Meta-analysis Finds Strong Placebo Response in Treatment of ADHD, Mid-range Among Nine Neurological Disorders

The United Kingdom has a National Health Service (NHS) that encompasses virtually its entire population, with free access. The NHS records facilitate conducting nationwide studies.

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The Study

Using electronic health records from 794 primary care practices (roughly one in ten UK practices), largely representative of the UK population, a research team used mortality data to explore the life expectancy of adults diagnosed with ADHD compared with adults not diagnosed with ADHD.

For each adult diagnosed with ADHD, the team sampled ten controls matched by age, sex, and primary care practice. They identified 30,039 individuals with an ADHD diagnosis in their electronic health records and matched them with 300,390 without an ADHD diagnosis.

The team also gathered data on socioeconomic deprivation, diabetes, elevated cholesterol, hardening of the coronary arteries, high blood pressure, chronic respiratory disease, epilepsy, anxiety, depression, severe mental illness, self-harm/suicide, autism, intellectual disability, personality disorder, current smoking, and potentially harmful alcohol use. All these conditions examined at baseline were more common among participants with ADHD than comparison participants.

Both men and women with ADHD were about twice as likely to die during follow-up as Those without ADHD. A diagnosis of ADHD was associated with a 6.8-year reduction of life expectancy in males and an 8.6-year reduction of life expectancy in females.

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Conclusion

The authors wrote, “We believe that this is unlikely to be because of ADHD itself and likely caused by modifiable factors such as smoking, unmet mental and physical health support, and unmet treatment needs. The findings illustrate an important inequity that demands urgent attention.”

They also noted, “…we did not adjust for socioeconomic status (SES), as we believe that SES is best understood as part of the causal pathway between ADHD and premature mortality (i.e. SES is a mediator).” These results confirm other studies which also document that those with ADHD have a decreased life expectancy, primarily due to accidents and suicide. 

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Background

A meta-analysis examined whether noninvasive brain stimulation (NIBS) techniques could help reduce core symptoms of ADHD and improve cognitive function. NIBS refers to techniques that stimulate brain activity using low electrical or magnetic currents applied from outside the head. They studied transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), while newer methods like tRNS (random noise) and tACS (alternating current) lacked enough studies to be included in the analysis.

Methods

Only randomized controlled trials (RCTs)—considered the gold standard in clinical research—were included in the review. For tDCS, the results were promising:

-A meta-analysis of 12 studies (582 participants) showed small but statistically significant improvements in inhibitory control (the ability to stop or delay responses).

-Nine studies (390 participants) showed small-to-medium improvements in working memory.

-Two smaller studies (94 participants) hinted at improvement in cognitive flexibility, but the results were not strong enough to be considered reliable.

-Seven studies (277 participants) found medium-to-large improvements in linattention, though results varied significantly between studies.

 Hyperactivity and impulsivity showed some improvement, but again, the number of studies was too small to draw firm conclusions.

 For rTMS, however, the results were not as encouraging. A meta-analysis of three studies (137 participants) found no significant improvement in ADHD symptoms.

Conclusion

While the results suggest that tDCS may offer some benefit for executive functions and attention in people with ADHD—especially when targeting specific brain areas like the F3/F4 regions (roughly over the dorsolateral prefrontal cortex)—the authors emphasize the need for further research. Most studies didn’t include long-term follow-up, and there’s still a lack of consistency in how stimulation is applied across studies.  Moreover, even when positive findings emerged for executive functions is not clear how these translate into changes that are meaningful for the patient.

Importantly, this study doesn’t suggest that NIBS should replace standard treatments. Although the paper highlights challenges with medication adherence and side effects, ADHD medications and behavior therapies remain the most well-established and effective treatments for most patients. The improvements seen with NIBS so far are relatively small and preliminary in comparison.

Instead, the findings support the idea that NIBS could one day serve as a complementary tool—especially for individuals who don’t respond well to existing treatments. But until more rigorous and long-term studies are done, NIBS should be viewed as an experimental approach, not a substitute.

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ADHD is associated with deficits in executive functions. These are mental processes that enable individuals to plan, focus attention, manage tasks, and regulate emotions. These skills encompass working memory, cognitive flexibility, and inhibitory control, which are crucial for goal-directed behavior and decision-making. 

Working memory, which temporarily stores and processes information, contributes to language development by helping individuals make sense of what they read or hear.  

Cognitive flexibility refers to the ability to change perspectives, adapt thinking strategies, adjust to changing needs and priorities, recognize errors, and grasp opportunities.  

Inhibition switching involves intentional control of attention and emotions, suppressing automatic responses when necessary to prevent inappropriate behavior.  

These elements are critical to academic, social, and professional success. 

An international study team (Li et al.) conducted a meta-analysis of randomized controlled trials (RCTs) to explore the efficacy of physical activity for improving executive functions among children with ADHD aged 6 to 12. 

Meta-analysis of eleven RCTs encompassing 388 children reported a medium-to-large effect size improvement in cognitive flexibility. However, it found no benefit from aerobic exercise (such as running, jumping). When limited to the nine studies with 301 children that focused on cognitively engaging exercise (such as soccer and water sports that require constant monitoring of other players and strategizing), it found a large effect size improvement. Correcting for possible publication bias had no effect on the outcome. 

Meta-analysis of nine RCTs totaling 398 children reported a large effect size improvement in working memory. Once again, it found no benefit from aerobic exercise. Focusing on the seven RCTs with 288 children that used cognitively engaging exercise, it found a very large effect size improvement. There was no sign of publication bias. 

Meta-analysis of fourteen RCTs combining 579 children reported a small-to-medium effect size improvement in inhibition switching. But whereas it found a medium effect size improvement for shorter interventions of less than an hour (eight RCTs, 334 children), it found no benefit from interventions lasting an hour or more (six RCTs, 245 children. Again, there was no sign of publication bias. 

The team concluded, “Our study shows that physical activity interventions have a positive effect on improving executive function in school-age children with ADHD, with cognitive-engaging exercises showing greater benefits across three executive function measures.” 

A Chinese study team (Yang et al.) performed a related meta-analysis on the effect of exercise on inhibitory control in adults. Combining eight RCTs with a total of 372 participants, it reported a very large effect size improvement in inhibitory control, primarily from regular exercise. However, the effects were heavily influenced by a couple of outliers. The team claimed to have performed a sensitivity analysis but offered no evidence. Likewise, they noted signs of publication bias but did not use the standard trim-and-fill analysis to correct for it. 

Another Chinese study team (Xiangqin Song et al.) examined the effect of exercise on working memory in children and adolescents.  

Meta-analysis of 17 RCTs encompassing 419 participants found a medium effect size improvement in working memory. The large effect size improvement for cognitive aerobic exercise (4 RCTs, 233 participants) was twice the effect size for simple aerobic exercise (8 RCTs, 397 participants), though this meta-analysis still found a small-to-medium effect size gain from the latter. There was no sign of publication bias.  

The team concluded, “The results indicate that cognitive-aerobic exercise and ball sports are significantly more effective than other types of exercise interventions in improving working memory. This difference may be attributed to the varying cognitive load, task complexity, and the degree of activation of executive functions across different exercise types. The findings suggest that when designing exercise interventions for children with ADHD, priority should be given to exercise types with higher cognitive load in order to more effectively enhance working memory.” 

A joint Australian-U.S. team (Singh et al.) conducted a meta-meta-analysis on the effect of exercise on executive functions, that is, a meta-analysis of previous meta-analyses of RCTs.  

Combining ten separate meta-analyses with well over 2,800 children and adolescents with ADHD, it reported large effect size improvements in executive functions overall. There was no further breakdown by type of executive function and type of physical activity.  

The team concluded, “While exercise was seen to have a moderate and similar positive impact across all populations with respect to general cognition and memory, benefits for executive function were particularly marked in individuals with ADHD. This subgroup was unique in demonstrating a large effect size. This could be attributed to the task selection and the fact that many ADHD studies involved children. While the exact reason for this finding is unclear, there is evidence to suggest that impairments in executive function are common among individuals with ADHD. As such, it is plausible that this population may have a greater capacity for improvement due to starting from a lower baseline, compared with those with ‘normal’ executive function.” 

Another Chinese study team (Yagang Song et al.) performed a meta-analysis of RCTs examining the effects of physical exercise on anxiety, depression, and emotion regulation among children and adolescents with ADHD.  

Meta-analysis of eleven studies with a combined total of 384 participants reported a medium effect size reduction in symptoms of anxiety, with a dose-effect response. Physical exercise once a week had no significant effect, while twice a week was associated with a medium effect size reduction, and three or more times a week with a very large effect size improvement. Moderate intensity exercise was three times more effective than low intensity exercise.  

Meta-analysis of seven studies encompassing 187 individuals similarly reported a medium effect size reduction in symptoms of depression. Once again, moderate intensity was far more effective than low intensity exercise. 

Meta-analysis of seven studies totaling 429 children and adolescents reported a very large effect size improvement in emotion regulation, especially for physical exercise conducted at least twice a week. 

There was no sign of publication bias in the anxiety, depression, or emotion regulation findings. 

The team concluded, “Physical exercise demonstrated a substantial overall impact on enhancing anxiety, depression, and emotional regulation in children with ADHD, exhibiting a dose-response effect correlated with the period, frequency, duration, and intensity of the exercise. This investigation ... presents an additional evidence-based therapeutic approach for the considerable number of children with ADHD who are not appropriate candidates for pharmacological intervention.” 

A joint U.S.-Hong Kong study team (Liu et al.) performed a meta-analysis exploring the effect of physical exercise on motor proficiency. Motor proficiency includes both gross motor skills (like walking and running) and fine motor skills (like writing and buttoning).  

Meta-analysis of ten studies encompassing 413 children and adolescents with ADHD reported a very large effect size improvement in motor proficiency from physical exercise. The gains for object control, fine manual control, and manual coordination were roughly twice the gains for body coordination. There was no sign of publication bias. 

Finally, a Spanish research team (González-Devesa et al.) conducted a meta-analysis examining the effect of exercise on objectively measured sleep status among persons with ADHD. 

Meta-analysis of three RCTs with a combined total of 131 individuals that used accelerometers to measure sleep duration reported no significant effect one way or the other from exercise. 

The team concluded, “The existing evidence regarding the use of exercise to manage sleep problems in individuals with ADHD remains inconclusive. Preliminary findings from this review suggest a potential positive effect of exercise on self-reported sleep quality; however, its efficacy in improving sleep duration could not be confirmed.” 

The Take-Away:

An ideal exercise regimen for children with ADHD should focus on cognitively engaging physical activities rather than simple aerobic exercise. Sports and activities that require strategic thinking, attention to others’ actions, and rapid decision-making—such as soccer, martial arts, or water-based team sports—gave the best results, especially for working memory and cognitive flexibility. These types of exercise also show strong benefits for emotional regulation, reducing anxiety and depression, and enhancing motor proficiency.

To maximize benefits, the regimen should include moderate-intensity sessions at least two to three times per week, each lasting less than an hour, as longer durations appear less effective for improving inhibitory control. This structured, cognitively demanding approach offers an evidence-based, non-pharmacologic treatment option for children with ADHD, particularly for those who cannot or prefer not to use medication.  We need, however, more work to determine if exercise will provide the same symptom reduction and protection from adverse outcomes as has been shown for medications.

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