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January 17, 2025
Exposure to heavy metals like lead, arsenic, mercury, cadmium, and manganese is known to harm developing nervous systems. However, past studies on whether heavy metals specifically increase the risk of ADHD have shown mixed results.
A research team from China (Gu et al., 2024) reviewed medical studies and conducted meta-analyses to better understand this issue.
The team included studies on children and teens, focusing on cohort studies, case-control studies, and cross-sectional studies. They only used articles written in English and required validated biomonitoring (like blood tests) to measure heavy metal exposure. ADHD diagnoses had to come from clinical evaluations.
To be included, studies had to report effect sizes such as odds ratios and relative risks with confidence intervals. The team focused on comparisons between groups with high, low, or no exposure, which made it harder to analyze dose-response relationships.
They also evaluated the quality of each study. All cohort studies were rated high-quality. Of the 15 case-control studies, 6 were high-quality, and 9 were moderate-quality. Among cross-sectional studies, only 2 were high-quality, and the rest were moderate-quality.
There was no evidence linking ADHD to other heavy metals like arsenic, mercury, cadmium, or manganese. Both meta-analyses suggest that lead exposure is associated with the risk for ADHD. However, because these studies cannot rule out other explanations, one cannot conclude that lead exposure causes ADHD. For example, other work shows that people with ADHD are likely to have lower incomes than those without ADHD.
Qianfei Gu, Jiayu Liu, Xuanzhi Zhang, Anyan Huang, Xinle Yu, Kusheng Wu, and Yanhong Huang, “Association between heavy metals exposure and risk of attention deficit hyperactivity disorder (ADHD) in children: a systematic review and meta-analysis,” European Child & Adolescent Psychiatry (2024), https://doi.org/10.1007/s00787-024-02546-z.
Victoria Rosenauer, Magdalena Isabell Schwarz, Thomas Vlasak, and Alfred Barth, “Childhood lead exposure increases the risk of attention-deficit-hyperactivity disorder: A meta-analysis,” Science of the Total Environment (2024), https://doi.org/10.1016/j.scitotenv.2024.175574.
A large international research team has just released a detailed analysis of studies looking at the connection between parents' mental health conditions and their children's mental health, particularly focusing on ADHD (Attention Deficit Hyperactivity Disorder). This analysis, called a meta-analysis, involved carefully examining previous studies on the subject. By September 2022, they had found 211 studies, involving more than 23 million people, that could be combined for their analysis.
Most of the studies focused on mental disorders other than ADHD. However, when they specifically looked at ADHD, they found five studies with over 6.7 million participants. These studies showed that children of parents with ADHD were more than eight times as likely to have ADHD compared to children whose parents did not have ADHD. The likelihood of this result happening by chance was extremely low, meaning the connection between parental ADHD and child ADHD is strong.
The researchers wanted to figure out how common ADHD is among children of parents both with and without ADHD. To do this, they first analyzed 65 studies with about 2.9 million participants, focusing on children whose parents did not have ADHD. They found that around 3% of these children had ADHD.
Next, they analyzed five studies with over 44,000 cases where the parents did have ADHD. In this group, they found that 32% of the children also had ADHD, meaning about one in three. This is a significant difference—children of parents with ADHD are about ten times more likely to have the condition than children whose parents who do not have ADHD.
The researchers also wanted to see if other mental health issues in parents, besides ADHD, were linked to ADHD in their children. They analyzed four studies involving 1.5 million participants and found that if a parent had any mental health disorder (like anxiety, depression, or substance use issues), the child’s chances of having ADHD increased by 80%. However, this is far less than the 840% increase seen in children whose parents specifically had ADHD. In other words, ADHD is much more likely to be passed down in families compared to other mental disorders.
The study had a lot of strengths, mainly due to the large number of participants involved, which helps make the findings more reliable. However, there were also some limitations:
Despite these limitations, the research team concluded that their analysis provides strong evidence that children of parents with ADHD or other serious mental health disorders are at a higher risk of developing mental disorders themselves. While more research is needed to fill in the gaps, the findings suggest that it would be wise to carefully monitor the mental health of children whose parents have these conditions to provide support and early intervention if needed
Stimulant medications like methylphenidate and amphetamines are well-established treatments for reducing ADHD symptoms, making a notable difference in focus and behavior. Given that caffeine is also a stimulant, researchers have wondered whether it might offer similar benefits for managing ADHD symptoms. A recent meta-analysis conducted by a Brazilian research team sought to explore this question.
The researchers faced an immediate challenge: there is surprisingly little research directly investigating caffeine's effects on ADHD symptoms. After a thorough review of peer-reviewed literature, they identified only four randomized controlled trials (RCTs) suitable for their analysis, encompassing a combined total of just 152 participants.
The limited number of studies—and participants—meant that the meta-analysis was not as robust as the research team might have hoped. However, they proceeded to examine the available data to determine whether caffeine showed any measurable benefit over a placebo.
The results of the meta-analysis showed a slight decrease in ADHD symptoms among those who consumed caffeine compared to those given a placebo. However, this reduction was not statistically significant. The small sample size likely played a role in this outcome, making the study underpowered. Even if future studies with larger groups of participants were to show statistical significance, the observed effect size would likely remain too small to be clinically meaningful.
Interestingly, the four trials included in the meta-analysis showed very little variation in their findings. Each study slightly favored caffeine over placebo, but none came close to achieving statistical significance.
Ultimately, the researchers concluded that “overall, the totality of the evidence suggests no significant benefit of caffeine over placebo in the treatment of children with ADHD.” The findings indicate that while caffeine might produce a slight reduction in symptoms, it is not an effective alternative to established ADHD treatments like methylphenidate or amphetamines.
This study highlights the importance of relying on proven medications for ADHD management rather than seeking alternatives that lack substantial evidence. While caffeine might offer a slight stimulant effect, it falls short of delivering the therapeutic benefits needed for those with ADHD to manage their symptoms effectively. For clinicians, parents, and individuals with ADHD, these results underscore the value of evidence-based treatments in improving quality of life and daily functioning.
A team of U.S. endocrinologists recently published the results of a meta-analysis examining a possible association between bisphenol A(BPA) and childhood ADHD. BPA is used in a variety of consumer products, including plastic bottles for food and drink, epoxy resins used to line cans of food, dental sealants, and the thermal receipts issued by stores.
A review of the literature found 29 rodent studies, but only three with humans. The human studies were too different from each other to be suitable for meta-analysis. One found no association between prenatal exposure and ADHD. A second found prenatal BPA exposure to be associated with teacher-reported hyperactivity in 4-year-old boys, but not girls. The third found is to be associated with hyperactivity scores in 3-year-old girls.
As the authors note, "Often, there is little human data available, particularly in the environmental toxicology/health fields, due to the time and expense of conducting epidemiological studies and the ethical barriers for human-controlled trials that involve human exposure to potentially hazardous chemicals. Thus, it is important to have methods for using animal data to inform human health hazard conclusions; indeed, animal models are traditionally used to study human health."
Twelve of the mice and rat studies, with a total of 709 rodents, were suitable for meta-analysis.
Overall these pointed to a tiny SMD effect size of 0.09, but it was not significant, with the odds of such a result being obtained by chance being almost one in four (p = 0.237). But when results from the 356 males and353 females were looked at separately, a significant sex difference emerged. There was essentially no effect on female rodents, with an effect size of -0.07and a 95% confidence interval of -0.27 to 0.14, widely spanning the zero mark, rendering the result statistically non-significant. Among male rodents, however, there was a small but statistically significant effect size (0.24), with a 95%confidence interval from 0.04 to 0.45. The odds of obtaining this outcome by chance were only one in 50 (p = .02).
This result must be viewed with caution, as rodent physiology often differs substantially from that of humans. The authors, therefore, conclude, "early BPA exposure is associated with a presumed hazard of hyperactivity in humans. Our conclusion is based on 'moderate' levels of evidence for the human and 'high' levels of evidence for animal literature."
Many studies have shown that ADHD is associated with increased risks of suicidal behavior, substance misuse, injuries, and criminality. As we often discuss in our blogs, treatments for ADHD include medication and non-medication options, such as CBT (Cognitive Behavioral Therapy). While non-drug approaches are often used for young children or mild cases of ADHD, medications – both stimulants and non-stimulants – are common for adolescents and adults.
Global prescriptions for ADHD drugs have risen significantly in recent years, raising questions about their safety and effectiveness. Randomized controlled trials have demonstrated that medication can help reduce the core symptoms of ADHD. However, research from these trials still offers limited or inconclusive insights into wider and more significant clinical outcomes, such as suicidal behavior and substance use disorder.
An international study team conducted a nationwide population study using the Swedish national registers. Sweden has a single-payer national health insurance system, which covers nearly every resident, enabling such studies. The researchers examined all Swedish residents aged 6 to 64 who received their first ADHD diagnosis between 2007 and 2018. Analyses of criminal behavior and transport accidents focused on a subgroup aged 15 to 64, since individuals in Sweden must be at least 15 years old to be legally accountable for crimes or to drive.
The team controlled for confounding factors, including demographics (age at ADHD diagnosis, calendar year, sex, country of birth, highest education (using parental education for those under 25), psychiatric and physical diagnoses, dispensations of psychotropic drugs, and health care use (outpatient visits and hospital admissions for both psychiatric and non-psychiatric reasons).
Time-varying covariates from the previous month covered diagnoses, medication dispensations, and healthcare use. During the study, ADHD treatments licensed in Sweden included amphetamine, atomoxetine, dexamphetamine, guanfacine, lisdexamphetamine, and methylphenidate.
After accounting for covariates, individuals diagnosed with ADHD who received medication treatment showed better outcomes than those who did not. Specifically:
-Suicidal behaviors dropped by roughly 15% in both first-time and recurrent cases.
-Initial criminal activity decreased by 13%, with repeated offences falling by 25%.
-Substance abuse initiation declined by 15%, while recurring substance abuse was reduced
by 25%.
-First automotive crashes were down 12%, and subsequent crashes fell by 16%.
There was no notable reduction in first-time accidental injuries, and only a marginally significant 4% decrease in repeated injuries.
The team concluded, “Drug treatment for ADHD was associated with beneficial effects in reducing the risks of suicidal behaviours, substance misuse, transport accidents, and criminality, but not accidental injuries when considering first event rate. The risk reductions were more pronounced for recurrent events, with reduced rates for all five outcomes.”
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Background:
Pharmacotherapies, such as methylphenidate, are highly effective for short-term ADHD management, but issues remain with medication tolerability and adherence. Some patients experience unwanted side effects from stimulant medications, leaving them searching for alternative ADHD treatments. Alternative treatments such as cognitive training, behavioral therapies, psychological interventions, neurofeedback, and dietary changes have, so far, shown limited success. Thus, there is a critical need for non-pharmacological options that boost neurocognitive performance and address core ADHD symptoms.
First— What Are NIBS (Non-Invasive Brain Stimulation) Techniques?
Non-invasive brain stimulation (NIBS) techniques, including transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS), transcranial alternating current stimulation (tACS), and repetitive transcranial magnetic stimulation (rTMS) are generating growing attention within the scientific community.
NIBS techniques are methods that use external stimulation, such as magnets or electrical currents, to affect brain activity without any invasive procedures. In transcranial alternating current stimulation (tACS), for example, small electrodes are placed on the scalp of the patient, and a weak electrical current is administered.
The theory behind these techniques is that when a direct current is applied between two or more electrodes placed on specific areas of the head, it makes certain neurons more or less likely to fire. This technique has been successfully used to treat conditions like depression and anxiety, and to aid recovery from stroke or brain injury.
The Study:
Previous meta-analyses have produced conflicting indications of efficacy. A Chinese research team consisting of sports and rehabilitative medicine professionals has just published a network meta-analysis to explore this further, through direct comparison of five critical outcome domains: inhibitory control, working memory, cognitive flexibility, inattention, hyperactivity and impulsivity.
To be included, randomized controlled trials needed to have participants diagnosed with ADHD, use sham control groups, and assess ADHD symptoms and executive functions – such as inhibitory control, working memory, cognitive flexibility, inattention, hyperactivity, and impulsivity – using standardized tests.
A total of thirty-seven studies encompassing 1,615 participants satisfied the inclusion criteria. It is worth noting, however, that the authors did not specify the number of randomized controlled trials nor the number of participants included in each arm of the network meta-analysis.
Furthermore, the team stated, “We checked for potential small study effects and publication bias by conducting comparison-adjusted funnel plots,” but did not share their findings. They also did not provide information on outcome variation (heterogeneity) among the RCTs.
Results:
Ultimately, none of the interventions produced significant improvements in ADHD symptoms, whether in inattention symptoms or hyperactivity/impulsivity symptoms. Likewise, none of the interventions produced significant improvements in inhibitory control. Some tDCS interventions enhanced working memory and cognitive flexibility, but details about trial numbers and participants were missing. The team concluded, “none of the NIBS interventions significantly improved inhibitory control compared to sham controls. … In terms of working memory, anodal tDCS over the left DLPFC plus cathodal tDCS over the right DLPFC … and anodal tDCS over the right inferior frontal cortex (rIFC) plus cathodal tDCS over the right supraorbital area ... were associated with significant improvements compared to sham stimulation. For cognitive flexibility, only anodal tDCS over the left DLPFC plus cathodal tDCS over the right supraorbital area demonstrated a statistically significant benefit relative to sham. ... Compared to the sham controls, none of the NIBS interventions significantly improved inattention. ... Compared to the sham controls, none of the NIBS interventions significantly improved hyperactivity and impulsivity.”
How Should We Interpret These Results?
In a word, skeptically.
If one were to read just the study’s abstract, which states, “The dual-tDCS and a-tDCS may be considered among the preferred NIBS interventions for improving cognitive function in ADHD”, it might seem that the takeaway from this study is that this combination of brain stimulation techniques might be a viable treatment option for those with ADHD. Upon closer inspection, however, the results do not suggest that any of these methods significantly improve ADHD symptoms. Additionally, this study suffers from quite a few methodological flaws, so any results should be viewed critically.
Background:
Despite recommendations for combined pharmacological and behavioral treatment in childhood ADHD, caregivers may avoid these options due to concerns about side effects or the stigma that still surrounds stimulant medications. Alternatives like psychosocial interventions and environmental changes are limited by questionable effectiveness for many patients. Increasingly, patients and caregivers are seeking other therapies, such as neuromodulation – particularly transcranial direct current stimulation (tDCS).
tDCS seeks to enhance neurocognitive function by modulating cognitive control circuits with low-intensity scalp currents. There is also evidence that tDCS can induce neuroplasticity. However, results for ADHD symptom improvement in children and adolescents are inconsistent.
The Method:
To examine the evidence more rigorously, a Taiwanese research team conducted a systematic search focusing exclusively on randomized controlled trials (RCTs) that tested tDCS in children and adolescents diagnosed with ADHD. They included only studies that used sham-tDCS as a control condition – an essential design feature that prevents participants from knowing whether they received the active treatment, thereby controlling for placebo effects.
The Results:
Meta-analysis of five studies combining 141 participants found no improvement in ADHD symptoms for tDCS over sham-TDCS. That held true for both the right and left prefrontal cortex. There was no sign of publication bias, nor of variation (heterogeneity) in outcomes among the RCTs.
Meta-analysis of six studies totaling 171 participants likewise found no improvement in inattention symptoms, hyperactivity symptoms, or impulsivity symptoms for tDCS over sham-TDCS. Again, this held true for both the right and left prefrontal cortex, and there was no sign of either publication bias or heterogeneity.
Most of the RCTs also performed follow-ups roughly a month after treatment, on the theory that induced neuroplasticity could lead to later improvements.
Meta-analysis of four RCTs combining 118 participants found no significant improvement in ADHD symptoms for tDCS over sham-TDCS at follow-up. This held true for both the right and left prefrontal cortex, with no sign of either publication bias or heterogeneity.
Meta-analysis of five studies totaling 148 participants likewise found no improvement in inattention symptoms or hyperactivity symptoms for tDCS over sham-TDCS at follow-up. AS before, this was true for both the right and left prefrontal cortex, with no sign of either publication bias or heterogeneity.
The only positive results came from meta-analysis of the same five studies, which reported a medium effect size improvement in impulsivity symptoms at follow-up. Closer examination showed no improvement from stimulation of the right prefrontal cortex, but a large effect size improvement from stimulation of the left prefrontal cortex.
Interpretation:
It is important to note that the one positive result was from three RCTs combining only 90 children and adolescents, a small sample size. Moreover, when only one of sixteen combinations yields a positive outcome, that begins to look like p-hacking for a positive result.
In research, scientists use something called a “p-value” to determine if their findings are real or just due to chance. A p-value below 0.05 (or 5%) is considered “statistically significant,” meaning there's less than a 5% chance the result happened by pure luck.
When testing twenty outcomes by this standard, one would expect one to test positive by chance even if there is no underlying association. In this case, one in 16 comes awfully close to that.
To be sure, the research team straightforwardly reported all sixteen outcomes, but offered an arguably over-positive spin in their conclusion: “Our study only showed tDCS-associated impulsivity improvement in children/adolescents with ADHD during follow-ups and anode placement on the left PFC. ... our findings based on a limited number of available trials warrant further verification from large-scale clinical investigations.”
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