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April 24, 2024
Are attention-deficit/hyperactivity disorder (ADHD) medications associated with risk of cardiovascular disease (CVD)?
An international study team has just explored this question with a meta-analysis of nineteen studies with a total of almost four million participants of all ages. It included 3,931,532 participants from six countries or regions: United States, South Korea, Canada, Denmark, Spain, and Hong Kong.
Overall, using the entire data set, it found no significant association between any ADHD medication use and any cardiovascular event.
The same held true when breaking this down by children and adolescents (twelve studies with over 1.7 million participants), young and middle-aged adults (seven studies with over 850,000 participants), and older adults (six studies with over a quarter million participants).
The team then compared the data for stimulant medications with data for non-stimulant medications. A meta-analysis of 17 studies with over 3.8 million participants found no significant association between stimulant medications and cardiovascular risk. Similarly, a meta-analysis of three studies with over 670,000 participants found no significant association between non-stimulant medications and cardiovascular risk.
Distinguishing between types of cardiovascular risk made no difference. For instance, a meta-analysis of nine studies with over 900,000 participants found no effect of stimulant medications on risk of myocardial infarction (heart attack), and a meta-analysis of six studies, also with over 900,000 participants, found no effect of stimulant medications on risk of cerebrovascular disease, including stroke, brain aneurysm, brain bleed, and carotid artery disease. A meta-analysis of eight studies with over 1.1 million participants did find an increase in the occurrence of cardiac arrest and tachyarrhythmias (racing heart rate accompanied by arrhythmias), but it was not statistically significant.
A meta-analysis of eleven studies with over 3.1 million persons with no prior history of cardiovascular disease found absolutely no effect of ADHD medications on subsequent risk for any cardiovascular event. Another meta-analysis, of eight studies encompassing over 1.8 million individuals with a prior history of cardiovascular disease, reported a higher rate of subsequent occurrence, but it was not considered statistically significant.
The team concluded, “Overall, our meta-analysis provides reassuring data on the putative cardiovascular risk with ADHD medications.” An international team of researchers recently investigated whether medications for attention-deficit/hyperactivity disorder (ADHD) are linked to an increased risk of cardiovascular disease (CVD). They conducted a comprehensive review, known as a meta-analysis, which included 19 studies with nearly four million participants from six countries or regions: the United States, South Korea, Canada, Denmark, Spain, and Hong Kong.
The findings from the entire data set showed no significant link between the use of any ADHD medications and the occurrence of cardiovascular events. This lack of association was consistent across all age groups: children and adolescents (12 studies with over 1.7 million participants), young and middle-aged adults (7 studies with over 850,000 participants), and older adults (6 studies with over 250,000 participants).
The researchers also compared the effects of stimulant medications against non-stimulant medications on cardiovascular risk. Both categories showed no significant risks in a meta-analysis of 17 studies with more than 3.8 million participants for stimulants, and three studies with over 670,000 participants for non-stimulants.
Further analysis differentiated between types of cardiovascular risks, such as myocardial infarction (heart attack) and cerebrovascular diseases (like stroke, brain aneurysm, and carotid artery disease). Again, stimulant medications showed no significant impact on these conditions in studies involving over 900,000 participants each. However, a review of eight studies with over 1.1 million participants suggested a slight increase in incidents of cardiac arrest and tachyarrhythmias (a racing heart rate with irregular rhythms), but these findings were not statistically significant.
Additionally, an analysis of 11 studies involving more than 3.1 million people without a prior history of cardiovascular disease found no effect of ADHD medications on the risk of developing cardiovascular events. Likewise, an analysis of eight studies with over 1.8 million individuals who had a history of cardiovascular disease showed a higher occurrence rate of events, but this increase was also not statistically significant.
The conclusion of the research team was clear: the data is reassuring and does not suggest a substantial cardiovascular risk associated with ADHD medications. Keep in mind that this reflects current standards of care. Most guidelines call for monitoring of pulse and blood pressure during treatment so that adverse cardiovascular outcomes can be avoided.
Le Zhang, Honghui Yao, Lin Li, Ebba Du Rietz, Pontus Andell, Miguel Garcia-Argibay, Brian M. D’Onofrio, Samuele Cortese, Henrik Larsson, Zheng Chang, “Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis,” JAMA Network Open (2022) 5(11), e2243597, https://doi.org/10.1001/jamanetworkopen.2022.43597.
Methylphenidate, a psychostimulant, is among the drugs most frequently prescribed to children with ADHD.
Using magnetic resonance imaging(MRI), studies have shown that as children mature, those with ADHD differ from controls in developing regionally thinner cortices (the folded outer layer of the cerebrum that is essential to rational thought) and smaller lower basal ganglia(structures linked to the thalamus in the base of the brain and involved in the coordination of movement). The cortical differences were found in the right medial frontal motor region, the left middle/inferior frontal gyrus, and the right posterior parieto-occipital region in children with ADHD who were not taking psychostimulants.
A Dutch/Norwegian team of researchers conducted a randomized, double-blind, placebo-controlled trial with 96 males recruited from Dutch clinical programs. 48 were boys aged 10-12 years, and 47 were men between the ages of 23 and 40. None had previously been on methylphenidate. There were no significant differences in baseline age, ADHD symptom severity, estimated intelligence quotient, the proportion of right-handedness, or region of interest brain characteristics between the placebo and medication groups.
The trial was carried out during the standard 17-week waiting list time for evaluation and treatment to begin so that those receiving a placebo during the trial would not ultimately be at a disadvantage. The same MRI scanner was used for all measurements, both before and after treatment.
Among the boys, the methylphenidate group showed increased thickness in the right medial cortex, while the placebo group showed cortical thinning. In adults, both groups showed cortical thinning. When converted into an estimated mean rate of change in cortical thickness for the right medial cortex, boys taking methylphenidate could expect to lose about 0.01 mm per year, versus about 0.14 mm for boys not on methylphenidate.
In the right posterior cortex, scans also showed reduced thinning in the methylphenidate treatment group, though to a lesser extent. But there was no reduced thinning in the left frontal cortex.
The authors noted several limitations. The sample size was small. Second, "because we did not detect significant relationships between changes in cortical [regions of interest] and changes in symptom severity, the functional significance remains uncertain." Third, the follow-up period was relatively short, not allowing any assessment of the longer-term effects of the medication. Fourth, the differences in effects on the three brain regions examined were uneven, contrary to what had been expected from previous studies. They recommended replication with larger groups and longer follow-ups.
A Chinese research team performed two types of meta-analyses to compare the risk of suicide for ADHD patients taking ADHD medication as opposed to those not taking medication.
The first type of meta-analysis combined six large population studies with a total of over 4.7 million participants. These were located on three continents - Europe, Asia, and North America - and more specifically Sweden, England, Taiwan, and the United States.
The risk of suicide among those taking medication was found to be about a quarter less than for unmediated individuals, though the results were barely significant at the 95 percent confidence level (p = 0.49, just a sliver below the p = 0.5 cutoff point). There were no significant differences between males and females, except that looking only at males or females reduced sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications produced divergent outcomes. A meta-analysis of four population studies covering almost 900,000 individuals found stimulant medications to be associated with a 28 percent reduced risk of suicide. On the other hand, a meta-analysis of three studies with over 62,000 individuals found no significant difference in suicide risk for non-stimulant medications. The benefit, therefore, seems limited to stimulant medication.
The second type of meta-analysis combined three within-individual studies with over 3.9 million persons in the United States, China, and Sweden. The risk of suicide among those taking medication was found to be almost a third less than for unmediated individuals, though the results were again barely significant at the 95 percent confidence level (p =0.49, just a sliver below the p = 0.5 cutoff point). Once again, there were no significant differences between males and females, except that looking only at males or females reduced the sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications once again produced divergent outcomes. Meta-analysis of the same three studies found a 25 percent reduced risk of suicide among those taking stimulant medications. But as in the population studies, a meta-analysis of two studies with over 3.9 million persons found no reduction in risk among those taking non-stimulant medications.
A further meta-analysis of two studies with 3.9 million persons found no reduction in suicide risk among persons taking ADHD medications for 90 days or less, "revealing the importance of duration and adherence to medication in all individuals prescribed stimulants for ADHD."
The authors concluded, "exposure to non-stimulants is not associated with a higher risk of suicide attempts. However, a lower risk of suicide attempts was observed for stimulant drugs. However, the results must be interpreted with caution due to the evidence of heterogeneity ..."
Counting umbilical cord vessels is standard in prenatal ultrasounds and confirmed at birth. Single umbilical artery (SUA) occurs in about 1 in 200 cases, with roughly 10% associated with anomalies, including central nervous system defects. Isolated SUA (iSUA) means one artery is missing without other structural issues.
Research on SUA, especially isolated iSUA, and childhood neurodevelopmental disorders (NDD) is limited and inconclusive. iSUA is linked to preterm birth and small-for-gestational age (SGA), both of which are NDD risk factors.
This Norwegian nationwide population study aimed to assess NDD risk in children with iSUA at birth, the influence of sex, and how preterm birth and SGA mediate this relationship.
The nation’s universal single-payer health insurance and comprehensive population registries made it possible to analyze all 858,397 single births occurring from 1999 to 2013, with follow-up continuing through 2019. Among these cases, 3,532 involved iSUA.
After adjusting for confounders such as parental age, education, and maternal health factors, no overall link was found between iSUA and later ADHD diagnosis. However, females with iSUA had about a 40% higher risk of subsequent ADHD compared to those without iSUA, even after adjustment.
The authors concluded, “The present study indicates that iSUA is weakly associated with ID [intellectual disability] and ADHD, and these associations are influenced by sex. This association is mediated negligibly through preterm birth and SGA. The associations were not clinically significant, and the absence of associations of iSUA with other NDD is reassuring. This finding can be useful in the counseling of expectant parents of fetuses diagnosed with iSUA.”
Refractive errors, such as myopia (nearsightedness), hyperopia (farsightedness), and astigmatism (distorted vision due to irregular curvature of the eye or lens), are common worldwide. These conditions affect 12%, 5%, and 15% of children, and rise significantly in adults to 26.5%, 31%, and 40%. Additionally, strabismus (misalignment of the eyes) and amblyopia (reduced vision in one eye from uneven image formation, often linked to strabismus) occur globally at rates of 2% and 1.4%, respectively.
Visual impairment can affect children’s concentration in school, and studies suggest a link between eye disorders and ADHD.
To investigate this relationship, two researchers – one based in the US and the other in Israel –carried out a nationwide retrospective cohort study using electronic medical records of all insured individuals aged 5 to 30 who were part of Maccabi Health Services, Israel’s second largest health maintenance organization, between 2010 and 2022.
Of over 1.6 million insured members (2010–2020), inclusion/exclusion criteria and propensity score matching for age and sex were applied, along with a one-year wash-out period between the first eye diagnosis and ADHD diagnosis. In total, 221,707 cases were matched with controls without eye disorders at a 1:2 ratio, resulting in a cohort of 665,121 participants.
Overall, those with any previous eye diagnosis were 40% more likely to have a subsequent ADHD diagnosis. This was slightly higher for females (45%) than for males (35%). It was also slightly higher for children and adolescents (42%) than for adults (37%).
More specifically:
The authors concluded that eye disorders are associated with ADHD. They noted these associations were more marked in females and children and adolescents, although, as noted above, those differences were small. They recommended that primary care providers and neurologists consider risk stratification for early screening, and that ophthalmologists refer high-risk patients for ADHD evaluation.
Acid-suppressive medications, including proton pump inhibitors (PPIs) and histamine-2 (H2) receptor antagonists, are often prescribed during pregnancy to treat heartburn and gastroesophageal reflux disease.
Research shows changes in the gut microbiome can negatively affect neurodevelopment. Since acid-suppressive medications alter gut microbiota, maternal use during pregnancy may impact offspring’s neurodevelopment. Because PPIs and H2 receptor antagonists readily cross the placental barrier, they could potentially influence fetal neurodevelopment.
The link between prenatal exposure to acid-suppressive medications and major neuropsychiatric disorders is not well understood. With the use of these medications during pregnancy rising, it is important to assess their impact on children's long-term neurodevelopment. This study examined whether maternal use of acid-suppressive drugs is associated with increased risk of neuropsychiatric disorders in children, using a large, nationwide birth cohort from South Korea.
South Korea operates a single-payer health insurance system, providing coverage for over 97% of its citizens. The National Health Insurance Service (NHIS) maintains a comprehensive database with sociodemographic details, medical diagnoses, procedures, prescriptions, health examinations, and vital statistics for all insured individuals.
A Korean research team analyzed data from over three million mother-child pairs (2010–2017) to assess the risks of prenatal exposure to acid-suppressing medications. They applied propensity scoring to adjust for maternal age, number of children, medical history, and outpatient visits before pregnancy, to minimize confounding factors. That narrowed the cohort to just over 800,000 pairs, with half in the exposed group.
With these adjustments, prenatal exposure to acid-suppressing medications was associated with 14% greater likelihood of being subsequently diagnosed with ADHD.
Yet, when 151,737 exposed births were compared to the same number of sibling controls, no association was found between prenatal exposure and subsequent ADHD, which suggests unaccounted familial and genetic factors influenced the preceding results.
The Take-Away:
Evidence of these medications negatively affecting pregnancies is mixed, mostly observational, and generally reassuring when these medications are used appropriately. Untreated GERD and gastritis, however, have known risks and associations with the development of various cancers. With no evidence of an association with ADHD (or for that matter any other neuropsychiatric disorder), there is no current evidence-based reason for expectant mothers to discontinue use of acid-suppressing medications.
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