July 23, 2025

Are There Adverse Effects to Long-Term Treatment of ADHD with Methylphenidate?

Methylphenidate (MPH) is one of the most widely-prescribed medications for children. Given that ADHD frequently persists over a large part of an individual’s lifespan, any side effects of medication initiated during childhood may well be compounded over time. With funding from the European Union, a recently released review of the evidence looked for possible adverse neurological and psychiatric outcomes.

From the outset, the international team recognized a challenge: “ADHD severity may be an important potential confounder, as it may be associated with both the need for long-term MPH therapy and high levels of underlying neuropsychiatric comorbidity.” Their searches found a highly heterogeneous evidence base, which made meta-analysis inadvisable. For example, only 25 of 39 group studies reported the presence or absence of comorbid psychiatric conditions; even among those, only one excluded participants with comorbidities. Moreover in only 24 of 67 studies was the type of MPH used (immediate or extended-release) specified. The team, therefore, focused on laying out an “evidence map” to help determine priorities for further research.

The team found the following breakdown for specific types of adverse events:

·  Low mood/depression. All three non-comparative studies found MPH safe. Two large cohort studies, one with over 2,300 participants, and the other with 142,000, favored MPH over the non-stimulant atomoxetine. But many other studies, including a randomized controlled trial (RCT), had unclear results. Conclusion: “the evidence base regarding mood outcomes from long-term MPH treatment is relatively strong, includes two well-powered comparative studies, and tends to favor MPH.”

·  Anxiety. Here again, all three non-comparative studies found MPH safe. But only two of seven comparative studies favored MPH, with the other five having unclear results. Conclusion: “while the evidence about anxiety as an outcome of long-term MPH treatment tends to favor MPH, the evidence base is relatively weak.”

·   Irritability/emotional reactivity. A large cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: “the evidence base  is limited, although it includes one well-powered study that found in favor of MPH over atomoxetine.”

·  Suicidal behavior/ideation. There were no non-comparative studies, but all five comparative studies favored MPH. That included three large cohort studies, with a combined total of over a hundred thousand participants, that favored MPH over atomoxetine. Conclusion: “the evidence base  is relatively strong, and tends to favor MPH.”

·  Bipolar disorder. A very large cohort study, with well over a quarter-million participants, favored MPH over atomoxetine. A much smaller cohort study comparing MPH with atomoxetine, with less than a tenth the number of participants, pointed toward caution. Conclusion: “the evidence base  is limited and unclear, although it includes two well-powered studies.”

·  Psychosis/psychotic-like symptoms. By far the largest study, with over 145,000 participants, compared MPH with no treatment and pointed toward caution. A cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: “These findings indicate that more research is needed into the relationship between ADHD and psychosis, and into whether MPH moderates that risk, as well as research into individual risk factors for MPH-related psychosis in young people with ADHD.”

· Substance use disorders. A cohort study with over 20,000 participants favored MPH over anti-depressants, anti-psychotics, and no medication. Other studies looking at dosages and durations of treatment, age at treatment initiation, or comparing with no treatment or “alternative” treatment, all favored MPH except a single study with unclear results. Conclusion: “the evidence base … is relatively strong, includes one well-powered study that compared MPH with antipsychotic and antidepressant treatment, and tends to favor MPH.”

·Tics and other dyskinesias. Of four non-comparative studies, three favored MPH, the other, with the smallest sample size, urged caution. In studies comparing with dexamphetamine, pemoline, Adderall, or no active treatment, three had unclear results and two pointed towards caution. Conclusion: “more research is needed regarding the safety and management of long-term MPH in those with comorbidities or tic disorder.”

·  Seizures or EEG abnormalities. With one exception, the studies had small sample sizes. The largest, with over 2,300 participants, compared MPH with atomoxetine, with inconclusive results. Two small studies found MPH safe, one had unclear results, and two others pointed towards caution. Conclusion: “While the evidence is limited and unclear, the studies do not indicate evidence for seizures as an AE of MPH treatment in children with no prior history  more research is needed into the safety of long-term MPH in children and young people at risk of seizures.”

·  Sleep Disorders. All three non-comparative studies found MPH safe, but the largest cohort study, with over 2,300 participants, clearly favored atomoxetine. Conclusion: “more research is needed into the relationship between ADHD, sleep, and long-term MPH treatment.”

· Other notable psychiatric outcomes. Two non-comparative studies, with 118 and 289 participants, found MPH safe. A cohort study with over 700 participants compared with atomoxetine, with inconclusive results. Conclusion: “there is limited evidence regarding long-term MPH treatment and other neuropsychiatric outcomes, and that further research may be needed into the relationship between long-term MPH treatment and aggression/hostility.”

Although this landmark review points to several gaps in the evidence base, it mainly supports prior conclusions of the US Food and Drug Administration) and other regulatory agencies (based on short-term randomized controlled trials) that MPH is safe for the treatment of ADHD in children and adults. Given that MPH has been used for ADHD for over fifty years and that the FDA monitors the emergence of rare adverse events, patients, parents, and prescribers can feel confident that the medication is safe when used as prescribed.

Helga Krinzinger, Charlotte L Hall, Madeleine J Groom,Mohammed T Ansari, Tobias Banaschewski, Jan K Buitelaar, Sara Carucci, DavidCoghill, Marina Danckaerts, Ralf W Dittmann, Bruno Falissard, Peter Garas,Sarah K Inglis, Hanna Kovshoff, Puja Kochhar, Suzanne McCarthy, Peter Nagy,Antje Neubert, Samantha Roberts, Kapil Sayal, Edmund Sonuga-Barke , Ian C KWong , Jun Xia, Alexander Zuddas, Chris Hollis, Kerstin Konrad, Elizabeth BLiddle and the ADDUCE Consortium, “Neurological and psychiatric adverse effectsof long-term methylphenidate treatment in ADHD: A map of the current evidence,”Neuroscience and Biobehavioral Reviews (2019) DOI: https://doi.org/10.1016/j.neubiorev.2019.09.023.

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From Meds to Mindfulness: What Actually Works for Adult ADHD?

A new large-scale study has shed light on which treatments for attention-deficit/hyperactivity disorder (ADHD) in adults are most effective and best tolerated. 

Researchers analyzed 113 randomized controlled trials involving nearly 15,000 adults diagnosed with ADHD. These studies included medications (like stimulants and atomoxetine), psychological therapies (such as cognitive behavioral therapy), and newer approaches like neurostimulation.

The Findings

Stimulant medications (lisdexamfetamine and methylphenidate) as well as selective norepinephrine reuptake inhibitors (SNRI) (atomoxetine) were the only treatments that consistently reduced core ADHD symptoms—both from the perspective of patients and clinicians. It may be worth noting that atomoxetine, while effective, was less well tolerated, with more people dropping out due to side effects.

Psychological therapies such as CBT, mindfulness, and psychoeducation showed some benefits, but mainly according to clinician ratings—not necessarily from the patients themselves. Neurostimulation techniques like transcranial direct current stimulation also showed some improvements, but only in limited contexts and with small sample sizes.  

Conclusion 

So, what does this mean for people navigating ADHD in adulthood? Stimulant medications remain the most effective treatment for managing ADHD symptoms day-to-day but nonstimulant medication are not far behind, which is good given the problems we’ve had with stimulant shortages. This study also supports structured psychotherapy as a viable treatment option, especially when used in conjunction with medication. 

The study emphasizes the importance of ongoing, long-term research and the need for treatment plans that are tailored to the individual ADHD patient– Managing adult ADHD effectively calls for flexible, patient-centered care.

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April 9, 2025

What is Evidenced-Based Medicine?

What is Evidenced-Based Medicine?

With the growth of the Internet, we are flooded with information about attention deficit hyperactivity disorder from many sources, most of which aim to provide useful and compelling "facts" about the disorder.  But, for the cautious reader, separating fact from opinion can be difficult when writers have not spelled out how they have come to decide that the information they present is factual. 

My blog has several guidelines to reassure readers that the information they read about ADHD is up-to-date and dependable. They are as follows:

Nearly all the information presented is based on peer-reviewed publications in the scientific literature about ADHD. "Peer-reviewed" means that other scientists read the article and made suggestions for changes and approved that it was of sufficient quality for publication. I say "nearly all" because in some cases I've used books or other information published by colleagues who have a reputation for high-quality science.

When expressing certainty about putative facts, I am guided by the principles of evidence-based medicine, which recognizes that the degree to which we can be certain about the truth of scientific statements depends on several features of the scientific papers used to justify the statements, such as the number of studies available and the quality of the individual studies. For example, compare these two types of studies.  One study gives drug X to 10 ADHD patients and reported that 7 improved.  Another gave drug Y to 100 patients and a placebo to 100 other patients and used statistics to show that the rate of improvement was significantly greater in the drug-treated group. The second study is much better and much larger, so we should be more confident in its conclusions. The rules of evidence are fairly complex and can be viewed at the Oxford Center for Evidenced Based Medicine (OCEBM;http://www.cebm.net/).


The evidenced-based approach incorporates two types of information: a) the quality of the evidence and b) the magnitude of the treatment effect. The OCEBM levels of evidence quality are defined as follows (higher numbers are better:

  1. Mechanism-based reasoning.  For example, some data suggest that oxidative stress leads to ADHD, and we know that omega-3 fatty acids reduce oxidative stress. So there is a reasonable mechanism whereby omega-3 therapy might help ADHD people.
  2. Studies of one or a few people without a control group, or studies that compare treated patients to those that were not treated in the past.

Non-randomized, controlled studies.    In these studies, the treatment group is compared to a group that receives a placebo treatment, which is a fake treatment not expected to work.  

  1. Non-randomized means that the comparison might be confounded by having placed different types of patients in the treatment and control groups.
  2. A single randomized trial.  This type of study is not confounded.
  3. Systematic review and meta-analysis of randomized trials. This means that many randomized trials have been completed and someone has combined them to reach a more accurate conclusion.

It is possible to have high-quality evidence proving that a treatment works but the treatment might not work very well. So it is important to consider the magnitude of the treatment effect, also called the "effect size" by statisticians. For ADHD, it is easiest to think about ranking treatments on a ten-point scale. The stimulant medications have a quality rating of 5 and also have the strongest magnitude of effect, about 9 or 10.Omega-3 fatty acid supplementation 'works' with a quality rating of 5, but the score for the magnitude of the effect is only 2, so it doesn't work very well. We have to take into account patient or parent preferences, comorbid conditions, prior response to treatment, and other issues when choosing a treatment for a specific patient, but we can only use an evidence-based approach when deciding which treatments are well-supported as helpful for a disorder.

April 23, 2021

Unmedicated Adult ADHD Linked to Dementia in Population Study

Background:

Noting that “the association between adult ADHD and dementia risk remains a topic of interest because of inconsistent results,” an Israeli study team tracked 109,218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. 

Israeli law forbids nonprofit HMOs from turning anyone away based on demographic factors,  health conditions, or medication needs, thereby limiting sample selection bias.  

The estimated prevalence of dementia in this HMO, as diagnosed by geriatricians, neurologists, or psychiatrists, is 6.6%. This closely matches estimates in Western Europe (6.9%) and the United States (6.5%). 

Method:

The team considered, and adjusted for, numerous covariates: age, sex, socioeconomic status, smoking, depression, obesity, chronic obstructive pulmonary disease, hypertension, atrial fibrillation, heart failure, ischemic heart disease, cerebrovascular disease, diabetes, Parkinson’s disease, traumatic brain injury, migraine, mild cognitive impairment, psychostimulants. 

With these adjustments, individuals diagnosed with ADHD were almost three times as likely to be subsequently diagnosed with dementia as those without ADHD. Men with ADHD were two and a half times more likely to be diagnosed with dementia, whereas women with ADHD were over three times more likely, than non-ADHD peers. 

More concerning still, persons with ADHD were 5.5 times more likely to be subsequently diagnosed with early onset dementia, as opposed to 2.4 times more likely to be diagnosed with late onset dementia. 

On the other hand, the team found no significant difference in rates of dementia between individuals with ADHD who were being treated with stimulant medications and individuals without ADHD. Those with untreated ADHD had three times the rate of dementia. The team nevertheless cautioned, “Due to the underdiagnosis of dementia as well as bidirectional misdiagnosis, this association requires further study before causal inference is plausible.” 

Conclusions and Relevance:

This study reinforces existing evidence that adult ADHD is associated with an increased risk of dementia. Notably, the increased risk was not observed in individuals receiving psychostimulant medication, however the mechanism behind this association is not clear.

These findings underscore the importance of reliable ADHD assessment and management in adulthood. They also highlight the need for further study into the link between stimulant medications and the decreased risk of dementia.

 

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February 25, 2025

Population Study Finds Strong Association Between Assisted Reproductive Technologies and Offspring ADHD

Taiwanese Nationwide Population Study Finds Strong Association Between Assisted Reproductive Technologies and Offspring ADHD

Background: 

Since the first in vitro fertilization (IVF) in 1978, assisted reproductive technology (ART) has led to over 10 million births worldwide.  

There are four types of embryo transfers, depending on whether they are fresh or frozen, and on their developmental stage. 

Fresh cleavage stage embryos are transferred on day 2 or 3 following fertilization and typically contain four to eight relatively large, undifferentiated cells. Fresh blastocyst embryos are transferred on day 5 or 6 after fertilization. At this point, they have developed over a hundred cells and have differentiated into two types: the inner cell mass, which develops into the fetus, and the outer cell layer, which forms the placenta. 

Globally, more children are now born through assisted reproductive technology using frozen-thawed embryo transfer than fresh embryo transfer.  

Research suggests that ART-conceived offspring may face increased risks of cardiovascular, musculoskeletal, chromosomal, urogenital diseases, and cancers. Might they also be at increased risk for ADHD? 

Study:

Taiwan’s single-payer health insurance covers over 99% of people and records all their healthcare activity. Since 1998, it has kept an ART database for all couples registered for IVF treatment. 

A Taiwanese research team reviewed all records for the five-year period from 2013 through 2017, ultimately analyzing 3,125 live singleton births from fresh cleavage stages, 1,332 from fresh blastocysts, 1,465 from frozen cleavage stages, and 4,708 from frozen blastocysts, alongside 878,643 naturally conceived singleton births. 

The team controlled for the following potential confounders: pregnancy-induced hypertension, chronic hypertension, diabetes mellitus, gestational diabetes mellitus, unhealthy lifestyle, placenta previa, placenta abruption, preterm premature rupture of membrane, and postpartum hemorrhage. 

Results:

With these adjustments, cleavage stage embryo transfers, whether fresh or frozen, were associated with a seven-fold higher rate of ADHD diagnosis in offspring than natural conception. 

Frozen blastocyst embryo transfers were likewise linked to a seven-fold increase in ADHD diagnoses in offspring compared to natural conception. Notably, fresh blastocyst transfers showed a 19-fold increase, likely due to the smaller number of cases in this category. 

The team concluded, “Compared to natural conception, ART is associated with higher risks, particularly for preterm birth, ADHD, and developmental delay.” 

Conclusion: 

This large national cohort suggests that ART-conceived singletons face higher rates of several adverse outcomes, including preterm birth, ADHD, and developmental delay. Clinicians and prospective parents should therefore weigh these potential associations when counseling and planning care, prioritize optimized ART protocols and perinatal management, and ensure early developmental surveillance for ART-conceived children so concerns can be identified and addressed promptly.

It is important to note that the findings also point to the likely contribution of underlying parental infertility in these developmental outcomes. Future research should aim to disentangle parental- versus procedure-related risks to clarify absolute risk magnitudes. As always, associations of this time should not be interpreted as causal due to the inability of observational studies to rule out all possible confounding factors.

October 1, 2025

Why Do So Many Young People Miss an ADHD Diagnosis? Insights from a New Study

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental conditions, yet many young people, especially girls, receive a diagnosis late or not at all. This matters, because a delayed diagnosis often means missed opportunities for support, treatment, and improved long-term outcomes. A recent study by Barclay and colleagues (2024) sheds new light on why ADHD recognition is inconsistent, and what we can do about it.

The Study:

Researchers analyzed data from nearly 10,000 children in the UK Millennium Cohort Study. They compared children whose ADHD was recognized early (ages 5–7), later (ages 11–14), or not recognized at all, despite evidence of symptoms. The team also looked at differences between boys and girls to better understand why diagnosis patterns vary by sex.

Key Findings:
  1. Severity Drives Earlier Recognition
    Children who were diagnosed at a younger age often had more visible difficulties: emotional outbursts, peer conflict, conduct issues, and lower cognitive scores. In other words, the “louder” and more disruptive the symptoms, the more likely ADHD was flagged early.

  2. “Quieter” ADHD May Be Overlooked
    Children with stronger prosocial skills or higher cognitive ability were less likely to be recognized, even if they had clear ADHD symptoms. These children may be able to “mask” their difficulties, or adults may misinterpret their struggles as personality quirks rather than signs of ADHD.

  3. Emotional Dysregulation Matters
    Emotional dysregulation—big swings in mood, difficulty calming down, intense frustration—was strongly linked to recognized ADHD in boys, but not in girls. This suggests that clinicians may pay closer attention to these behaviors in boys, while overlooking them in girls.

  4. Co-occurring Conditions Can Influence Diagnosis
    Children with autism were more likely to have their ADHD identified. On the flip side, those who engaged in more physical activity were slightly less likely to be recognized, though the reasons for this are not yet clear.

What This Means for Clinicians:

The study highlights the importance of looking beyond the “classic” hyperactive child stereotype when considering ADHD. Clinicians should:

  • Pay attention to symptoms of emotional dysregulation, even if they are not part of standard diagnostic checklists.

  • Consider ADHD in children with good grades or strong social skills if other symptoms are present.

  • Be mindful of gender differences, since girls may be more likely to internalize symptoms or present with inattentiveness rather than hyperactivity.

What This Means for Parents and Patients:

If you’re a parent, it’s important to trust your observations. If your child struggles with focus, organization, or emotional regulation—even if they are doing well academically or socially—these could still be signs of ADHD. Advocating for an evaluation can make a big difference.

Moving Forward

This study makes clear that ADHD is not one-size-fits-all. Recognition often depends on how symptoms show up, how disruptive they appear, and even the child’s gender. By broadening our awareness and refining our screening practices, we can ensure that fewer children slip through the cracks and more receive the support they need early in life.

September 30, 2025

ADHD Medication and Academic Achievement: What Do We Really Know?

Parents and teachers often ask: Does ADHD medication actually improve grades and school performance? The answer is: yes, but with important limitations. Medications are very effective at reducing inattention, hyperactivity, and impulsivity but their impact on long-term academic outcomes like grades and test scores is not as consistent.

In the Classroom

The medications for ADHD consistently: Improve attention, reduce classroom disruptions, increase time spent on-task and help children complete more schoolwork and homework. Medication can help children with ADHD access learning by improving the conditions for paying attention and persisting with work.

Does Medication Improve Test Scores and Grades?

This is where the picture gets more complicated.  Medications have  stronger effect on how much work is completed but a weaker effect on accuracy. Many studies show that children on medication attempt more problems in reading, math, and spelling, but the number of correct answers doesn’t always improve as much. Some studies find small but significant improvements in national exam scores and higher education entrance tests during periods when children with ADHD are medicated.

Grades improve, as well, but modestly. Large registry studies in Sweden show that students who consistently take medication earn higher grades than those who don’t. However, these gains usually do not close the achievement gap with peers who do not have ADHD.

Keep in mind that small improvements for a group as a whole mean that some children are benefiting greatly from medication and others not at all.  We have no way of predicting which children will improve and which do not. 

Medication Alone Isn’t Enough

Academic success depends on more than just reducing inattention, hyperactivity and impulsivity. Skills like organization, planning, studying, and managing long-term projects are also critical.  Medication cannot teach these skills.

So, in addition to medication, the patient's treatment program should include educational support (tutoring, structured study skills programs), behavioral interventions (parent training, classroom management strategies), and accommodations at school (extra time, reduced distractions, organizational aids) Parents should discuss with their prescriber which of these methods would be appropriate.

Conclusions 

ADHD medication is a powerful tool for reducing symptoms and supporting learning. It improves test scores and grades for some children, especially when taken consistently. But it is not a magic bullet for academic success. The best results come when medication is combined with educational and behavioral supports that help children build the skills they need to thrive in school and beyond.

September 17, 2025