November 21, 2021

Safety of long-term methylphenidate treatment of adults with ADHD

The Comparison of Methylphenidate and Psychotherapy in adult ADHD Study (COMPAS) was a prospective, randomized multicenter clinical trial, comparing methylphenidate (MPH) with placebo in combination with cognitive-behavioral group psychotherapy or (GPT) individual clinical management (CM), the latter two being active controls. This was a year-long trial.

The German study team randomly assigned 433 participants with adult ADHD to each of the four study groups. As this was a 2 x 2 matrix trial, each study group included both one pharmacological intervention (MPH or placebo) and one psychological intervention (GPT or CM).

GPT included mindfulness training, skills for stress management, emotion regulation, and time management as well as behavioral analyses. CM sessions focused on participants' current concerns and medication.

As is usual in such trials, the number of participants decreased throughout the study as some individuals dropped out. At 13 weeks, 337 participants were still taking their study medication.

Both MPH and placebo were started at 10 mg doses, then up-titrated depending on clinical response. After 13 weeks, the mean MPH dose had risen to 50 mg, and the mean dose of placebo to 58 mg.

Safety

Among those taking MPH, 96 percent of participants reported at least one adverse event. Among those on placebo, the equivalent figure was 88 percent.

The principal adverse events occurring significantly more frequently in the MPH group were decreased appetite (22 vs. 3.8 %), dry mouth (15 vs. 4.8 %), palpitations (13 vs. 3.3 %), gastrointestinal infection (11 vs. 4.8 %), agitation (11 vs. 3.3 %), restlessness (10 vs. 2.9 %), excessive sweating, rapid heartbeat, and weight decrease (all 6.3 vs. 1.9 %).

The only adverse event that occurred significantly more frequently in the placebo group was a temporary loss of consciousness caused by a fall in blood pressure (2.4 vs. 0%).

Serious adverse events were infrequent in both groups, affecting 7.3 percent of those in the MPH group and 4.3 percent of those in the placebo group. The difference between groups was not statistically significant. There were no deaths.

While patients on MPH lost an average of 1.2 Kg during the year, those on placebo remained constant (gained 0.3 Kg). Changes in blood pressure were negligible in both groups. Average heart rate rose by 3 beats per minute in the MPH group, versus a 1 beat per minute decline in the placebo group. There were no significant differences in clinically relevant electrocardiogram abnormalities between the two treatment groups.

Turning to psychological interventions, 90 percent of participants in the GPT group and 94 percent in the CM group experienced at least one adverse event. Differences between the two groups were not statistically significant. Serious adverse events occurred in 3.9% of the GPT participants and 7.7 percent of the CN participants, but again the difference between groups was not statistically significant. There were no clinically relevant changes in weight, blood pressure, or heart rates in these groups throughout the study.

The study team found no modulating effects of either form of psychological treatment on the distribution of adverse events under MPH and placebo treatment.

The authors concluded, "adverse events were found more frequently in patients receiving MPH compared to placebo and were mostly attributable to the centrally stimulating and sympathomimetic action of MPH, including agitation, restlessness, dry mouth, decreased appetite, palpitations, tachycardia [rapid heartbeat], and hyperhidrosis [excessive sweating]. About these adverse events, a causal relationship with MPH seems likely, supported by both the pharmacological effects of MPH as well as previous safety data. ... It is important to note that patients receiving MPH in COMPAS significantly profited from the medication about the reduction of ADHD symptom load, thus the risks of adverse events have to be weighed against the clear benefits. ... Premature termination of MPH due to an adverse event as major reason occurred in less than 10 % of patients and was not statistically significantly different from placebo."

Bernhard Kis, Caroline Lücke, Mona Abdel-Hamid, Philipp Heßmann, Erika Graf, Mathias Berger, Swantje Matthies, Patricia Borel, Esther Sobanski, Barbara Alm, Michael Rösler, Wolfgang Retz, Christian Jacob, Michael Colla, Michael Huss, Thomas Jans, Ludger Tebartz van Elst, Helge H. O. Müller, Alexandra Philipsen, "Safety Profile of Methylphenidate Under Long-Term Treatment in Adult ADHD Patients - Results of the COMPAS Study," Pharmacopsychiatry (2020), https://doi.org/10.1055/a-1207-9851.

Related posts

No items found.

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