Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report

Abstract

Recommended treatment for attention deficit hyperactivity disorder (ADHD) includes stimulant medication. While these medicines are effective for most ADHD patients, benefits may wear off, suggesting tolerance. This paper reviews the published literature on tolerance to stimulant medication treatment for ADHD. As there are relatively few studies published, pivotal studies and ADHD treatment guidelines were also reviewed. Research demonstrates physiological changes related to continued stimulant usage in neurons and certain brain regions, suggesting a mechanism for tolerance development. One clinical study showed that 24.7% of patients developed tolerance to stimulants in the time of days to weeks; another showed 2.7% developed tolerance over 10 years. Long term follow-up studies demonstrate that medication response may lessen over longer durations of treatment in a high percentage of patients. Strategies to manage tolerance include switching stimulant medicines, drug holidays, or clinical reassessment. Three cases illustrate challenges with treating patients who develop tolerance to stimulant medication. The paucity of research and lack of guidance to clinicians may contribute to significant under recognition of tolerance to stimulant medication. Further research is required to define clinical tolerance for stimulants in ADHD and to provide guidance on identifying and managing tolerance in clinical practice.

Characteristics and outcomes of cases with methylphenidate abuse, dependence or withdrawal: an analysis of spontaneous reports in EudraVigilance

“…Furthermore, inconsistent doses, unconventional ROAs, or combination with other substances probably increase the risk for serious outcomes, including fatalities (Farquhar et al , 2002; Ruwald et al , 2012; Hay et al , 2015; Faraone et al , 2020; Kariisa et al , 2021). The combination with benzodiazepines often used to intensify recreational experiences or reduce unwanted side effects (Grimsrud et al , 2019), and especially the co-use of opioids increases the risk of fatality (UNODC, 2021) as shown for the latter for cocaine and other psychostimulants with abuse potential (Kariisa et al , 2021). Unexpectedly, our study found similar proportions of intravenous administration in fatal and nonfatal cases.…”

“…The MPH-induced dopamine signaling affects the reward system and, especially when administered via the nasal or intravenous route, leads to euphoric effects and 'highs' similar to cocaine (Morton and Stockton, 2000;Volkow et al, 2002). Although the development of tolerance to MPH is not yet fully understood, it may probably be caused by the upregulation of dopamine transporters in the striatum (Volkow et al, 2012;Taylor, 2019;Handelman and Sumiya, 2022). Dependence and withdrawal symptoms (e.g.…”

A novel jigsaw game with eye‐tracking: A multimodel interaction based on psycholinguistics for ADHD therapeutic

“…1 ADHD is considered a chronic condition, and many individuals diagnosed in childhood continue to experience symptoms and functional impairment as adults. 3 Traditional pharmacological interventions and behavioral therapy for ADHD may have potential negative effects, as seen with Dextromethorphan (DM) and its impact on ADHD symptoms. 2 While these treatments show efficacy in many cases, their therapeutic benefits may diminish over time, leading to tolerance development.…”

“…Medication and behavioral treatment are frequently used, with 62.0% of children with ADHD receiving medication and 46.7% receiving behavioral treatment 1 . ADHD is considered a chronic condition, and many individuals diagnosed in childhood continue to experience symptoms and functional impairment as adults 3 . Traditional pharmacological interventions and behavioral therapy for ADHD may have potential negative effects, as seen with Dextromethorphan (DM) and its impact on ADHD symptoms 2 .…”

“…While these treatments show efficacy in many cases, their therapeutic benefits may diminish over time, leading to tolerance development. Studies have reported that approximately 24.7% of patients develop tolerance to stimulants within days to weeks of treatment 3 . As an alternative to conventional treatments, novel digital therapeutics have shown promise in addressing cognitive deficits associated with ADHD and may mitigate the adverse effects of traditional therapies.…”