Sex Differences in ADHD Symptoms and Related Cognitive Deficits in Youths

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: 

• Myopia (425,000+ participants): 30% higher ADHD rate. 

• Hyperopia (120,000+) and astigmatism (175,000+): over 50% higher ADHD rate. 

• Strabismus (13,000+): over 60% higher ADHD rate. 

• Amblyopia (14,000+): 40% higher ADHD rate. 

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. 

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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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For years, a persistent concern has shadowed the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD): Does the medication eventually stop working? Patients often report that their symptoms seem to return despite consistent use, leading to "dose escalation" or "medication holidays." A new systematic review from Sam Cortese’s team  published in CNS Drugs finally puts these concerns to the test by synthesizing decades of empirical research.

Before diving into the findings, you must understand two often-confused phenomena:

• Tachyphylaxis (Acute Tolerance): A rapid decrease in response to a drug, often occurring within a single day (24 hours).
• Tolerance: A gradual reduction in responsiveness over long-term exposure, requiring higher doses to achieve the original effect.

The review analyzed 17 studies covering over 10,000 individuals, and the results provide a much-needed reality check for the clinical community.

The researchers found preliminary evidence that acute tolerance (tachyphylaxis) can occur within a 24-hour window.

• Subjective Effects: Studies showed that "drug liking" or feelings of euphoria from stimulants often peak and fade faster than the actual drug concentration in the blood.
• Clinical Impact: This phenomenon is why some older, flat-release formulations were less effective than modern "ascending" delivery systems (like OROS-methylphenidate), which are designed to overcome this daily dip in efficacy.

The most important finding is that tolerance does not commonly develop to the therapeutic effects of ADHD medication in the long term. In one landmark study following children for up to 10 years, only 2.7% of participants lost their response to methylphenidate without a clear external explanation.  Doses, when adjusted for natural body growth, remained remarkably stable over years of treatment.

Consistent with the lack of therapeutic tolerance, the body does not become tolerant to the physical side effects of stimulants.  Increases in heart rate and blood pressure typically persist for as long as the medication is taken.  This underscores why clinicians must continue monitoring cardiovascular health throughout the entire duration of treatment.

If it’s Not Tolerance, What Is It?

If "tolerance" isn't real, why do some patients feel their medication is failing? The review suggests clinicians look at these alternative explanations:

1. Natural Symptom Fluctuations: ADHD is not a static condition; symptoms naturally wax and wane over time regardless of treatment.
2. Limited Compliance: Missed doses or inconsistent timing are often the real culprits behind "failing" efficacy.
3. Life Events & Transitions: New jobs, academic pressures, or stressful life changes can increase the "functional demand" on a patient, making their current dose feel insufficient.
4. Co-occurring Conditions: The emergence of anxiety, depression, or substance use disorders can mask or mimic a return of ADHD symptoms.

Why This Matters

These results provide clinicians the confidence to tell patients that their medication is unlikely to "wear out" permanently. Rather than immediately increasing a dose when symptoms flare, the first step should be a "clinical deep dive" into the patient's lifestyle, stress levels, and adherence.

For researchers, the review highlights a major gap: most existing studies are small, dated, or of low quality. There is a dire need for robust, longitudinal studies that track both the brain's response and the patient's environment over several years.

For people with ADHD, while your body might get "used to" the initial "buzz" of a stimulant within hours, its ability to help you focus and manage your life remains remarkably durable over the years.