News. A guide to treatment for ADHD in children and adolescents. December 2021. https://www.worstpills.org/newsletters/view/1439. Accessed August 2, 2024.

[7] Teva Pharmaceuticals. Label: dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate (ADDERALL). October 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/011522s045lbl.pdf. Accessed August 2, 2024.

[8] Janssen Pharmaceuticals. Label: methylphenidate HCL (CONCERTA). October 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021121s049lbl.pdf. Accessed August 2, 2024.

[9] Lilly USA. Label: atomoxetine (STRATTERA). January 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021411s050lbl.pdf. Accessed August 2, 2024.

[10] Zhang L, Li L, Andell P, et al. Attention-deficit/hyperactivity disorder medications and long-term risk of cardiovascular diseases. JAMA Psychiatry. 2024;81(2):178-187.

[11] Ibid.

[12] Holt A, Strange JE, Rasmussen PV, et al. Long-term cardiovascular risk associated with treatment of attention-deficit/hyperactivity disorder in adults. J Am Coll Cardiol. 2024;83(19):1870-1882.