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Comparison of serious adverse effects of methylphenidate, atomoxetine and amphetamine in the treatment of ADHD: an adverse event analysis based on the FAERS database

BMC Pharmacology and Toxicology volume 26, Article number: 38 (2025) Cite this article

Abstract

Background

Methylphenidate, atomoxetine, and amphetamine are the most commonly prescribed medications for ADHD, approved by the FDA. Despite their widespread use, real-world studies on their serious adverse effects are limited. This study leverages the FAERS database to analyze the safety of these drugs.

Methods

A retrospective analysis was conducted using FAERS data from 2004 to 2023. Adverse event (AE) signals for methylphenidate, atomoxetine, and amphetamine were identified by calculating reporting odds ratios (RORs), proportional reporting ratios (PRRs), information components (ICs), and empirical Bayesian geometric mean (EBGM).

Results

The analysis included 72,298 reports, with 37,471 linked to methylphenidate, 17,335 to atomoxetine, and 17,492 to amphetamine. Significant AE signals were found, especially in psychotic disorders for methylphenidate (ROR = 4.47, PRR = 3.7) and amphetamines (ROR = 4.06, PRR = 3.43), and psychiatric and reproductive disorders for atomoxetine (ROR = 5.44, PRR = 4.29; ROR = 2.49, PRR = 2.46). At the PT level, the most common adverse safety signals for the three ADHD drugs were Application site erythema, Somnolence, and Headache. Further analysis showed that “Aggression”, “Mydriasis”, “Trichotillomania” and suicide-related adverse reactions showed strong signals in the three ADHD drugs. However, there are also differences between the three ADHD medications. For example, serious adverse effects related to cardiovascular and neurological effects were stronger in amphetamines, with the “coronary artery dissection” and “carotid artery dissection” signals being the most significant; “Precocious puberty” has a stronger signal in methylphenidate, and the signal associated with elevated liver enzymes is strongest in atomoxetine. In addition, we also found some PTs that were not included in the drug label, such as “Disturbance in social behaviour” and “Trichotillomania”.

Conclusions

In this study, pharmacovigilance analysis of methylphenidate, atomoxetine, and amphetamine was performed using the FAERS database, and we identified significant safety signals. Of note, three ADHD medications are associated with suicide-related signals, amphetamine associated with coronary artery dissection, methylphenidate associated with precocious puberty, and atomoxetine associated with testicle, penile lesions, and liver damage, which require special attention. This study provides a reference for the clinical personalized medication of ADHD patients.

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Introduction

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that typically begins in childhood, with some individuals experiencing symptoms that persist into adulthood. The primary symptoms include developmental delays, inattention, hyperactivity, and impulsivity, with a prevalence of approximately 1.4–3.0% [1]. Globally, ADHD affects about 5% of children and adolescents and 2.5% of adults [2, 3]. The exact pathophysiology of ADHD remains unclear [1], but it is commonly associated with dysregulation of neurotransmitters, particularly dopamine and norepinephrine.

Treatment for ADHD in both children and adults is primarily pharmacological. Stimulants have been shown to significantly improve ADHD symptoms, including hyperactivity and difficulties in maintaining mental focus [4,5,6]. Various stimulants are often the first-line treatment, while non-stimulant medications are prescribed for patients who do not respond well to or cannot tolerate stimulants [2, 7,8,9,10]. Currently, 6.1 million children and adolescents in the United States are taking FDA-approved ADHD medications, which include stimulants such as amphetamine salts, methylphenidate, lisdexamfetamine, and methamphetamine, as well as non-stimulants like atomoxetine [11]. In 2018, Cortese et al. conducted a comprehensive analysis of the efficacy and tolerability of ADHD medications in children, adolescents, and adults. Their systematic review of data from 133 studies found that methylphenidate was the drug of choice for children and adolescents, while amphetamines were most effective for adults in the short-term treatment of ADHD. The study also highlighted that amphetamine was not only the most effective compound for adults but also the most acceptable, whereas methylphenidate was more acceptable than placebo in children and adolescents [6]. However, the FDA does not differentiate between these compounds in its recommendations for ADHD treatment.

Most existing studies on ADHD medications are based on case reports and reviews with limited sample sizes, making it challenging to identify potential adverse events (AEs). The United States Food and Drug Administration’s Adverse Event Reporting System (FAERS) is an open-source database that includes reports of adverse events and medication errors submitted to the FDA. Given the ongoing uncertainty among clinicians regarding the choice between methylphenidate, atomoxetine, or amphetamine, this study explores the safety profiles of these three drugs using the FAERS database. The study aims to evaluate the associated risk factors, providing a reference for the safe and rational clinical use of these medications.

Data and methods

Study design and data source

OpenVigil 2.1 (http://openvigil.sourceforge.net/) is an online data mining and pharmacovigilance data analysis tool developed by German academics and now widely used in pharmacovigilance research [12]. In order to gain insight into adverse drug reactions, we conducted a comprehensive retrospective analysis of adverse events from the first quarter of 2004 to the third quarter of 2023 using the OpenVigil drug monitoring tool. The researchers employed application programming interfaces (APIs) to extract structured adverse event data directly from the FAERS database. The quarterly data summaries comprise a range of adverse event reports, albeit with the potential for biases, including the omission of reports, false positive reports, and duplicate reports, to exist within the FAERS database. Additionally, the summaries encompass medication error reports, as well as product quality complaints. The MedDRA version 25.0 Adverse Drug Reaction Terminology Set was employed for the purposes of classification and description, with Standardized Oncology Categories (SOCs) serving as the classification of adverse events (AEs) and Preferred Terms (PTs) representing the standardised name for AEs. To guarantee the precision and uniformity of the data, the reporting odds ratio (ROR) method and the Bayesian confidence propagation neural network (BCPNN) method were employed in conjunction to identify the signals of AEs [13, 14]. Furthermore, data pertaining to the patient’s sex, age at the time of the adverse event (AE), date of report receipt, country of report origin, and details of the event and its outcome were also extracted. Furthermore, consideration was given to the generalisability of the results, with particular attention paid to potential differences between patients of diverse ethnicities and regions. Additionally, the extraction of drug names and information on primary drugs suspected of being associated with adverse events was conducted. It is anticipated that these comprehensive and in-depth analyses will provide valuable insights into drug safety and patient health.

Adverse event and drug identification

The identification of records pertaining to target drugs is conducted through the utilisation of generic nomenclature. In particular, we extracted adverse events labelled as ‘methylphenidate’, ‘amphetamine’, and ‘atomoxetine’ and designated them as the primary focus. In the course of the search process, the Personal Safety Report (ISR) was consulted in addition to PT and Count records. Two researchers, including a professor of psychiatry and a head nurse, were involved in the process. They classified AE reports and independently collected patients’ clinical characteristics, including gender, age, and AE outcomes. This rigorous approach was employed in order to gain a deeper understanding of the potential adverse events associated with patients taking methylphenidate, amphetamine, and atomoxetine. Furthermore, it was intended to provide more comprehensive and reliable data support for drug safety assessments.

Statistical analysis

To assess whether a drug was significantly associated with ADR, we calculated reporting odds ratios (RORs), proportional reporting ratios (PRRs), information components (ICs), and empirical Bayesian geometric mean (EBGMs) based on disproportionate and Bayesian analyses. The greater the ROR and PRR, the stronger the ADR signal, indicating the stronger the statistical relationship between the target drug and the target ADR [15, 16]. The AEs signal is deemed significant if the following criteria are met: a ≥ 3, ROR or PRR ≥ 2.0, and a 95% confidence interval (95% CI) value of more than 1.0. To minimise the number of false-positive AEs signals, we employed EBGM and IC to corroborate the AEs signals that we had identified [17,18,19]. The equations and criteria for the four algorithms are presented in Table 1 [20]. The data were subjected to statistical analysis using the R 4.3.2 software.

Table 1 Summary of four algorithms used for signals detection
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Results

Year of adverse reaction reporting

Adverse reactions from the use of methylphenidate were the most prominent in 2017, reaching 4,365 cases. Notably, there were more than 4000 reports of adverse effects of atomoxetine in both 2004 and 2015. Fewer adverse effects were reported with amphetamines than with the first two drugs, with more than 2,000 in 2018 and 2022 alone. Adverse effects were reported mainly from consumers, followed by physicians. Most of the reports came from the United States. The most serious adverse consequences are ranked first for “other serious conditions”, followed by hospitalization, followed by death, life-threatening conditions, etc. From these reports, it can be seen that the main indication of methylphenidate, atomoxetine, amphetamine is ADHD, of which methylphenidate and amphetamine can also be used for narcolepsy. In addition, we visualized the distribution of the number of adverse reaction reports, as shown in Fig. 1.

Fig. 1
figure 1

Number of reported adverse effects of methylphenidate, atomoxetine, and amphetamine per quarter from 2004 to 2023

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Basic demographic information

As shown in Table 2, from the first quarter of 2004 to the third quarter of 2023, the FAERS collected a total of 72,298 AE reports, of which 37,471 were related to Methylphenidate, 17,335 were related to Atomoxetine, and 17,492 were related to Amphetamine. In the AE report of methylphenidate, there were more males (51.04%) than females (27.53%), and the age of the patients was 6–12 years old (24.15%), and in the AE report of atomoxetine, there were more males (62.28%) than females (32.76%), and the age of the patients was 6–12 years old (31.79%), while in the AE reports of amphetamine, there were more females (45.42%) than males (34.06%), and the patients aged 19 years and older (43.52%)) for the main.

Table 2 ADE reports and clinical information
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System organ classes disproportionality analysis

As shown in Table 3, in the disproportionate analysis of SOC, we selected signals that met the criteria of the four algorithms, namely ROR > 2, PRR > 2, IC025 > 0, EBGM05 > 2, and Table 3 showed only two indicators, ROR and PRR. The significant signal of methylphenidate was a psychotic disorder (ROR = 4.47, PRR = 3.7). Significant signals for atomoxetine were observed in the categories of psychiatric disorders (ROR = 5.44, PRR = 4.29) and reproductive system and breast disorders (ROR = 2.49, PRR = 2.46). The significant signal of amphetamines is psychotic disorders (ROR = 4.06, PRR = 3.43). A review of the data in Table 3 indicates that all three substances are associated with an increased risk of psychiatric disorders. It can be seen that mental illness is common for all three.

Table 3 Significant safety signals on the SOC level
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Adverse reaction frequency analysis

A more comprehensive and detailed analysis was conducted at the PT level, which revealed a significant discrepancy. The PTs associated with methylphenidate, atomoxetine, and amphetamine indications were excluded from the analysis and ranked in descending order of PT frequency. The top 20 safety signals for the three drugs are presented in Table 4 and compared with the adverse reactions listed in the drug insert, which are not mentioned in the label and marked with an asterisk (*). The 95% CI of the ROR exhibited only the lower limit of the ROR 95% bilateral CI, EBGM and IC, which were not displayed. The greater the signal intensity, the stronger the correlation between PT and the drug.

Table 4 Top 20 signals on the PT level
Full size table

Our study found that the most common adverse safety signals for methylphenidate, atomoxetine, and amphetamine were “Application site erythema”, “Somnolence”, and “Headache”, respectively. The undesirable signal not mentioned in the instruction manual is “Disturbance in social behaviour”.

Comparison of serious adverse effects

The serious PTs in a single SOC are listed in additional table S1, and their list of adverse reactions from the medication instructions was compared with it. * indicates those that are not included in the instructions. The ROR 95% bilateral CI is only displayed as the bottom bound; EBGM and IC are not displayed in the ROR 95% CI.

In addition, we calculated the logarithm of the ROR value (+ 1) and plotted a heat map to compare the differences in serious adverse effects of the three drugs in each system (Fig. 2). Among them, “Aggression”, “Mydriasis”, “Trichotillomania” and suicide-related adverse reactions showed strong signals in the three ADHD drugs. However, there are also differences between the three ADHD medications. For example, serious adverse reactions related to the cardiovascular and nervous system were stronger in amphetamines, with the “Coronary artery dissection” and “carotid artery dissection” signals being the most significant, while not detected in the other two drugs; “Precocious puberty” and genital lesions-related signals had a stronger signal in methylphenidate, but were also not detected in the other two drugs. In addition, we also found that the signals associated with elevated liver enzymes, as well as those associated with genital lesions, were strongest in atomoxetine, while not detected in the other two drugs.

Fig. 2
figure 2

Logarithmic heat map of the ROR (+ 1) of methylphenidate, atomoxetine, and amphetamine

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Discussion

Based on the data from the first quarter of 2004 to the second quarter of 2023 in the FAERS database, this study used ROR and PRR as the main detection methods, and IC and EBGM as the confirmatory methods, and conducted pharmacovigilance analysis of methylphenidate, atomoxetine and amphetamine, which provided a reference for the safe and rational use of drugs in clinical practice, and provided a real-world reference value for adverse reaction signals.

Adverse event and clinical information

Regarding the demographics of adverse effect reports, we discovered that, in line with the epidemiology of ADHD, the majority of patients reported were males, and that adverse events associated with methylphenidate and atomoxetine were most common in children and adolescents aged 6 to 12 years, with more males than females [21]. Although adults 19 years of age and older are the most common age group for adverse events related to amphetamines, women report more adverse events than men do, primarily due to the fact that women use prescription psychostimulants more frequently than men do for non-medical purposes [22] and because they have higher proportions and more severe amphetamine dependence [23, 24]. Three drugs are mainly used to treat ADHD, and methylphenidate and amphetamine can also be used to treat narcolepsy. The reporters for the three drugs were mainly users, followed by doctors, and the reports were mainly from the United States. These findings are consistent with a number of studies that have used the FAERS database to investigate adverse drug reactions. The main reason for this is the emphasis on individual rights by US citizens, which has led to an increase in adverse reactions reported by consumers rather than health professionals, reflecting a possible under-reporting by health professionals [25, 26].

Common adverse reactions

It is worth mentioning that we found that the most common adverse reaction of methylphenidate was “Application site erythema”, which was mainly caused by the transdermal dosage form, which is suitable for children or patients who are unwilling to swallow tablets. The active ingredients and excipients in methylphenidate transdermal patches may irritate the skin, causing local telangiectasia, which can lead to erythema, but this erythema is usually mild and temporary [27], but if symptoms persist or worsen, a doctor should be consulted promptly.

Psychiatric disorders

In terms of systemic adverse effects, we found that the main adverse effects of methylphenidate, atomoxetine, and amphetamine were related to psychiatric disorders, with the most common manifestations being various psychiatric disorders, including aggression, abnormal behavior, and restlessness. ADHD is associated with multiple mental health comorbidities and poor health, academic, and psychosocial outcomes [28,29,30]. Individuals with ADHD have been found to have an increased risk of suicide attempts and suicide, even when comorbid psychiatric disorders are clinically treated [31], so there is great concern about a possible association between ADHD medications and suicide-related events. Our study found a significant association between all three ADHD drugs and suicide, with suicidal ideation or behaviour included as a black box warning in the label for atomoxetine [32] and no mention of suicidal ideation or behaviour in the label for methylphenidate and amphetamine. A registry-based study in Sweden investigated the risk of suicidal behaviour in people treated with methylphenidate and other stimulants [33]. When comparing treated and untreated ADHD patients, this study found that the use of methylphenidate or other stimulants was associated with a 31% increase in the incidence of suicidal behaviour in suicide-related events, but the analysis was not adjusted for potential confounders that might explain this association. When comparing treatment and non-treatment periods in the same patient, no increased risk of suicide-related events was found during the treatment period [33]. The study by Kenneth K. C. Man et al. found that the incidence of suicide attempts was higher in the period before the start of methylphenidate therapy and that the risk remained elevated immediately after the start of methylphenidate therapy and returned to baseline levels during continued methylphenidate therapy. Their findings do not support a causal relationship between methylphenidate treatment and suicide attempts. Although the selective norepinephrine reuptake inhibitor atomoxetine is not approved by the US Food and Drug Administration for the treatment of depression, it was originally developed as an antidepressant [34, 35]. About a year after the 2004 antidepressant black box warning, the US Food and Drug Administration and the European Medicines Agency ordered atomoxetine manufacturers to add a black box warning that children and adolescents treated for ADHD may be at increased risk of suicidal thoughts [36, 37]. However, a small number of studies have found no significant association between atomoxetine and increased risk of suicide [38]. Unregulated amphetamines, including methamphetamines, are a growing concern, particularly in some North American regions, where the use of these drugs has surged, resulting in drug overdoses [39,40,41] and an increase in amphetamine-related medical visits. One study showed that methamphetamine-related deaths in Australia doubled between 2009 and 2015, with violent suicide identified as the leading cause of these deaths [42]. In conclusion, clinically, for safety reasons, patients using ADHD medications should be under strict supervision by a doctor, especially those with mental health problems or at risk of suicide.

Neurological disorders

Among the neurological adverse effects, our study found that amphetamine was significantly associated with serious neurological adverse effects, but no relevant literature has been reported that amphetamine directly causes basal ganglia haemorrhage or carotid artery dissection. However, as a central nervous system stimulant, amphetamines are known to cause cardiovascular side effects such as high blood pressure and increased heart rate [43]. Hypertension is one of the major risk factors for bleeding in the basal ganglia, and therefore, amphetamine-induced hypertension may indirectly increase the risk of bleeding in the basal ganglia. However, the evidence that amphetamines directly cause carotid artery dissection is unclear. Given the above potential risks, it is recommended that amphetamines should be carefully assessed and used under the guidance of a physician, especially in patients with a history of cardiovascular disease or hypertension. If you have symptoms, you should seek medical attention promptly.

Cardiovascular disorders

In this study, we found that amphetamines were significantly associated with severe cardiovascular disease-related signals, with the “Coronary artery dissection” signal being the most significant, while methylphenidate and atomoxetine were not detected. Some studies have shown that ADHD medication increases mean blood pressure, heart rate, and QT interval in children, adolescents, and adults [44,45,46]. Although these increases have been described as relatively small, their presence raises concerns about the extent to which ADHD medication may affect the likelihood of serious cardiovascular (CV) events such as stroke, myocardial infarction (MI), and arrhythmias, particularly in people with underlying heart problems [46]. A limited number of observational studies have generally found that the use of ADHD medication does not increase the risk of CVD events, but the results are inconsistent [47]. To date, there have been only three case reports of patients diagnosed with spontaneous coronary artery dissection with a prior history of amphetamine use [48,49,50]. Although rare, amphetamine use may be associated with the development of spontaneous coronary artery dissection (SCAD). However, given the limited number of cases, more research is needed to clarify the causal relationship. In clinical practice, the possibility of SCAD in acute coronary syndrome in amphetamine users should be considered. Therefore, methylphenidate or atomoxetine may be safer than amphetamines in patients with heart disease.

Reproductive and endocrine system disorders

Our study also found serious adverse effects of atomoxetine in the reproductive system, such as testicular and penile lesions, but no serious adverse effects of methylphenidate and amphetamine on the reproductive system have been found, and there are no relevant studies. In the endocrine system, we found that methylphenidate was significantly associated with precocious puberty, but atomoxetine and amphetamine were not significantly associated with precocious puberty. Precocious puberty has traditionally been defined as the onset of secondary sexual characteristics in girls and boys before the age of 8 and 9 years, respectively [51]. This can lead to faster growth, sexual development, and faster bone maturation. In the AEsiani et al. [52] study, rats between 30 and 44 days of age were injected with 2 mg/kg/day of MPH and normal saline. They observed an increase in testicular weight and sperm count in the group injected with MPH, and these findings explained that subchronic MPH exposure in adolescent rats may have a trophic effect on testicular growth and negatively affect testosterone metabolism. Chatterjee-Chakrabarty et al. [53] investigated the effect of long-term MPH on the reproductive axis in adolescent female rats by comparing results with no drug treatment. They determined that LH levels were higher in the pituitary gland in the MPH group and that histologically follicular luteinization was premature. Data on the unintended effects of MPH on the reproductive system of children are extremely rare. Kelly et al. [54] reported a 1-year-old prepubertal boy with recurrent erections who had been treated with MPH for 2 years. In another case report, a 7-year-old girl with ADHD experienced excessive sexual masturbation and behavior during MPH treatment. Although the results of animal studies have revealed that methylphenidate may adversely affect the maturation and function of the reproductive system, there are still too few studies in humans or too small sample size. In conclusion, atomoxetine should be avoided as much as possible in adults with ADHD who need to have children, and methylphenidate or amphetamine can be used according to the situation. Children with ADHD (girls < 8 years and boys < 9 years) treated with methylphenidate should be evaluated by a pediatric endocrinology unit as early as possible, which may help to correctly diagnose precocious puberty and allow for early intervention.

Investigations anomalies

Among the various tests, atomoxetine was significantly associated with elevated liver enzymes and jaundice, whereas methylphenidate and amphetamine were not. Oral toxicity studies of repeated doses of atomoxetine conducted by Eli Lilly and Company in rats, mice, and dogs did not show any major organ toxicity [55]. Hepatotoxicity was not observed with intravenous atomoxetine in either rats or dogs [55]. However, Lim et al. [56] and Stojanovski et al. [57] reported three cases of significant liver injury after atomoxetine use, which is consistent with our findings. One study recommended that patients with laboratory evidence of jaundice or liver injury should discontinue atomoxetine and should not be restarted [57]. Overall, combined with our findings, we suggest that clinicians may switch to methylphenidate or amphetamine if they experience liver damage during atomoxetine use.

Limitations

Although this study explored the adverse effects of methylphenidate, atomoxetine, and amphetamine in clinical practice from multiple perspectives, there are still certain limitations. First of all, the FAERS database, as a classic spontaneous reporting system, may affect the accuracy of our research results due to multiple data sources, inconsistent data formats, duplicate data, and missing data. Second, because our study is retrospective in nature, it can only establish associations between drugs and adverse events, not causal relationships. Third, FAERS data cannot be used to calculate the incidence of adverse events or medication errors in the monitored population, and are primarily used to generate hypotheses rather than validate them. Fourth, our study only looked at the use of ADHD medications as monotherapy and did not consider their combination with other medications, which may have an impact on the incidence and severity of adverse events. Fifth, the dosage form of the drug was not analysed in this study, as this key information may be missing from the spontaneous report, and future studies can further compare drugs in different dosage forms.

Conclusion

In this study, pharmacovigilance analysis of methylphenidate, atomoxetine, and amphetamine was performed using the FAERS database, and the ADR signals at SOC and PT levels were detected using a disproportionate method, providing some supplemental ADR signals that were not mentioned in the label.We found significant safety signals, including those associated with suicide with three ADHD medications, amphetamine with coronary artery dissection, methylphenidate with precocious puberty, and atomoxetine with testicular and penile lesions, and liver damage, requiring special attention. These findings underscore the principle of clinical personalization. Despite its clinical importance, this study has limitations due to self-reported data, potentially leading to reporting biases and incomplete information. Future studies could more accurately assess the safety risks of methylphenidate, atomoxetine and amphetamines by using a more rigorous prospective study design in combination with clinical and epidemiological studies.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

FAERS:

The Food and Drug Administration Adverse Event Reporting System

ADRs:

Adverse drug reactions

PT:

Preferred Terms

SOC:

System Organ Classes

ROR:

Reporting Odds Ratio

PRR:

Proportional Reporting Ratio

BCPNN:

Bayesian Confidence Propagation Neural Network

MGPS:

Multi-Item Gamma Poisson Shrinker

IC:

Information component

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Authors and Affiliations

  1. Nanchong Mental Health Center of Sichuan Province, Nanchong, China

    Linman Wu, Dan Zhao, Yongqing Lan & Lijuan Yang

  2. The Second People’s Hospital of Lishui, Lishui, China

    Liuyin Jin

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Contributions

Conceptualization: Linman Wu. Data curation: Linman Wu, Liuyin Jin. Formal analysis: Linman Wu, Liuyin Jin. Methodology: Linman Wu. Supervision: Lijuan Yang, Liuyin Jin. Validation: Lijuan Yang, Liuyin Jin. Writing—original draft: Linman Wu. Writing—review & editing: Dan Zhao, Yongqing Lan. Funding acquisition: Lijuan Yang.

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Wu, L., Zhao, D., Lan, Y. et al. Comparison of serious adverse effects of methylphenidate, atomoxetine and amphetamine in the treatment of ADHD: an adverse event analysis based on the FAERS database. BMC Pharmacol Toxicol 26, 38 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40360-025-00868-5

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Keywords

BMC Pharmacology and Toxicology

ISSN: 2050-6511

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