Meta-analysis Reports No Significant Evidence for Efficacy of Neuromechanistic Treatments for Adult ADHD

The Background on ADHD Treatments, rTMS and tDCS:

Methylphenidate is known as the gold-standard treatment for ADHD, increasing dopamine concentrations and helping to focus. However, these psychostimulants may be less well-tolerated in adults. Adverse effects include decreased appetite, nausea, racing heartbeat, restlessness, nervousness, and insomnia. 

Neurofeedback is a non-pharmaceutical treatment that combines cognitive behavioral therapy techniques like conditioning and positive reinforcement with electroencephalography (EEG) feedback. Electrodes are placed on specific brain areas, guiding patients to regulate their brainwave activity. 

Repetitive transcranial magnetic stimulation (rTMS) uses electromagnetism to induce an electric field by passing a magnetic field through the scalp. Transcranial direct current stimulation (tDCS), on the other hand, directly applies an electric current through the scalp. Both repetitive transcranial magnetic stimulation (rTMS) and tDCS primarily target the outermost layers of neurons, as they are non-invasive methods. Nevertheless, both techniques are believed to affect deeper layers through interconnected neuronal networks.  

The Study:

A French research team conducted a systematic search of the peer-reviewed medical literature to perform a meta-analysis to explore the efficacy of these experimental treatment techniques. 

Eight studies – four using rTMS and another four using tDCS – met the inclusion criteria. Studies had to be randomized controlled trials (RCTs), and had to involve multiple sessions of treatment. Participants had to be adults previously diagnosed with ADHD.  

Outcomes were measured through self-rated scales, neuropsychological tests, and electrophysiological pre-post evaluations. 

Separate meta-analyses of the four tDCS RCTs combining 154 participants and of the four rTMS RCTs encompassing 149 participants likewise reported no significant improvements. In all cases variation in outcomes between studies was moderate, and there were no signs of publication bias. 

The Conclusion on Neuromechanistic Treatments for ADHD:

Meta-analysis of all eight studies with a combined total of 421 participants reported no significant improvements over controls. Narrowing down to studies that used sham controls likewise produced no significant improvements. So, despite the title of this study, these neuromechanistic treatments do not appear to be the future of treatment for adult ADHD.

Margaux Courrèges, Marie Hoareau, Carole Levenes, and Hassan Rahioui, “Comparative efficacy of neurofeedback, tDCS, and TMS: The future of therapy for adults with ADHD. A systematic review and meta-analysis,” Journal of Affective Disorders (2025), 388: 119585, https://doi.org/10.1016/j.jad.2025.119585

Related posts

Transcranial Direct Current Stimulation: Can It Treat ADHD?

How effective and safe is transcranial direct current stimulation for treating ADHD?

ADHD is hypothesized to arise from 1) poor inhibitory control resulting from impaired executive functions which are associated with reduced activation in the dorsolateral prefrontal cortex and increased activation of some subcortical regions; and 2)hyperarousal to environmental stimuli, hampering the ability of the executive functioning system, particularly the medial frontal cortex, orbital and ventromedial prefrontal areas, and subcortical regions such as the caudate nucleus, amygdala, nucleus accumbens, and thalamus, to control the respective stimuli.

These brain anomalies, rendered visible through magnetic resonance imaging, have led researchers to try new means of treatment to directly address the deficits. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that uses a weak electrical current to stimulate specific regions of the brain.

Efficacy:

A team of researchers from Europe and ran performed a systematic search of the literature and identified fourteen studies exploring the safety and efficacy of tDCS. Three of these studies examined the effects on ADHD symptoms. They found a large effect size for the inattention subscale and a medium effect size for the hyperactivity/impulsivity. Yet, as the authors cautioned, "a definite conclusion concerning the clinical efficacy of tDCS based on the results of these three studies is not possible."

The remaining studies investigated the effects on specific neuropsychological and cognitive deficits in ADHD:

  •  Working memory was improved by anodal stimulation - but not cathodal stimulation - of the left dorsolateral prefrontal cortex. Anodal stimulation of the right inferior frontal gyrus had no effect.
  •  Response inhibition: Anodal stimulation of the left or right dorsolateral prefrontal cortex was more effective than anodal stimulation of the bilateral prefrontal cortex.
  • Motivational and emotional processing was improved only with stimulation of both the dorsolateral prefrontal cortex and orbitofrontal cortex.

The fact that heterogeneity in the methodology of these studies made meta-analysis impossible means these results, while promising, cannot be seen as in any way definitive.

Safety:

Ten studies examined childhood ADHD. Three found no adverse effects either during or after tDCS. One study reported a feeling of "shock" in a few patients during tDCS. Several more reported skin tingling and itching during tDCS. Several also reported mild headaches.

The four studies of adults with ADHD reported no major adverse events. One study reported a single incident of acute mood change, sadness, diminished motivation, and tension five hours after stimulation. Another reported mild instances of skin tingling and burning sensations.

To address side effects such as tingling and itching, the authors suggested reducing the intensity of the electrical current and increasing the duration. They also suggested placing electrodes at least 6 cm apart to reduce current shunting through the ski. For children, they recommended the use of smaller electrodes for better focus in smaller brains.

The authors concluded, "The findings of this systematic review suggest at least a partial improvement of symptoms and cognitive deficits in ADHD by tDCS. They further suggest that stimulation parameters such as polarity and site are relevant to the efficacy of tDCS in ADHD. Compared to cathodal stimulation, Anodal tDCS seems to have a superior effect on both the clinical symptoms and cognitive deficits. However, the routine clinical application of this method as an efficient therapeutic intervention cannot yet be recommended based on these studies ..."

January 10, 2022

What the MAHA Report Gets Right—and Wrong—About ADHD and Children's Health

The U.S. government released a sweeping document titled The MAHA Report: Making Our Children Healthy Again, developed by the President’s “Make America Healthy Again” Commission. Chaired by public figures and physicians with ties to the current administration, the report presents a broad diagnosis of what it calls a national health crisis among children. It cites rising rates of obesity, diabetes, allergies, mental illness, neurodevelopmental disorders, and chronic disease as signs of a generation at risk.

The report's overarching goal is to shift U.S. health policy away from reactive, pharmaceutical-based care and toward prevention, resilience, and long-term well-being. It emphasizes reforming the food system, reducing environmental chemical exposure, addressing lifestyle factors like physical inactivity and screen overuse, and rethinking what it calls the “overmedicalization” of American children.

While some of the report’s arguments are steeped in political rhetoric and controversial claims—particularly around vaccines and mental health diagnoses—others are rooted in well-established public health science. This blog aims to highlight where the MAHA Report gets the science right, especially as it relates to childhood health and ADHD.

Some of the Good Ideas in the MAHA Report:

Although the MAHA Report contains several debatable assertions, it also outlines six key public health priorities that are well-supported by decades of research. If implemented thoughtfully, these recommendations might make a meaningful difference in the health of American children:

Reduce Ultra-Processed Food (UPF) Consumption

UPFs now make up nearly 70% of children’s daily calories. These foods are high in added sugars, refined starches, unhealthy fats, and chemical additives, but low in nutrients. Studies—including a 2019 NIH-controlled feeding study—show that UPFs promote weight gain, overeating, and metabolic dysfunction.  What can help: Tax incentives for fresh food retailers, improved school meals, front-of-pack labeling, and food industry regulation.

Promote Physical Activity and Limiting Sedentary Time

Most American children don’t get the recommended 60 minutes of physical activity per day. This contributes to obesity, cardiovascular risk, and even mental health issues. Physical activity is known to improve attention, mood, sleep, and self-regulation.   What can help: Mandatory daily PE, school recess policies, walkable community infrastructure, and screen-time education.

Addressing Sleep Deprivation

Teens today sleep less than they did a decade ago, in part due to screen use and early school start times. Sleep loss is linked to depression, suicide risk, poor academic performance, and metabolic problems.  What can help: Later school start times, family education about sleep hygiene, and limits on evening screen exposure.

Improving Maternal and Early Childhood Nutrition

The report indirectly supports actions that are backed by strong evidence: encouraging breastfeeding, supporting maternal whole-food diets, and improving infant nutrition. These are known to reduce chronic disease risk later in life.

What MAHA Says About ADHD:

ADHD is one of the most discussed neurodevelopmental disorders in the MAHA Report, but many of its claims about ADHD are misleading, oversimplified, or inconsistent with decades of scientific evidence, much of which is described in the International Consensus Statement on ADHDand other references given below.

✔️ Accurate: ADHD diagnoses are increasing.

This is true. Diagnosis rates have risen over the past two decades, due in part to better recognition, broadened diagnostic criteria, and changes in healthcare access.  Diagnosis rates in some parts of the country are too high, but we don’t know why.  That should be addressed and investigated.  MAHA attributes increasing diagnoses to ‘overmedicalization’.   That is a hypothesis worth testing but not a conclusion we can draw from available data.

❌ Misleading: ADHD is caused by processed food, screen time, or chemical exposures.

These have been associated with ADHD but have not been documented as causes. ADHD is highly heritable, with genetic factors accounting for 70–80% of the risk.   Unlike genetic studies, environmental risk studies are compromised by confounding variables.   There are good reasons to address these issues but doing so is unlikely to reduce diagnostic rates of ADHD. 

❌ Inaccurate: ADHD medications don’t work long-term.

The report criticizes stimulant use but fails to note that ADHD medications are among the most effective psychiatric treatments, especially when consistently used.  They cite the MTA study’s long term outcome study of kids assigned to medication vs. placebo as showing medications don’t work in the long term.  But that comparison is flawed because during the follow-up period, many kids on medication stopped taking them and many on placebo started taking medications.   Many studies document that medications for ADHD protect against many real-world outcomes such as accidental injuries, substance abuse and even premature death.

How the MAHA Report Could Still Help People with ADHD:

Despite the issues discussed above, the MAHA Report can indirectly help children and adults with ADHD by pushing for systemic changes that reduce ultra-processed food consumption, increase physical activity, and motivate better sleep practices.

In other words, you don’t need to reject the diagnosis of ADHD to support broader changes in how we feed, educate, and care for children. A more supportive, less toxic environment benefits everyone—including those with ADHD.

May 28, 2025

Meta-analysis finds improvements in executive functioning in children and adolescents from non-pharmacological treatments, but with methodological shortcomings

Meta-analysis Finds Improvements in Executive Functioning From Some Non-Pharmacological ADHD Treatments

ADHD is associated with impaired executive functioning. Executive functions are a set of mental skills that include working memory, flexible thinking, and self-control. These are skills we use every day to learn, work, and manage daily life. Trouble with executive function can make it hard to focus, follow directions, and handle emotions. 

A Chinese study team searched for studies on non-pharmacological treatments of children and adolescents with ADHD aged 5 to 18 years intended to improve their executive functioning. 

An initial methodological weakness was the decision to combine studies using formal ADHD diagnoses based on professional psychiatric manuals (DSM 3/4/5 and ICD 10/11) and studies relying on other methods such as parent reports.

This lack of rigor in identifying ADHD is surprising given that the team used studies that directly measured executive functioning through neurocognitive tasks, excluding those that relied on parent- or teacher-reported questionnaires. 

67 studies involving 74 training interventions met the criteria. Meta-analysis of all these studies, encompassing a total of 3,101 participants, suggested medium-to-large effect size improvements in executive functioning. There was evidence of publication bias, but trim-and-fill adjustment increased the estimated effect size to large.

Nevertheless, there were further methodological shortcomings:

  • The meta-analysis mixed studies of substantially different interventions: cognitive training, executive function-specific curriculum, game-based training, neurofeedback, mindfulness, and physical exercise.
  • There was tremendous variation (heterogeneity) between study outcomes. Such inconsistency casts doubt on the outcome unless subgroup analysis can explain it. 

In this case, subgroup analysis mostly failed to explain the heterogeneity, with a single exception. Meta-analysis of the 16 studies with 744 participants that explored executive function-specific curriculum found small-to-medium effect size improvements, with no heterogeneity. 

Unfortunately, the team did not perform a separate publication bias analysis on this subgroup, just as it failed to do so on any of the other subgroups.

By far the strongest evidence of benefit came from meta-analysis of the 17 studies with 558 participants evaluating physical exercise. Here the outcome pointed to very large effect size improvements in executive functioning. Yet once again, heterogeneity was extremely high. Breaking this down further between aerobic exercise and cognitively engaged physical exercise made no difference. Both types had the same very high effect size, with very wide heterogeneity. Again, there was no separate evaluation of publication bias on this group.

Meta-analyses of thirteen studies of neurofeedback combining 444 participants, and fifteen studies of cognitive training encompassing 727 participants, both pointed to just-short-of-large effect size improvements in executive function. Meta-analysis of twelve studies of game-based training with 598 participants indicated medium effect size gains. But again, in all three subgroups there was great variation between studies, and no analysis of publication bias.

While these meta-analyses are suggestive of efficacy, especially for physical exercise interventions, their methodological shortcomings mean we will have to await more rigorous meta-analyses to draw any more settled conclusions. Moreover, these meta-analyses did not evaluate the adequacy of the control groups used in the trials, which is a big shortcoming given prior work showing that the effect of non-pharmacologic treatments are very weak or non-existent when adequate controls are used.

March 13, 2024

A New ADHD Medication That Works Differently in the Brain

The FDA has approved a new once-daily pill called centanafadine (trade name SIMTRIYO®). Approved for adults and kids aged 6 and older (weighing at least 44 lbs / 20 kg), centanafadine is a new category of ADHD treatment that aims to give fast results with fewer of the downsides of traditional stimulants.

What Makes This Drug Different?

To understand why centanafadine is unique among medications for ADHD, it helps to look at how ADHD brain chemistry works:

  1. Norepinephrine: Powers focus, alertness, and attention span.
  1. Dopamine: Drives motivation, reward system, and decision-making.
  1. Serotonin: Regulates mood, anxiety levels, and emotional stability.

Stimulants like Ritalin and Adderall work mainly in the dopamine system.  Nonstimulants like atomoxetine, viloxazine, clonidine and guanfacine work mainly on the norepinephrine system.  Centanafadine is the first drug in a new class called NDSRIs (Norepinephrine, Dopamine, and Serotonin Reuptake Inhibitors). We can describe its effects as follows:

  • Heavy boost to Norepinephrine: Delivers the strong focus and attention boost you need.
  • Moderate, smooth increase to Dopamine: Helps with motivation and brain executive function without triggering massive dopamine spikes that lead to addiction or heavy crashes.
  • Moderate boost to Serotonin: Helps smooth out mood swings and keeps anxiety under control.

What Did Clinical Trials Show?

The FDA approved centanafadine based on studies involving thousands of adults, teens, and children. Here are the key findings:

Centanafadine showed some improvement in ADHD symptoms within the very first week of taking it although a full effect takes about six weeks.

In adult trials, taking 200 mg or 400 mg daily led to significant improvements in real-world skills:

  • Time management and prioritizing tasks
  • Starting projects without procrastinating
  • Planning complex tasks and staying organized
  • Short-term working memory

In trials with children (ages 6–12) and teens (ages 13–17), centanafadine significantly reduced core ADHD symptoms like hyperactivity, impulsivity, and lack of focus compared to a placebo.

About 30% to 40% of adults with ADHD also suffer from anxiety. Traditional stimulants can make anxiety worse. In a trial specifically designed for adults dealing with both ADHD and anxiety, centanafadine effectively treated ADHD symptoms without firing up their anxiety, which might be due to its serotonin boost.

Does Centanafadine have Side Effects?

While Centanafadine was well-tolerated by most people in studies, like any prescription medication, it comes with important safety guidelines.

Prescribing Warnings:

  • Suicidal Thoughts in Children: In trials for kids aged 6 to 12, centanafadine was linked to a higher risk of suicidal thoughts and behaviors compared to a sugar pill.  Although rare, parents and doctors should look for changes in mood or behavior, especially when starting or changing doses.
  • Stimulant Classification: Because it acts on central nervous system pathways, especially dopamine, centanafadine is classified as a CNS stimulant so might lead to addiction. While it has a much lower abuse risk than stimulants like Ritalin or Adderall, doctors should still evaluate patients for any history of substance abuse before prescribing.

Common Side Effects:

  • Kids & Teens: Decreased appetite, stomach ache, nausea, rash, and headache.
  • Adults: Dry mouth, difficulty sleeping (insomnia), decreased appetite, nausea, and headaches.

Other Warnings:

  • Heart & Blood Pressure: It can cause small increases in heart rate and blood pressure, so doctors will check these regularly.
  • Drug Interactions: It cannot be taken with certain antidepressants (MAOIs) due to dangerous blood pressure risks.

The Bottom Line

Overall, centanafadine is a new step forward in how we treat ADHD. Because it acts differently in the brain than traditional treatments, patients who struggle with stimulant-related anxiety or side effects may find it useful to explore with their doctor.

Nitrogen Dioxide Linked to Higher ADHD Risk: Insights from a Massive South Korean Study

A landmark nationwide study from South Korea has uncovered a significant link between prenatal exposure to air pollution — specifically nitrogen dioxide (NO2) — and an increased risk of ADHD in children. 

While researchers have long suspected that air pollutants interfere with fetal brain development through inflammation and oxidative stress, this study is one of the largest and most comprehensive of its kind, following nearly 1.5 million births for up to 13 years. 

Why South Korea? 

South Korea provided a unique countrywide “laboratory” for this research due to two key infrastructure strengths: 

  • Universal Health Data: A national insurance database that tracks the health outcomes of the entire population. 
  • Granular Air Monitoring: A network of 642 monitoring stations that allowed researchers to precisely estimate what pollutants mothers were breathing based on their postal codes. 

Key Findings: The “Smoking Gun” of NO2 

While the study looked at several pollutants, nitrogen dioxide — a byproduct of fossil fuel combustion in cars and power plants — emerged as the primary concern. 

Pollutant 

Association with ADHD Risk 

Nitrogen Dioxide (NO2) 

Strongest Link: Every 1-ppb (part-per-billion) increase in exposure linked to a 22% rise in risk. 

Sulfur Dioxide (SO2) 

Minimal Link: Only a slight 4% increase per ppb. 

Ozone (O3) carbon monoxide (CO), & particulates 

No significant association was found. 

The scale of the NO2 risk is particularly striking. Over the typical range of exposure levels found in the study (an interquartile range of 13 ppb), the data suggest a threefold increase in ADHD risk for children in the highest-exposure groups compared to the lowest. 

Accounting for Other Factors 

To ensure the results weren’t skewed by other variables, the researchers controlled for a wide range of confounders including: 

  • Socioeconomic and employment status. 
  • Maternal age and baseline health. 
  • The child’s sex. 
  • The presence of 14 different medical conditions around childbirth. 

The authors emphasized the strong association between maternal nitrogen dioxide exposure and ADHD, while also noting the small but significant association with sulfur dioxide.  

The Take-Away: A New Frontier for Public Health 

Historically, air quality laws have been designed to protect our lungs and hearts. However, this study adds to a growing body of evidence suggesting that the brain is likewise vulnerable. 

In a commentary on the findings, expert George Ayoub argued that “neurodevelopment should be explicitly considered” when governments perform cost-benefit analyses on air quality regulation.  My view is a bit different.  The association is intriguing but the study does not establish cause and effect.  Many statistically significant environmental risk associations for neurodevelopmental disorders have disappeared after controlling for maternal risk for ADHD.  I hope this research team will do those analyses if feasible.

New Meta-analysis Finds Structured Executive Function Training Largely Ineffective

Executive functions (EFs) are the cognitive control systems that allow people to pursue goals, make decisions, and adapt to changing circumstances. Researchers generally break them into three overlapping capacities: working memory (holding and manipulating information in mind), inhibitory control (suppressing impulses and filtering out distractions), and cognitive flexibility (switching between tasks or mental frameworks). Strong EFs in childhood predict academic achievement, social competence, and long-term mental health; weaknesses in these areas that go unaddressed can persist into adulthood, undermining school performance, career prospects, and well-being. 

The Background:

Interest in training these skills has grown rapidly, but most research has been conducted in Western settings. China presents a distinctive context. Collectivist values make group-based programs culturally natural, and parental investment in academic outcomes is high. Both of these factors should, in theory, work in an intervention’s favor. At the same time, tightly scheduled school days (sessions typically capped at 30 minutes or less) constrain what is actually deliverable. A growing number of randomized controlled trials (RCTs) have tested EF interventions with Chinese children, but until now, no one has pulled that evidence together systematically. 

The Study:

A new network meta-analysis did exactly that. The researchers screened RCTs involving Chinese children aged 3–12, including both typically developing children and those showing subclinical signs of ADHD or autism spectrum disorder (ASD), for instance, siblings of children with an ASD diagnosis. Children who already carried a formal neurodevelopmental diagnosis were excluded. Fifty-two trials covering nearly 3,000 children met the inclusion criteria. Interventions fell into four categories: 

  • Computerized adaptive n-back training with metacognitive coaching (strategy instruction and self-monitoring): 14 trials, 486 children 
  • Stop-signal and rule-switching tasks targeting inhibitory control and cognitive flexibility, delivered face-to-face: 18 trials, 632 children 
  • Hybrid physical-cognitive training moderate-to-vigorous aerobic exercise combined with concurrent cognitive demands (e.g., brisk walking while counting backward) in 20–30-minute sessions: 10 trials, 298 children 
  • Computerized cognitive flexibility training (set-shifting, dual-task coordination), self-paced with progressive difficulty: 10 trials, 312 children 

The headline finding is that three of the four intervention types produced statistically significant improvements across all three EF domains. The exception was the hybrid physical-cognitive program, which did not reach significance for inhibitory control. Positive results across the board might sound encouraging until you look at the actual effect sizes. 

The Results:

The actual effects were negligible. Every significant result fell well below what methodologists define as a “small” effect (a standardized mean difference, or SMD, of 0.2). The largest effect size in the entire analysis was an SMD of 0.097  (less than half that threshold). The authors summarize the interventions’ effects as “modest,” but that is generous phrasing for numbers that, in practical terms, amount to very little. The analysis also showed signs of publication bias, meaning that studies with null or negative results may not have been published, potentially inflating even these modest figures. 

The Take-Away: 

It is important to note that these results don’t necessarily mean that this is the last word on EF training. The results apply specifically to Chinese children working within the time constraints of Chinese school schedules, and they exclude children with diagnosed ADHD, a population for whom cognitive interventions sometimes show larger effects. Generalizing beyond those boundaries is unwarranted. 

What the findings do suggest is that structured EF programs, as currently implemented in Chinese educational settings, are not delivering meaningful real-world benefits. Statistical significance, it is worth remembering, is not the same as practical significance, and the gap between the two is sharp here. 

July 17, 2026