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

The Neurocognitive Roots of Boredom in ADHD: a Meta-Analysis

Boredom is more than just feeling restless or under-stimulated — it’s a negative emotional state that arises when activities feel meaningless or dull. Researchers increasingly view it as functional: an internal signal pushing people to seek more rewarding and meaningful experiences. But for some, that signal becomes chronic and overwhelming.

People who are highly prone to boredom face a range of psychological and behavioral consequences, including anxiety, depression, difficulty identifying their own emotions (alexithymia), impulsivity, and physical complaints. These struggles often surface in harmful behaviors: overeating, substance use, compulsive internet use, and gambling.

For people with ADHD, boredom can cross into genuine distress. Many describe it as “torture” or “an itchy coat you can’t scratch”,  language that conveys not mild discomfort but an urgent, almost unbearable need to escape. This makes sense given that ADHD involves core difficulties with attention, arousal regulation, and motivation, all of which make sustained engagement harder and boredom far more likely.

The Study:

A recent meta-analysis of 18 studies involving more than 22,000 participants confirmed a moderately strong and consistent positive association (an overall effect size of r = 0.40) between ADHD and self-reported boredom. All but one study found significant results, and there was no evidence of publication bias.

“While the relationship between ADHD and boredom may seem obvious,” the authors state, “this has paradoxically led to the phenomenon being understudied.”

Despite how significant this connection appears to be, the researchers noted it has attracted surprisingly little scientific attention; a gap they attribute to a widespread assumption that boredom in ADHD is simply a byproduct of inattention or impulsivity, and therefore not worth studying on its own terms. They push back on that view, arguing that boredom may be a more fundamental part of the ADHD experience: a bridge between atypical brain function and the behavioral, emotional, and cognitive difficulties that shape long-term outcomes.

The Take-Away: 

Ultimately, addressing the profound boredom experienced by individuals with ADHD requires a multifaceted approach that goes beyond simply treating inattention. Researchers emphasize the need for rigorous studies to determine if stimulant medications actively reduce this intense boredom by repairing underlying brain mechanisms, rather than just as a side effect of improved focus. Beyond medication, tailored psychological therapies may offer promise; psychoeducation can help individuals reframe boredom as a biological signal rather than a personal failure or character flaw. 

Additionally, another approach suggests that rather than solely focusing on treating the individual, systemic issues must be addressed, such as the effects of low-stimulation environments. For example, prioritizing a better "person-environment fit" through smaller class sizes, flexible academic pacing, and/or offering highly stimulating, novel tasks, schools and workplaces can offer meaningful relief from the chronic distress of ADHD-related boredom. 

May 11, 2026

Early Skull Fusion in Infants Linked to Higher ADHD Risk

A new study from Japan suggests that infants born with craniosynostosis are significantly more likely to be diagnosed with ADHD later in childhood. Craniosynostosis is a condition in which the bony plates of the skull fuse prematurely, leading to increased intracranial pressure. 

The Background:

Craniosynostosis affects roughly one in every 2,000 births. When the skull’s natural seams close prematurely, it can restrict brain growth and increase intracranial pressure, potentially reducing blood flow to the brain. Because the condition is relatively rare, it has been difficult to study at scale until now. 

The Study:

To overcome this, researchers tapped into a large Japanese insurance database compiled by JMDC, Inc., which holds records on around 20 million people, or about 15% of Japan’s population. Drawing on two decades of data, the team tracked over 338,000 mother-child pairs. Children with related genetic syndromes or chromosomal conditions such as Down syndrome were excluded to keep the focus on craniosynostosis itself. 

Of the children studied, around 1,145 had craniosynostosis, and 7,325 were diagnosed with ADHD. After accounting for factors like sex, birth year, maternal age, mental health history, pregnancy infections, and birth complications, children with craniosynostosis were found to have roughly 2.4 times the risk of a subsequent ADHD diagnosis compared to those without it. 

To test whether shared family genetics or home environment might be driving the association rather than the skull condition itself, the researchers conducted a separate analysis among siblings. The elevated risk remained at 2.2 times. The consistency of the finding across both analyses strengthens the case for a genuine biological link. 

The Results:

The results point to raised intracranial pressure and restricted cerebral blood flow as plausible mechanisms, though the study’s observational design means causation cannot be confirmed. Ultimately, these findings highlight the need for proactive, long-term care strategies for those born with craniosynostosis. By establishing a solid link between premature skull fusion and a significantly higher risk of ADHD, the research demonstrates that medical care for this condition should not end once the skull's physical structure is addressed.

The Takeaway:

Pediatricians, neurologists, and parents can use this data to implement early, routine behavioral and developmental screening for these children as they grow. This additional support would ensure that those who do develop ADHD can receive timely interventions, educational aids, and therapies, ultimately improving their long-term developmental outcomes.

Population Study Indicates ADHD Drug Treatment May Reduce Contact with Child Welfare Services

Children and adolescents with ADHD come into contact with child welfare services (CWS) far more often than their peers. There are many contributing factors to consider, including the fact that hyperactivity and impulsivity frequently lead to behaviors that are considered disruptive and cause academic and social difficulties. Many of these children are also growing up in households marked by parental conflict and/or single-parent arrangements.  All of these circumstances can compound vulnerability and, historically, increase the likelihood of CWS involvement.

Background: 

In Norway, Child Welfare Services operate at the municipal level and are legally required in every local authority. Their scope spans investigation, family support, and, where necessary, out-of-home placement and ongoing monitoring. Grounds for intervention include abuse, neglect, behavioral or psychosocial difficulties, and inadequate care-giving. Norwegian CWS works closely with health, education, and social services and places a strong emphasis on keeping families together. Compared with systems in countries such as the United States, Poland, Romania, and the Czech Republic, the Norwegian approach sets a lower bar for intervention and leans toward home-based support, while setting a higher bar for out-of-home placements. This model is shared by other Nordic countries, as well as Germany and the United Kingdom. 

Research into whether ADHD medication affects child welfare caseloads is remarkably sparse. A single Danish study previously found that medication treatment accounted for much of an observed decline in foster care cases, but no study had examined medication’s broader impact on CWS involvement, covering both supportive interventions and out-of-home placements. 

Norway’s universal single-payer health system and comprehensive national registers make population-wide research of this kind feasible. Drawing on these resources, a Norwegian research team set out to test whether ADHD medication reduces children’s contact with CWS and their need for out-of-home placement. 

The Study:

This study included all 5,930 children and adolescents aged 5 to 14 who received a clinical ADHD diagnosis from Child and Adolescent Mental Health Services between 2009 and 2011. Each was followed for up to 4 years post-diagnosis, the upper age limit being 18, at which point CWS jurisdiction ends. This group was compared with more than 53,000 peers who had no CWS contact during the same period. 

The results showed a meaningful, though not dramatic, association between medication and reduced CWS contact. At one year, treated children had approximately 7% fewer contacts with CWS; by two years, that figure had risen to around 12%. The effect then narrowed, settling at roughly 7–8% reductions at the three- and four-year marks. 

The picture for out-of-home placements is considerably less convincing. The research team highlighted a 3% reduction at two-year follow-up, but this finding barely crossed the threshold of statistical significance, and no effect was observed at the one-, three-, or four-year follow-up points. 

The Take-Away:

The authors concluded that pharmacological treatment for ADHD is associated with reductions in both supportive CWS services and out-of-home placements among children affected by clinicians’ prescribing decisions in Norway. A more cautious reading of the same data, however, would emphasize an overall reduction in CWS contact of roughly 8%, while treating the out-of-home placement finding as, at best, inconclusive. 

May 4, 2026