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For years, a persistent concern has shadowed the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD): Does the medication eventually stop working? Patients often report that their symptoms seem to return despite consistent use, leading to "dose escalation" or "medication holidays." A new systematic review from Sam Cortese’s team published in CNS Drugs finally puts these concerns to the test by synthesizing decades of empirical research.
Before diving into the findings, you must understand two often-confused phenomena:
The review analyzed 17 studies covering over 10,000 individuals, and the results provide a much-needed reality check for the clinical community.
The researchers found preliminary evidence that acute tolerance (tachyphylaxis) can occur within a 24-hour window.
The most important finding is that tolerance does not commonly develop to the therapeutic effects of ADHD medication in the long term. In one landmark study following children for up to 10 years, only 2.7% of participants lost their response to methylphenidate without a clear external explanation. Doses, when adjusted for natural body growth, remained remarkably stable over years of treatment.
Consistent with the lack of therapeutic tolerance, the body does not become tolerant to the physical side effects of stimulants. Increases in heart rate and blood pressure typically persist for as long as the medication is taken. This underscores why clinicians must continue monitoring cardiovascular health throughout the entire duration of treatment.
If it’s Not Tolerance, What Is It?
If "tolerance" isn't real, why do some patients feel their medication is failing? The review suggests clinicians look at these alternative explanations:
Why This Matters
These results provide clinicians the confidence to tell patients that their medication is unlikely to "wear out" permanently. Rather than immediately increasing a dose when symptoms flare, the first step should be a "clinical deep dive" into the patient's lifestyle, stress levels, and adherence.
For researchers, the review highlights a major gap: most existing studies are small, dated, or of low quality. There is a dire need for robust, longitudinal studies that track both the brain's response and the patient's environment over several years.
For people with ADHD, while your body might get "used to" the initial "buzz" of a stimulant within hours, its ability to help you focus and manage your life remains remarkably durable over the years.
Smith, C., Walker, H., Parlatini, V., & Cortese, S. (2026). Tolerance and tachyphylaxis to medications for attention-deficit/hyperactivity disorder (ADHD): A systematic review of empirical studies. CNS Drugs. . https://doi.org/10.1007/s40263-025-01263-8
Noting that “the association between adult ADHD and dementia risk remains a topic of interest because of inconsistent results,” an Israeli study team tracked 109,218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020.
Israeli law forbids nonprofit HMOs from turning anyone away based on demographic factors, health conditions, or medication needs, thereby limiting sample selection bias.
The estimated prevalence of dementia in this HMO, as diagnosed by geriatricians, neurologists, or psychiatrists, is 6.6%. This closely matches estimates in Western Europe (6.9%) and the United States (6.5%).
The team considered, and adjusted for, numerous covariates: age, sex, socioeconomic status, smoking, depression, obesity, chronic obstructive pulmonary disease, hypertension, atrial fibrillation, heart failure, ischemic heart disease, cerebrovascular disease, diabetes, Parkinson’s disease, traumatic brain injury, migraine, mild cognitive impairment, psychostimulants.
With these adjustments, individuals diagnosed with ADHD were almost three times as likely to be subsequently diagnosed with dementia as those without ADHD. Men with ADHD were two and a half times more likely to be diagnosed with dementia, whereas women with ADHD were over three times more likely, than non-ADHD peers.
More concerning still, persons with ADHD were 5.5 times more likely to be subsequently diagnosed with early onset dementia, as opposed to 2.4 times more likely to be diagnosed with late onset dementia.
On the other hand, the team found no significant difference in rates of dementia between individuals with ADHD who were being treated with stimulant medications and individuals without ADHD. Those with untreated ADHD had three times the rate of dementia. The team nevertheless cautioned, “Due to the underdiagnosis of dementia as well as bidirectional misdiagnosis, this association requires further study before causal inference is plausible.”
Conclusions and Relevance:
This study reinforces existing evidence that adult ADHD is associated with an increased risk of dementia. Notably, the increased risk was not observed in individuals receiving psychostimulant medication, however the mechanism behind this association is not clear.
These findings underscore the importance of reliable ADHD assessment and management in adulthood. They also highlight the need for further study into the link between stimulant medications and the decreased risk of dementia.
...
Struggling to get the care you need to manage your ADHD? Support The ADHD Evidence Project and get this step-by-step guide to getting the treatment you deserve: https://bit.ly/41gIQE9
A Chinese research team performed two types of meta-analyses to compare the risk of suicide for ADHD patients taking ADHD medication as opposed to those not taking medication.
The first type of meta-analysis combined six large population studies with a total of over 4.7 million participants. These were located on three continents - Europe, Asia, and North America - and more specifically Sweden, England, Taiwan, and the United States.
The risk of suicide among those taking medication was found to be about a quarter less than for unmediated individuals, though the results were barely significant at the 95 percent confidence level (p = 0.49, just a sliver below the p = 0.5 cutoff point). There were no significant differences between males and females, except that looking only at males or females reduced sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications produced divergent outcomes. A meta-analysis of four population studies covering almost 900,000 individuals found stimulant medications to be associated with a 28 percent reduced risk of suicide. On the other hand, a meta-analysis of three studies with over 62,000 individuals found no significant difference in suicide risk for non-stimulant medications. The benefit, therefore, seems limited to stimulant medication.
The second type of meta-analysis combined three within-individual studies with over 3.9 million persons in the United States, China, and Sweden. The risk of suicide among those taking medication was found to be almost a third less than for unmediated individuals, though the results were again barely significant at the 95 percent confidence level (p =0.49, just a sliver below the p = 0.5 cutoff point). Once again, there were no significant differences between males and females, except that looking only at males or females reduced the sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications once again produced divergent outcomes. Meta-analysis of the same three studies found a 25 percent reduced risk of suicide among those taking stimulant medications. But as in the population studies, a meta-analysis of two studies with over 3.9 million persons found no reduction in risk among those taking non-stimulant medications.
A further meta-analysis of two studies with 3.9 million persons found no reduction in suicide risk among persons taking ADHD medications for 90 days or less, "revealing the importance of duration and adherence to medication in all individuals prescribed stimulants for ADHD."
The authors concluded, "exposure to non-stimulants is not associated with a higher risk of suicide attempts. However, a lower risk of suicide attempts was observed for stimulant drugs. However, the results must be interpreted with caution due to the evidence of heterogeneity ..."
Raising children is not easy. I should know.
As a clinical psychologist, I've helped parents learn the skills they need to be better parents. And my experience raising three children confirmed my clinical experience.
Parenting is a tough job under the best of circumstances, but it is even harder if the parent has ADHD.
For example, an effective parent establishes rules and enforces them systematically. This requires attention to detail, self-control, and good organizational skills. Given these requirements, it is easy to see how ADHD symptoms interfere with parenting. These observations have led some of my colleagues to test the theory that treating ADHD adults with medication would improve their parenting skills. I know about two studies that tested this idea.
In 2008, Dr. Chronis-Toscano and colleagues published a study using a sustained-release form of methylphenidate for mothers with ADHD. As expected, the medication decreased their symptoms of inattention and hyperactivity/impulsivity. The medication also reduced the mother's use of inconsistent discipline and corporal punishment and improved their monitoring and supervision of their children.
In a 2014 study, Waxmonsky and colleagues observed ADHD adults and their children in a laboratory setting once when the adults were off medication and once when they were on medication. They used the same sustained-release form of amphetamine for all the patients. As expected, the medications reduced ADHD symptoms in the parents. This laboratory study is especially informative because the researchers made objective ratings of parent-child interactions, rather than relying on the parents' reports of those interactions. Twenty parents completed the study. The medication led to less negative talk and commands and more praise by parents. It also reduced negative and inappropriate behaviors in their children.
Both studies suggest that treating ADHD adults with medication will improve their parenting skills. That is good news. But they also found that not all parenting behaviors improved. That makes sense. Parenting is a skill that must be learned. Because ADHD interferes with learning, parents with the disorder need time to learn these skills. Medication can eliminate some of the worst behaviors, but doctors should also provide adjunct behavioral or cognitive-behavioral therapies that could help ADHD parents learn parenting skills and achieve their full potential as parents.
Acid-suppressive medications, including proton pump inhibitors (PPIs) and histamine-2 (H2) receptor antagonists, are often prescribed during pregnancy to treat heartburn and gastroesophageal reflux disease.
Research shows changes in the gut microbiome can negatively affect neurodevelopment. Since acid-suppressive medications alter gut microbiota, maternal use during pregnancy may impact offspring’s neurodevelopment. Because PPIs and H2 receptor antagonists readily cross the placental barrier, they could potentially influence fetal neurodevelopment.
The link between prenatal exposure to acid-suppressive medications and major neuropsychiatric disorders is not well understood. With the use of these medications during pregnancy rising, it is important to assess their impact on children's long-term neurodevelopment. This study examined whether maternal use of acid-suppressive drugs is associated with increased risk of neuropsychiatric disorders in children, using a large, nationwide birth cohort from South Korea.
South Korea operates a single-payer health insurance system, providing coverage for over 97% of its citizens. The National Health Insurance Service (NHIS) maintains a comprehensive database with sociodemographic details, medical diagnoses, procedures, prescriptions, health examinations, and vital statistics for all insured individuals.
A Korean research team analyzed data from over three million mother-child pairs (2010–2017) to assess the risks of prenatal exposure to acid-suppressing medications. They applied propensity scoring to adjust for maternal age, number of children, medical history, and outpatient visits before pregnancy, to minimize confounding factors. That narrowed the cohort to just over 800,000 pairs, with half in the exposed group.
With these adjustments, prenatal exposure to acid-suppressing medications was associated with 14% greater likelihood of being subsequently diagnosed with ADHD.
Yet, when 151,737 exposed births were compared to the same number of sibling controls, no association was found between prenatal exposure and subsequent ADHD, which suggests unaccounted familial and genetic factors influenced the preceding results.
The Take-Away:
Evidence of these medications negatively affecting pregnancies is mixed, mostly observational, and generally reassuring when these medications are used appropriately. Untreated GERD and gastritis, however, have known risks and associations with the development of various cancers. With no evidence of an association with ADHD (or for that matter any other neuropsychiatric disorder), there is no current evidence-based reason for expectant mothers to discontinue use of acid-suppressing medications.
For years, a persistent concern has shadowed the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD): Does the medication eventually stop working? Patients often report that their symptoms seem to return despite consistent use, leading to "dose escalation" or "medication holidays." A new systematic review from Sam Cortese’s team published in CNS Drugs finally puts these concerns to the test by synthesizing decades of empirical research.
Before diving into the findings, you must understand two often-confused phenomena:
The review analyzed 17 studies covering over 10,000 individuals, and the results provide a much-needed reality check for the clinical community.
The researchers found preliminary evidence that acute tolerance (tachyphylaxis) can occur within a 24-hour window.
The most important finding is that tolerance does not commonly develop to the therapeutic effects of ADHD medication in the long term. In one landmark study following children for up to 10 years, only 2.7% of participants lost their response to methylphenidate without a clear external explanation. Doses, when adjusted for natural body growth, remained remarkably stable over years of treatment.
Consistent with the lack of therapeutic tolerance, the body does not become tolerant to the physical side effects of stimulants. Increases in heart rate and blood pressure typically persist for as long as the medication is taken. This underscores why clinicians must continue monitoring cardiovascular health throughout the entire duration of treatment.
If it’s Not Tolerance, What Is It?
If "tolerance" isn't real, why do some patients feel their medication is failing? The review suggests clinicians look at these alternative explanations:
Why This Matters
These results provide clinicians the confidence to tell patients that their medication is unlikely to "wear out" permanently. Rather than immediately increasing a dose when symptoms flare, the first step should be a "clinical deep dive" into the patient's lifestyle, stress levels, and adherence.
For researchers, the review highlights a major gap: most existing studies are small, dated, or of low quality. There is a dire need for robust, longitudinal studies that track both the brain's response and the patient's environment over several years.
For people with ADHD, while your body might get "used to" the initial "buzz" of a stimulant within hours, its ability to help you focus and manage your life remains remarkably durable over the years.
The Background:
Concerns remain about how ADHD and methylphenidate (MPH) use might affect children's health and growth, and especially how it may affect their adult height. While some studies suggest disrupted growth and a possible biological mechanism, the impact of ADHD prevalence and MPH use is still unclear. Children with ADHD may develop unhealthy habits – irregular eating, low physical activity, and poor sleep – that can contribute to obesity and reduced height. MPH’s appetite-suppressing effect can lead to skipped meals or overeating. Since growth hormone is mainly released during deep sleep, chronic sleep deprivation could plausibly slow growth and impair height development; however, a clear link between ADHD, MPH use, overweight, and shorter stature has never been firmly established.
The Study:
South Korea has a single payer health insurance system that covers more than 97% of its population. A Korean research team used the National Health Insurance Service database to perform a nationwide population study to explore this topic further.
The study involved 34,850 children, of whom 12,866 were diagnosed with ADHD. Of these children, 6,816 (53%) had received methylphenidate treatment, while 6,050 (47%) had not. Each patient with ADHD was precisely matched 1:1 by age, sex, and income level to a control participant without ADHD. The sex ratio was comparable in all groups.The team used Body Mass Index (BMI) as an indicator of overweight and obesity.
The Results:
The researchers found that being diagnosed with ADHD was associated with 50% greater odds of being overweight or obese as young adults, and over 70% greater odds of severe obesity (BMI > 30) compared to matched non-ADHD controls, regardless of whether or not they were medicated.
Those diagnosed with ADHD, but not on methylphenidate, had 40% greater odds of being overweight or obese, and over 55% greater odds of becoming severely obese, relative to matched non-ADHD controls.
Methylphenidate users had 60% greater odds of being overweight or obese, and over 85% greater odds of becoming severely obese, relative to matched non-ADHD controls.
There were signs of a dose-response effect. Less than a year’s exposure to methylphenidate was associated with roughly 75% greater odds of becoming severely obese, whereas exposure over a year or more raised the odds 2.3-fold, relative to matched non-ADHD controls. Using MPH increased the prevalence of overweight from 43.2% to 46.5%, with a greater prevalence among those using MPH for more than one year (50.5%).
It is important to note that most of this effect was from ADHD itself, with methylphenidate only assuming a predominant role in severe obesity among those with longer-term exposure to the medicine.
As for height, children with ADHD were no more likely to be short of stature than matched non-ADHD controls. Being prescribed methylphenidate was associated with slightly greater odds (7%) of being short of stature, but there was no dose-response relationship.
Conclusion:
The team concluded, “patients with ADHD, particularly those treated with MPH, had a higher BMI and shorter height at adulthood than individuals without ADHD. Although the observed height difference was clinically small in both sexes and age groups, the findings suggest that long-term MPH exposure may be associated with growth and body composition, highlighting the need for regular monitoring of growth.” They also point out that “Despite these findings, the clinical relevance should be interpreted with caution. In our cohort, the mean difference in height was less than 1 cm (eg, maximum −0.6 cm in females) below commonly accepted thresholds for clinical significance.” Likewise, increases in overweight/BMI were small.
One problem with interpreting the BMI/obesity results is that some of the genetic variants that cause ADHD also cause obesity. If that genetic load increases with severity of ADHD than the results from this study are confounded because those with more severe ADHD are more likely to be treated than those with less severe ADHD.
Due to these small effects along with the many study limitations noted by the authors, these results should be considered alongside the well-established benefits of methylphenidate treatment.
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