September 6, 2021

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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The Role of Serotonin in ADHD and Its Many Comorbidities

Serotonin is a key chemical in the body that helps regulate mood, behavior, and also many physical functions such as sleep and digestion. It has also been linked to how ADHD (attention-deficit/hyperactivity disorder) develops in the brain. This study looks at how serotonin may be involved in both the mental health and physical health conditions that often occur alongside ADHD.

It is well-established that ADHD is more than just trouble focusing or staying still. For many, it brings along a host of other physical and mental health challenges. It is very common for those with ADHD to also have other diagnosed disorders. For example, those with ADHD are often also diagnosed with depression, anxiety, or sleep disorders. When these issues overlap, they are called comorbidities. 

A new comprehensive review, led by Dr. Stephen V. Faraone and colleagues, delves into how serotonin (5-HT), a major brain chemical, may be at the heart of many of these common comorbidities.

Wait! I thought ADHD had to do with Dopamine–Why are we looking at Serotonin?

Serotonin is a neurotransmitter most often linked to mood, but its role in regulating the body has much broader implications. It regulates sleep, digestion, metabolism, hormonal balance, and even immune responses. Although ADHD has long been associated with dopamine and norepinephrine dysregulation, this review suggests that serotonin also plays a central role, especially when it comes to comorbid conditions.

The Study:

  • Objective: To systematically review which conditions commonly co-occur with ADHD and determine whether serotonin dysfunction might be a common thread linking them.

  • Method: The authors combed through existing literature up to March 2024, analyzing evidence for serotonin involvement in each comorbidity associated with ADHD.

  • Scope: 182 psychiatric and somatic conditions were found to frequently occur in people with ADHD.

Key Findings

  • 74% of Comorbidities Linked to Serotonin: Of the 182 comorbidities identified, 135 showed evidence of serotonergic involvement—91 psychiatric and 44 somatic (physical) conditions.

  • Psychiatric Comorbidities: These include anxiety disorders, depression, bipolar disorder, and obsessive-compulsive disorder—all of which have long-standing associations with serotoninergic dysfunction.

  • Somatic Comorbidities: Conditions like irritable bowel syndrome (IBS), migraines, and certain sleep disorders also showed a significant serotonergic link.

This research suggests that serotonin dysregulation could explain the diverse and sometimes puzzling range of symptoms seen in ADHD patients. It supports a more integrative model of ADHD—one that goes beyond the brain’s attention, reward and executive control circuits and considers broader physiological and psychological health.

future research into the role of serotonin could help develop more tailored interventions, especially for patients who don't respond well to stimulant medications. Future studies may focus on serotonin’s role in early ADHD development and how it interacts with environmental and genetic factors.

The Take-Away: 

This study is a strong reminder that ADHD is a complex, multifaceted condition. Differential diagnosis is crucial to properly diagnosing and treating ADHD. Clinicians' understanding of the underlying link between ADHD and its common comorbidities may help future ADHD patients receive the individualized care they need. By shedding light on serotonin’s wide-reaching influence, this study may provide a valuable roadmap for improving how we diagnose and treat those with complex comorbidities in the future. 

July 14, 2025

Undiagnosed ADHD May Be Undermining Diabetes Control in Adults with Type 1 Diabetes

Our recent study, published in the Journal of Clinical Medicine, aims to shed light on an under-recognized challenge faced by many adults with Type 1 diabetes (T1D): attention-deficit/hyperactivity disorder (ADHD) symptoms.

We surveyed over 2,000 adults with T1D using the Adult Self-Report Scale (ASRS) for ADHD and analyzed their medical records. Of those who responded, nearly one-third met the criteria for ADHD symptoms—far higher than the general population average. Notably, only about 15% had a formal diagnosis or were receiving treatment.

The findings are striking: individuals with higher ADHD symptom scores had significantly worse blood sugar control, as indicated by higher HbA1c levels. Those flagged as "ASRS positive" were more than twice as likely to have poor glycemic control (HbA1c ≥ 8.0%). They also reported higher levels of depressive symptoms.

As expected, ADHD symptoms decreased with age but remained more common than in the general public. No strong links were found between ADHD symptoms and other cardiometabolic issues.

This study highlights a previously overlooked yet highly significant factor in diabetes management. ADHD-related difficulties—such as forgetfulness, inattention, or impulsivity—can make managing a complex condition like T1D more difficult. The researchers call for more screening and awareness of ADHD in adults with diabetes, which could lead to better mental health and improved blood sugar outcomes.

Takeaway: If you or a loved one with T1D struggles with focus, organization, or consistent self-care, it may be worth exploring whether ADHD could be part of the picture. Early identification and support are crucial to managing this common comorbidity. 

July 10, 2025

Norwegian Population Study Finds ADHD Associated with Much Higher Odds of Contact with Child Welfare Services

Background:

This nationwide population study by a Norwegian team aimed to evaluate the relationship between ADHD and various types of child welfare services contacts over a long-term period of up to 18 years among children and adolescents aged 5 to 18 years diagnosed with ADHD, in comparison to the general population within the same age group. 

Norway has a single-payer national health insurance system that fully covers virtually the entirety of its population. In combination with a system of national population and health registers, this facilitates nationwide population studies, overcoming the limitations of relying on population sampling. 

Study:

The study population included all 8,051 children and adolescents aged 5 to 18 who were diagnosed with ADHD for the first time in the Norwegian Patient Registry between 2009 and 2011. 

The study also included a comparison sample of 75,184 children and adolescents aged 5–18 with no child welfare services contact during 2009–2011. 

The interventions delivered by child welfare services in Norway are largely divided into two primary categories: supportive intervention and out-of-home placement. 

Supportive interventions include improving parenting skills, promoting child development, providing supervision and control, facilitating cooperation with other services, assessments and treatments by other institutions, and offering housing support. 

Norway uses foster homes or child welfare institutions as a last resort. When supportive interventions fail to meet the child’s needs, the child welfare services can temporarily place the child in these facilities. If parents disagree, the county social welfare board decides based on a municipal request. 

The team adjusted for potential confounders: sex, age, parental socioeconomic status (father’s and mother’s education and income level), and marital status. 

Results:

With these adjustments, children and adolescents diagnosed with ADHD were over six times more likely to have any contact with child welfare services than their general population peers. This was equally true for males and females.  

Children and adolescents diagnosed with ADHD were also over six times more likely to receive supportive interventions from child welfare services. Again, there were no differences between males and females. 

Finally, children and adolescents diagnosed with ADHD were roughly seven times more likely to have an out-of-home placement than their general population peers. For males this rose to eight times more likely. 

Conclusion:

The team concluded, “This population-based study provides robust evidence of a higher rate and strong association between ADHD and contact with CWS [Child Welfare Service] compared to the general population in Norway.” 

July 8, 2025