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Organophosphate pesticides were originally developed as nerve agents for chemical warfare, then used in lower doses as insecticides. 

Their neurotoxicity raises the possibility of effects on development of the nervous system at lower doses, including psychiatric disorders.

Previous studies have found mixed results for any association with ADHD.

Norway has a single-payer health insurance system that covers virtually the entire population, facilitating nationwide population studies. 

A primarily Norwegian study team used the Norwegian Mother, Father, and Child Cohort Study, a prospective population-based cohort that enrolled participants between 1999 and 2008 to explore possible associations. The study invited all 227,702 pregnant mothers to enroll, of which 112,908 (41%) actually enrolled.

Children were eligible for the present study if they were born after 2002, did not have Down’s syndrome or cerebral palsy, had available maternal biospecimens, were the result of a singleton pregnancy, and lived near Oslo (the location of the clinic). That left a sample of 24,035.

The team used the Norwegian Patient Registry (NPR) to identify diagnosed cases of ADHD. 

From the final eligible population, the team randomly selected 552 mother-child pairs to represent the exposure distribution in the population of pregnancies that gave rise to the cases of ADHD.

At about 17 weeks into pregnancy, maternal spot urine samples were collected at the mother’s first ultrasound appointment. These samples were then tested for concentrations of organophosphate metabolites (breakdown chemicals). 

Adjustments were made for a variety of possible confounding variables: season, birth year, maternal education, vegetable intake, fruit intake, maternal self-reported ADHD, financial status, other organophosphorus pesticides, and sex.

Comparing higher versus lower maternal exposures to organophosphates, no significant differences emerged in rates of ADHD diagnosis among offspring.

Unprescribed amphetamines are the second most commonly used illicit drugs worldwide. Persons with methamphetamine or amphetamine use disorders (MAUD) have elevated rates of mortality, primarily from acute poisoning, but also from suicide, homicide, cardiovascular disease, and injuries. Illicit amphetamine use is also associated with aggressive behavior and criminality.

There are presently no approved pharmacological interventions for treating MAUD. 

A Finnish study team used the Swedish national registers to explore relationships between various drug treatments, including ADHD medications, and hard outcomes – hospitalization and death – among persons with MAUD.

The team looked at all Swedish residents aged 16 to 64 years with a registered first-time treatment contact due to MAUD between July 1, 2006 and December 31, 2018. They matched this cohort with data from the Prescribed Drug Register from July 2005 to December 2018.

They adjusted for the following confounding variables: age, sex, education, granted disability pension, long-term sickness absence during previous year (more than 90 days), and medication-related comorbidities.

The cohort consisted of 13,965 persons diagnosed with MAUD. Of these, 11,492 (about three out of four) were either hospitalized (10,341) or died (1,151) in the follow-up period.

The study looked at a variety of prescription drugs, including six ADHD medications: methylphenidate, atomoxetine, modafinil, amphetamine, dexamphetamine, and lisdexamphetamine. Prescriptions for none of these were significantly associated with higher risk of hospitalization or death from substance used disorder.

On the other hand, persons diagnosed with MAUD but prescribed lisdexamphetamine were in all instances at significantly lower risk. Lisdexamphetamine users were 18% less likely to be hospitalized for substance use disorder in within-individual and 25% less likely to be hospitalized in between-individual analyses. Lisdexamphetamine users also had half the risk of all-cause mortality. 

The authors concluded, “In this Swedish nationwide cohort study, use of lisdexamphetamine was consistently associated with a reduction in risk of death and hospitalization in persons with amphetamine or methamphetamine. Use of antidepressants were associated with an increase in risk of hospitalization due to SUD and any hospitalization or death. Benzodiazepine use was associated with poor outcomes.”

Thanks to improvements in cancer treatment, there is a growing population of childhood and adolescent cancer survivors (CACSs). CACSs are at an increased risk of chronic physical, psychological, and social problems because of their cancer experiences and intensive cancer treatments. These include depression, anxiety, suicidal ideation, and post-traumatic stress disorder (PTSD). 

To what extent, if at all, does this also apply to ADHD? Noting that “previous studies … have reported inconsistent findings,” a local research team took advantage of Taiwan’s mandatory single-payer National Health Insurance that covers over 99% of the island’s population. More specifically, the National Health Insurance Research Database (NHIRD) maintains data on the insured population available on formal request for study purposes.

Linking the catastrophic illness database, mental disorders database, and longitudinal health insurance database, they tracked children age younger than 10 years and adolescents aged 11-17 years who were diagnosed with any malignancy (cancer) between 2002 and 2011 with no history of major psychiatric disorders (including ADHD). Parental history of major psychiatric disorders was likewise controlled as a potential confounder.

The team identified 5,121 CACSs, which they matched one to ten with 51,210 age-, sex-, income-, and residence-matched cancer-free controls.

ADHD diagnoses were made by board-certified psychiatrists during the study follow-up period (from enrollment through 2011) based on a comprehensive clinical interview and clinical judgment. 

Cancer survivors were diagnosed with ADHD at more than six times the rate of matched controls. Survival duration made no significant difference in this outcome. 

Cancers of bone, connective tissue, skin, and breast were associated with a more than threefold increase in risk of an ADHD diagnosis. For cancers of the circulatory system, there was a more than sixfold increased risk of ADHD, and for those of the genitourinary organs, more than sevenfold increased risk. 

For brain cancer survivors, the increased risk of ADHD was more than twelvefold. That may be at least in part because the brain itself was targeted for treatment in these instances, which plausibly could cause damage resulting in psychiatric disorders.

The team concluded, “we observed a comparatively higher risk of MPDs [major psychiatric disorders] among CACSs than among controls and likewise found that such risks varied across different cancer types. Survivors of both CNS [central nervous system] and non-CNS cancers have increased risks of MPD diagnoses. Among the enrolled CACSs, ASD [autism spectrum disorder] and ADHD were associated with most types/categories of cancers. Long-term care of this vulnerable population must include psychosocial interventions for patients and their families. Physicians need to be aware of early signs of mental health problems in this high-risk subpopulation and arrange early interventions accordingly.”

A Chinese study team has performed an updated meta-analysis of randomized clinical trials (RCTs) published through July 2022, looking specifically at the effects of chronic exercise on ADHD core symptoms and executive functions in children and adolescents.

The researchers defined chronic to mean exercise interventions lasting at least six weeks, with the longest clocking in at well over a year (72 weeks). 

They only included RCTs with blinding of all assessors who measured the primary outcomes, to guard against any conscious or unconscious bias.

A total of 22 studies met criteria for inclusion in the series of meta-analyses they performed. The RCTs were widely distributed, with four from North America, three from Africa, three from Europe, eleven from Asia, and one from Oceania.

Three studies were rated as being at low risk of bias, the other 19 at moderate risk of bias.

Meta-analysis of eleven RCTs with a combined 514 participants reported a small-to-medium reduction in ADHD core symptoms. Between-study variation (heterogeneity) was moderate, and there was no indication of publication bias.

Breaking that down by age group, for children (eight RCTs, 357 children) the reduction in core symptoms was likewise small-to-medium, versus a medium effect size reduction among adolescents (three RCTs, 157 adolescents), with no heterogeneity.

When the control group received no treatment or was sedentary (8 RCTs, 422 participants), the effect size remained small-to-medium, whereas when the control group received education, it became large (two RCTs, 58 participants). 

Improvements in executive functions were even more pronounced. Meta-analysis of 17 RCTs with a combined 795 participants yielded a medium-to-large effect size reduction in executive functions overall. Heterogeneity was moderate, with absolutely no sign of publication bias.

More specifically, there was a medium effect size improvement in working memory (10 RCTs, 290 participants), a medium-to-large effect size improvement in cognitive flexibility (8 RCTs, 206 participants), and a large effect size improvement in inhibition (12 RCTs, 299 participants). 

Once again, adolescents benefited more than children. Whereas children showed medium effect size improvements in executive function (14 RCTs, 659 children), adolescents registered enormous improvements (3 RCTs, 136 adolescents).

One note of caution, though. Among RCTs rated low risk of bias, effect size improvements in both ADHD core symptoms (3 RCTs, 180 participants) and executive functions (2 RCTs, 86 participants) were small and did not reach statistical significance. That suggests a need for more and better RCTs to reach a more settled verdict.

For now, the authors concluded, “This meta-analysis suggests that CEIs [chronic exercise interventions] have small-to-moderate effects on overall core symptoms and executive functions in children and adolescents with ADHD.”

Mindfulness involves focusing on the present moment. Mindfulness meditations include choosing a point of focus, such as breathing, and focusing on it continuously. They may also involve focusing single-mindedly on body movements, as in Yoga. This could be potentially useful because in focusing on the present moment with attention and emotion regulation, it addresses regulatory capacities impaired in ADHD.

Previous studies of efficacy of mindfulness interventions have been inconclusive, limited by low methodological quality. A Taiwanese study team tried to remedy this with a fresh meta-analysis of randomized controlled trials (RCTs).

The team included three types of RCTs: yoga intervention, mindfulness-based psychological intervention, and mediation training. There was a lot of variation in the length of individual sessions and in the total number of hours of intervention.

Five studies used a waiting list control group. Two studies used treatment as usual or standard care as control groups. Only four studies followed best practices of using an active control group, such as a listening task, behavioral therapy, cooperative activities, or an emotional education program.

Twelve studies scored between 4 and 7 points from a possible total of 10 points, suggesting at best moderate methodological quality. More seriously, there was no indication of patient and therapist blinding.

With all these limitations, the one nominally positive result was for improvement in ADHD symptoms. A meta-analysis of seven RCTs with a combined 184 participants found a large reduction in ADHD symptoms post-treatment that did not persist at follow-up a couple months later. But between-study variation (heterogeneity) was extreme, with evidence of publication bias. The authors did not offer a revised estimate of efficacy based on the standard trim-and-fill adjustment.

Two additional meta-analyses, of seven RCTs with 200 participants, and seven RCTs with 215 participants, found no improvement in either externalizing or internalizing behaviors post-treatment. This time there was no sign of publication bias in either case. For externalizing behaviors, there was negligible heterogeneity, and moderate heterogeneity for internalizing behaviors.

A meta-analysis of four RCTs combining 122 participants found a moderate improvement in child mindfulness post-treatment, but it was not statistically significant.

Child abuse includes any of the following inflicted on a minor under 18 years old: physical or emotional harm, sexual abuse, or neglect.

It is known to be associated with environmental factors such as poverty, parents or neighbors with a history of violence, and gender inequality.

Chronic mental disorders in minors are also associated with child abuse. To what extent, if any, might that be true of ADHD?

Taiwan has a single-payer national health insurance system that covers more than 99.6% of all residents, enabling nationwide population studies.

A local research team used data from almost two million Taiwanese in their country’s National Health Insurance Research Database (NHIRD) spanning 15 years (2000-2015) to carry out a matched-cohort study. 

All diagnoses of ADHD were made by board-certified specialists such as psychiatrists, pediatricians, neurologists, or physiatrists with a specialty in child and adolescent development.

3,540 children and adolescents between 6 and 18 years old with a diagnosis of ADHD were matched on a one-to-three basis with 10,620 peers from the NHIRD without an ADHD diagnosis.

The team adjusted for age, gender, location of residence (Northern, Central, Southern, and Eastern Taiwan), urbanization level of residence, level of hospitals as medical centers, and monthly insured premium. They further adjusted for comorbid conditions: intellectual disability, autistic disorder/pervasive developmental disorder, conduct disorder (CD)/oppositional defiant disorder (ODD), other developmental disorders, childhood emotional disorder, Tourette syndrome/tics disorders, and involuntary urination and defecation.

Overall, children and adolescents with an ADHD diagnosis were 1.8 times as likely to be abused as those without an ADHD diagnosis.

Unmedicated children and adolescents with an ADHD diagnosis were three times more likely to be abused. ADHD medication cut that risk in half.

That held true whether the medication used was methylphenidate or atomoxetine. Methylphenidate appeared to be slightly more effective than atomoxetine, and the combination of methylphenidate and atomoxetine slightly more effective yet, but these differences were not statistically significant.

The team concluded, “The results support that pharmacotherapy may attenuate the risk of child abuse in ADHD patients.”

The three primary symptoms of ADHD are inattention, hyperactivity, and impulsivity, which can significantly limit personal, social, academic, or occupational functioning. 

In addition to these symptoms, between a third and a half of children and adolescents with ADHD have limited motor proficiency. They are less coordinated or skilled in performing motor tasks than their peers. This in turn reduces their participation in physical activities. They are more likely to become overweight or obese. They are also more likely to have difficulty socializing with peers.

Current ADHD medications are effective at treating the primary symptoms of ADHD, but have no known effect on impaired motor proficiency. 

Noting that “physical activity interventions are relatively easy to implement and have been shown to improve motor proficiency compared to other behavioral therapies,” a joint Chinese and American study team set out to explore effect sizes through a systematic review of the peer-reviewed medical literature.

They identified ten studies with a total of 413 participants suitable for meta-analysis. Overall, physical activity interventions led to very large effect size improvements in motor proficiency. There was no sign of publication bias, but considerable variation (heterogeneity) between studies.

To address this heterogeneity, the team next investigated how different types of physical activity intervention affected outcomes. Those that concentrated on body coordination, fine motor control (manual dexterity, using the small muscles in our hands and wrists), and object control (moving or receiving an object such as a ball with accuracy) were found to be responsible for the large effect size improvements in motor proficiency, this time with low heterogeneity.

By contrast, strength and agility training and locomotor training (such as walking, running, hopping, skipping) were associated with smaller effect size improvements that were no longer significant, and continued to vary significantly between studies.

Despite combining ten separate studies, sample sizes remained small, even more so when broken down by type of physical activity intervention. Strength and agility interventions were associated with a medium-to-large effect size improvement, but with only four studies combining 131 participants, may simply have been under-powered to achieve significance. Similarly, locomotor interventions were associated with small-to-medium effect size improvement, but with only three studies and a total of 117 participants, may again have been under-powered. 

While these preliminary findings look promising, they will need additional studies and greater numbers of total participants to be confirmed.

Now that ADHD pharmaceuticals are among the most widely prescribed medications during pregnancy, we need to be aware of any long-term harms to offspring from in-utero exposure.

Denmark has a single-payer public health care system that encompasses virtually its entire population. Combined with national registers that track demographic as well as health data for the whole population, this makes it easy to do population-wide studies.

Availing itself of these registers, an international study team looked at all 1,068,073 single births from 1998 to 2015. It then followed all these individuals through the end of 2018, or until any developmental diagnosis, death, or emigration, whichever came first.

The team compared children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy with children of mothers who discontinued ADHD medication before pregnancy. There were 898 of the former and 1,270 of the latter in the cohort.

To reduce the influence of potential confounding variables, the team adjusted for maternal age, parity, maternal psychiatric history, in- or outpatient admission to psychiatric ward within two years prior to pregnancy and until delivery, use of other psychotropic medications during pregnancy, number of hospitalizations during pregnancy not related to psychiatry, smoking during pregnancy, living alone, education, birthyear, and psychiatric history of the father. 

Children exposed in utero to ADHD medication were found to be at no greater risk of any developmental impairment.

The timing of the exposure by trimester of pregnancy made no difference. Neither did the duration of exposure.

Neither children exposed to stimulant medications (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil) nor to non-stimulants (atomoxetine, clonidine) were at greater risk of any developmental impairment. 

Focusing more narrowly on specific impairments, children exposed in utero to ADHD medication were no more likely to be autistic. They were more likely to have ADHD, but the association did not reach statistical significance.

Children exposed in utero to ADHD medication were also no more likely to develop hearing or cerebral vision impairment or febrile seizures or a growth impairment. Surprisingly, they were 40% less likely to become epileptic, the only statistically significant association found in the study.

The authors concluded, “Our results are important because stimulant medications are critical for many adults, including women of childbearing age, to perform their essential functions at work, home, and school. Pregnant women who depend on stimulants for daily functioning must weigh the potential of exposing their fetus to unknown developmental risks against potential medical, financial, and other consequences to both mother and child that are associated with exacerbation of ADHD symptoms when stopping the medication, such as inability to maintain employment and unsafe driving. The present study provides reassurance that several essential categories of child outcomes that could reasonably be suspected to be affected by stimulants, including body growth, neurodevelopment, and seizure risk, do not differ based on antenatal stimulant exposure. Future studies would benefit from larger sample sizes making it possible to conduct stratified analyses on ADHD medication type.”

Monitoring the Future is a multicohort U.S. national longitudinal study of adolescents followed up into young adulthood. 

The U.S. research team used data from this study to follow 5,034 twelfth graders over a period of six years, until they were 23 and 24 years of age.

Prescription stimulant misuse was assessed at baseline and each follow-up survey year by asking how often they used prescription stimulants without a physician’s orders. They were similarly asked about cocaine and methamphetamine use.

The study team adjusted for the following confounding variables: sex, race and ethnicity, parents’ level of education, urbanicity, U.S. region, cohort year, grade point average during high school, past-30-day cigarette use (at 18 years of age), past-2-week binge drinking (at 18), past-year marijuana use (at 18), past-year prescription opioid misuse (at 18), past-year prescription stimulant misuse (at 18), lifetime cocaine use (at 18), lifetime methamphetamine use (at 18), lifetime use of nonstimulant therapy for ADHD (at 18), and discontinued use of stimulant therapy for ADHD (at 18).

With these adjustments, they found that stimulant use for ADHD was in no way associated with subsequent cocaine use. In fact, it was associated with lesser odds of subsequent cocaine use, though the association was not statistically significant.

Likewise, they reported that stimulant use for ADHD was in no way associated with subsequent methamphetamine use.

On the other hand, those who used prescription stimulants without a physician’s orders were 2.6 times more likely to subsequently use either cocaine or methamphetamine.

The team concluded, “In this multicohort study of adolescents exposed to prescription stimulants, adolescents who used stimulant therapy for ADHD did not differ from population controls in initiation of illicit stimulant (cocaine or methamphetamine) use, which suggested a potential protective effect, given evidence of elevated illicit stimulant use among those with ADHD. In contrast, monitoring adolescents for PSM is warranted because this behavior offered a strong signal for transitioning to later cocaine or methamphetamine initiation and use during young adulthood.”

Noting that “little is known about whether school-level stimulant therapy for ADHD is associated with NUPS [nonmedical use of prescription stimulants] among US secondary school students,” a team of American researchers searched for answers in a nationally representative sample of 3,284 U.S. secondary schools with well over 150,000 high school students.

“Previous studies,” the authors continued, “have largely neglected school-level factors associated with NUPS among US secondary school students, including school size, school geographical location, school-level racial composition, school-level rates of substance use (eg, binge drinking), and school-level stimulant therapy for ADHD.”

In surveys, students were asked if they had ever taken stimulant medications for ADHD under a physician’s or health professional’s supervision, with three possible answers: no, yes but only in the past, and yes, currently. Responses for use in the past, and separately for current use, were combined and aggregated to the school level to reflect the percentage of the study body who used prescription stimulants for ADHD. 

The surveys explored NUPS by asking, “On how many occasions (if any) have you taken amphetamines or other prescription stimulant drugs on your own—that is, without a doctor telling you to take them... in your lifetime?...during the last 12 months?...during the last 30 days?” 

The study team controlled for sex, race and ethnicity, parental education, GPA, binge drinking, cigarette smoking, cannabis use, cohort year, school type, grade level, urbanicity, school size, US Census region, % of student body with low grades, % female, % with at least one parent with a college degree, % White, % binge drinking during past 2 weeks, % cigarette smoking in past 30 days, and % cannabis use during the past 30 days. The analysis also included individual-level medical use of stimulant therapy for ADHD history to estimate individual-level past-year NUPS. Finally, it included both individual-level and school-level risk factors to assess individual-level past-year NUPS.

With all these adjustments, at the individual level, both high school students presently on prescribed stimulant therapy for ADHD and those who had previously been on such prescribed therapy were more than twice as likely to engage in past-year NUPS as those who were never on prescribed stimulant medication.

Turning to the school level, in schools where 12% or more of students were on prescribed stimulant therapy for ADHD, students in general were 36% more likely to engage in past-year NUPS than in schools where none of the students were on prescribed stimulant therapy for ADHD.

This is not surprising, as it confirms that students who use prescription drugs for nonmedical often get their supply from fellow students who are prescribed those drugs.

While at the individual level, binge drinking, cigarette smoking, and cannabis use were strong predictors of NUPS, at the whole-school level they had no significant effect. A poor grade point average mildly increased risk in the individual, but high percentages of students with low grades had no effect on peer NUPS. Race and ethnicity made a difference at the individual level (NUPS significantly more likely among White students than Blacks and Hispanics), but made no difference at the school level.

The team concluded, “These findings suggest that school-level stimulant therapy for ADHD and other school-level risk factors were significantly associated with NUPS and should be accounted for in risk-reduction strategies and prevention efforts.”