By: JACC, Noel Torres-Acosta,James H. O’Keefe,Caroline L. O’KeefeandCarl J. Lavie
Central Illustration
Highlights
• Use of prescription sympathomimetic drugs for treating ADHD has markedly increased in the United States.
• ADHD medications, potent stimulants of the sympathetic nervous system, are associated with adverse cardiovascular events.
• ADHD medications should be prescribed only after safer options, such as regular exercise and omega-3, have been considered and/or tried.
Abstract
Although the prevalence of attention-deficit/hyperactivity disorder (ADHD) has been stable over the past 3 decades, prescriptions of sympathomimetic stimulants have steadily increased in the United States. This study consisted of a systematic review of PubMed articles screened for ADHD medications and potential cardiovascular toxicity as well as nondrug strategies for managing ADHD. The cumulative body of data showed that ADHD medications cause modest elevations in resting heart rate and blood pressure. Other adverse effects reported with ADHD stimulants included arrhythmia, nonischemic cardiomyopathy, Takotsubo cardiomyopathy, and sudden death. However, such reports did not imply causation, and there was a paucity of randomized trial evidence addressing long-term safety of ADHD medications, particularly among adults. Further studies are essential to clarify the risks and benefits of ADHD stimulant medications and to explore nonpharmacological options, including regular exercise and omega-3 fatty acids, which could be helpful for improving ADHD symptoms.
The most commonly diagnosed and pharmacologically treated behavioral disorder in children and adolescents is attention-deficit/hyperactivity disorder (ADHD). Stimulants have been shown to significantly improve the ADHD symptoms, physical hyperactivity and inability to sustain mental focus, in children and adults (1–3). All ADHD medications have warnings on their package inserts regarding potential serious adverse cardiovascular (CV) reactions and blood pressure (BP) elevations (4). Currently, 6.1 million U.S. children and adolescents are taking U.S. Food and Drug Administration (FDA)-approved ADHD medications, which include amphetamine salts, methylphenidate, lisdexamfetamine, atomoxetine, and methamphetamine (5).
All drugs used to treat ADHD are sympathomimetic amines with similar chemical structures and physiological activities. These compounds exert stimulant effects on the central nervous system by increasing the levels of noradrenaline and dopamine levels in the prefrontal cortex and stimulate adrenergic receptors in the heart and blood vessels leading to small increases in resting heart rate (RHR) and BP (6).
Rising Prescriptions for ADHD Drugs
The availability and use of sympathomimetic amines to treat ADHD have expanded in recent years; for example, there was a 3-fold increase in worldwide production of methylphenidate between 2000 and 2010 (7).
Presently, 5.2% of all U.S. children 2 to 17 years of age are using ADHD prescriptions (5). Although the global prevalence of ADHD has remained stable over the past 3 decades (8), the diagnosis of ADHD increased by 26% in U.S. children 5 to 11 years of age from 2007 to 2016, while the diagnosis in U.S. adults increased by 123% during the same period (9). ADHD medication prescriptions filled by adult females increased by 344% between 2003 and 2015 (10). This is of particular concern because adults ∼50 years of age appear to be more vulnerable to adverse CV effects of ADHD drugs than children (11–14), presumably because of the greater risk of underlying CV disease.
The American Academy of Pediatrics recommends that behavioral (nondrug) therapy should be the first line of treatment before ADHD medications (8). However, among U.S. children with diagnoses of ADHD, 77% were currently taking prescription sympathomimetic amines, whereas 47% had received behavioral therapy in the preceding 12 months (5). Similar findings have been published by the U.S. Centers for Disease Control and Prevention, showing 75% of the children with ADHD diagnoses were treated with stimulants, whereas psychological services were provided to approximately 50% of ADHD children (15). The percentage of children taking ADHD medications has been increasing in the United States and Canada and is now approximately 5- to 10-fold higher in North America than in other developed nations in Europe and Asia (Figure 1) (16). The reasons for this are speculative but could include greater familiarity with ADHD medications among practitioners in North America; cost and availability barriers to implementing behavioral therapy; and/or indirect effects of educational reform laws in which school personnel recommend that parents with low academically performing children be evaluated for ADHD (17).
Figure 1
Comparative Prevalence of ADHD Medication Use Internationally
Overall annual prevalence of attention-deficit/hyperactivity disorder (ADHD) medication use in children 3 to 18 years of age (16). UK = United Kingdom.
Autonomic Nervous System and CV Health
Chronic excessive sympathetic nervous system (SNS) activity increases the cardiac workload and predisposes to hypertension, endothelial dysfunction, left ventricular hypertrophy, and episodes of arrhythmia, whereas increased vagal activity vasodilates, slows RHR, lowers BP, and improves heart rate variability (18,19). Notably, the circadian peak of SNS activity usually occurs in the hours just before and after awakening in the morning, which correlates closely with the riskiest period during the 24-h daily cycle for myocardial infarction (MI), sudden cardiac death (SCD), and stroke (18,20).
Because the patients treated with ADHD medications are usually young with resilient CV health at baseline and because most of the published studies were of short duration and showed few adverse events, medical professionals and the general public typically consider sympathomimetic amines to be exempt from CV effects. However, other sympathomimetic drugs used for asthma, heart failure, and hypotension have been associated with increased risk of CV events, particularly among patients with existing CV disease (CVD) (18). Furthermore, ADHD medications have been shown to adversely affect the autonomic nervous system by decreasing heart rate variability and increasing arterial stiffness (21).
ADHD Drugs Raise BP and RHR
Generally, studies have found that amphetamines and methylphenidate increase RHR and systolic BP. A meta-analysis of 10 clinical trials reported that ADHD medications significantly increased RHR by +5.7 beats/min, and systolic BP by 2.0 mm Hg (22). Increments in RHR are directly correlated with higher rates of CVD and mortality during follow-up examinations in epidemiological studies (23), although specific data regarding the risks of pharmacologically induced rises in RHR are lacking (24–26).
Use of methylphenidate in a randomized placebo-controlled trial (RCT) has been associated with 4-fold increased odds of developing prehypertension in previously normotensive adults (27). The most recent American College of Cardiology guidelines recommend that, for patients with hypertension who are taking ADHD drugs, physicians should either decrease the dose of these sympathomimetic amines or discontinue the medications altogether because they may cause elevated BP (28).
Risk of adverse CV event studies of CV safety in children and young adults
The safety data considered by the FDA in 2011 for ADHD treatment in children was based on a retrospective cohort from insurance data, including 1,200,438 subjects 2 to 24 years of age and a mean follow-up of 2.1 years. That study found no increased risk of adverse CV events (MI, SCD, or stroke) with use of stimulants (29).
A longitudinal, prospective, nationwide cohort study focused on all children born in Denmark between 1990 and 1999 with a mean follow-up of 9.5 years. Among all the children with ADHD (n = 8,300), there was an increased risk of adverse CVD events including arrhythmia (23%), cerebrovascular disease (9%), hypertension (8%), ischemic heart disease (2%), heart failure (2%), and pulmonary hypertension (<1%) in a comparison of ADHD prescription medication users versus nonusers (adjusted hazard ratio: 2.3; 95% confidence interval [CI]: 1.2 to 4.8) (30).
A case series using the South Korean national health insurance claims database included 1,224 patients 17 years of age or younger who had been treated with methylphenidate for a mean of 6 months (31). That study found increased risk of arrhythmia in all exposure periods (adjusted incidence ratio: 1.6; 95% CI: 1.4 to 1.7), although the highest risk was observed during the first week after initiation of methylphenidate therapy. Also, in the subgroup analysis, the risk for arrhythmia was higher for patients with congenital heart disease (31).
In a retrospective cohort study of 55,383 subjects 3 to 20 years of age with a mean follow-up of 31 months, use of ADHD medication was associated with a 20% increased risk for emergency department visits due to cardiac causes (syncope 34%, arrhythmia 33%, tachycardia and palpitation 16%, and hypertensive disease 15%). However, the number of events was too small for meaningful statistical analysis for risk of CV death (32).
Olfson et al. (6) conducted a retrospective cohort including 171,000 subjects 6 to 21 years of age and found no increased risk of cardiac events (including angina pectoris, cardiac dysrhythmias, transient ischemic attack) or cardiac symptoms (including tachycardia, palpitations, and syncope) (6).
Over the past 3 decades, sporadic cases of SCD have been reported among children using methylphenidate or amphetamines for ADHD (33,34). A matched case-control study of individuals 7 to 19 years of age found an increased risk of SCD in the group taking sympathomimetic stimulants (35). To eliminate the uncertainty related to recall bias, a subgroup analysis of this study was performed based solely on cases with autopsy, toxicology, and medical examiner reports; analysis still showed a positive association between ADHD medications and SCD (35).
Studies of CV safety in adults
One study used by the FDA for safety, conducted by Habel et al. (36), is the largest and most comprehensive study performed in adults. That study used a design similar to the study by Habel et al. (36) including 443,198 adults 25 to 64 years of age with a median use of 4 months and follow-up of 1.3 years. They reported that, although the overall CV risk was not increased in people with a history of ADHD medication use, adverse CVD events (MI, SCD, or stroke) trended insignificantly higher in patients who had recently started ADHD medications (36). Unexpectedly, the current use of ADHD medications was protective against a composite of CV events (MI, SCD, or stroke) compared to nonuse (36).
A cohort study consisting of 43,999 individuals who were at least 18 years of age compared methylphenidate users to matched nonusers with a median follow-up of only 60 days (14). Among methylphenidate users, there was a significantly higher risk for SCD or ventricular arrhythmia (14). Moreover, a significant association was found for all-cause mortality, although similar trends were not found for stroke or MI. A year later, the same group of investigators, Schelleman et al. (37) found no increased risk of SCD/ventricular arrhythmia, stroke, MI, or all-cause death associated with the use of amphetamines or atomoxetine in adults with short median follow-up periods of 88 and 60 days, respectively.
A study of patients 65 years of age and older who were taking ADHD medications showed increased risk of 1 case of new heart failure per 10.5 person-years of stimulant use, with the symptoms usually appearing within the first 90 days of initiation of the ADHD medication (13). Not surprisingly, older patients were far more likely to present with new heart failure or cardiomyopathy than younger patients, and the older patients tended to present earlier after ADHD drug initiation (13). ADHD medications have been associated with acute coronary syndrome in the setting of normal coronary arteries on angiography (38,39). Stress-induced cardiomyopathy, also referred to as Takotsubo cardiomyopathy, has also been reported in patients taking ADHD medications (40,41).
As presented above, the current evidence is mixed regarding associations with CV events. All these studies have different age groups, outcomes, and use of medications. Three of the 6 studies were performed in children and adolescents, whereas 2 of the 4 studies performed in adults were negative. Future research needs to be done on very large cohorts as the incidence of these events is low and would be very hard to demonstrate on RCTs. Also, study samples should be enhanced with older adults as well as those at a high risk for CV disease. A longer follow-up may be required to assess chronic risks as the majority of the studies had follow-up times ongoing for1 to 2 years in comparison.
Exercise to Modify ADHD
Exercise is another natural and benign nondrug treatment for ADHD. Exercise has immediate and long-term positive effects on behavioral and cognitive measurements in patients with ADHD (42). The potential benefits of exercise for ADHD are likely due to the increase of norepinephrine, dopamine, and serotonin levels in the prefrontal cortex during and after physical activity (43). Also, brain-derived neurotrophic factors, synaptic proteins, glutamate receptors, and insulin-like growth factor all rise during and after strenuous physical activity, which improves cognitive function by contributing to cell proliferation and neural plasticity (42).
Ahmed and Mohamed (44) conducted an RCT involving 84 students in a 10-week aerobic exercise program for students with ADHD. After 10 weeks, the intervention group had significant improvements in attention, motor skills, and academic/classroom behavior with no improvements on task orientation or emotional and oppositional behavior. A comprehensive meta-analysis of 8 RCTs (n = 249) reported that aerobic exercise significantly improved attention, hyperactivity, impulsivity, anxiety, executive function, and social disorders (Figure 2) (45). Estimates from RCT data indicate that the dose of physical activity for treating ADHD should entail bouts of high-intensity aerobic exercise lasting at least 30 min, at least 3 to 5 times per week (42,43,46). However, this is still somewhat speculative, and the dose of exercise required to achieve a significant therapeutic effect on ADHD appears to vary by sex. Males appear to require high-intensity exercise to achieve significant changes in brain dopaminergic activity, whereas females perform better after submaximal exercise (46). Even with the current uncertainties, a regular exercise program has been proposed as an alternative to ADHD medications or as an adjuvant to pharmacotherapy that may help to lower the doses and frequency of use for ADHD medications (Central Illustration) (43).
Figure 2
Exercise and Attention-Deficit/Hyperactivity Disorder Symptoms
Effects of the aerobic exercise programs on symptoms and/or problems (45). SE = standard error.
Central Illustration
Cardiovascular Effects of Attention-Deficit/Hyperactivity Disorder Therapies
Psychostimulant activation of the sympathetic nervous system (SNS) leads to increments in resting heart rate and blood pressure as well as vasoconstriction and arrhythmogenic potential. The outcome of SNS stimulation could potentially result in hypertension, increment in cardiovascular mortality, myocardial infarction (MI), arrhythmia episodes, sudden cardiac death, and Takotsubo and amphetamine-associated cardiomyopathy. The effects of nonpharmacological strategies such as physical activity and omega-3 are cardioprotective by improvements in autonomic tone. ↑ = increases; ↓ = decreases; BP = blood pressure; CM = cardiomyopathy; CV = cardiovascular; MI = myocardial infarction; SNS = sympathetic nervous system.
Omega-3 Used to Modify ADHD
Omega-3 polyunsaturated fatty acids are found in high concentrations in the phospholipids of the neuronal and myocardial cell membranes, giving fluidity to the membranes and altering the function of membrane-bound proteins (47). Tellingly, omega-3 deficiency in animal studies is associated with reduced levels of dopamine and serotonin in the frontal cortex (47). Also, children with ADHD have been found to have significantly lower levels of omega-3 than controls (48). There have been several small RCTs of omega-3 for treating ADHD symptoms, with mixed results regarding its effectiveness; some of the trials were encouraging, while others were negative (49–52).
A meta-analysis of 7 RCTs including 534 young patients found that omega-3 supplementation significantly improved parental reports of inattention, hyperactivity, and total symptom scores (Figure 3) (53). Also, omega-3 improved total ADHD symptoms with a modest effect size (ES) and reduced omission/commission errors with a large ES (53). Only studies with eicosapentaenoic acid (EPA) doses >500 mg/day consistently showed improvements in hyperactivity symptoms (53). Another meta-analysis of omega-3 for ADHD, which included 10 RCTs of 699 children, found a modest but statistically significant ES of 0.31 for improving ADHD symptoms (54). An even larger meta-analysis of 16 studies of 1,408 children also found modest ES (0.26; 95% CI: 0.15 to 0.37) of omega-3 on the pooled composite of ADHD symptoms. Although omega-3 consistently reduced hyperactivity-impulsivity, it did not improve inattention behavior (55).
Figure 3
Omega-3 Effects on ADHD Symptoms Versus Placebo
Forest plots showing total effect sizes from pooled results comparing attention-deficit/hyperactivity disorder (ADHD) clinical symptoms in the omega-3 group and the and placebo group (53). CI = confidence interval; ES = effect size.
In most ADHD studies to date, the total daily omega-3 dose was approximately 500 mg, which produced an ES of approximately 0.36 (54). For reference, methylphenidate (ES = 0.78; 95% CI: 0.64 to 0.91) and atomoxetine (ES = 0.64; 95% CI: 0.51 to 0.76) show larger improvements in ADHD symptoms (54). However, a large body of RCT data indicate that the benefits of omega-3 for reducing CV risk were dose-dependent and linear, whereby every 1 g/day docosahexaenoic acid (DHA) plus 4 g/day EPA showed the best results, reducing risk of major CVD events by 8% (56). Similarly, higher doses of EPA appear to be associated with increasing efficacy in treating ADHD symptoms (Figure 4), suggesting that larger doses of omega-3 may be needed for optimal ADHD treatment as well. The current data suggest that the use of omega-3 may be reasonable to augment the efficacy of conventional therapies or as an option for families who decline stimulants, but more research with higher doses of omega-3 are needed to clarify these issues.
Figure 4
EPA Dose and Treatment Efficacy for Attention-Deficit/Hyperactivity Disorder
Scatterplot displays the measured efficacy of omega-3 fatty acid supplementation in trials as a function of eicosapentaenoic acid (EPA) dose used. Thesize of the circleindicates trial weight obtained through generic inverse variance method (54).
Conclusions
Although the prevalence of ADHD has been stable for the past 3 decades, the use of sympathomimetic drugs in the United States has been on the rise. ADHD medications increase RHR and BP and are associated with increased risks of CVD. Promising alternative treatments for ADHD include omega-3 and exercise. More high-quality prospective research is needed to explore the potential dangers of ADHD medications in both the children and adult populations and to evaluate nonpharmacological treatments for ADHD that have less potential for cardiac toxicity.
Footnotes
Dr. O’Keefe has a major ownership interest in CardioTabs. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit theJACCauthor instructions page.
