Tolerance and tachyphylaxis to medications for attention-deficit/hyperactivity disorder (ADHD): a systematic review of empirical studies

Abstract

Background and objectives: individuals with Attention-Deficit/Hyperactivity Disorder (ADHD), their families, and clinicians may report worsening symptoms despite compliant use of medication, suggesting potential tolerance, but evidence remains conflicting. Some studies have also suggested tachyphylaxis, or acute tolerance, though research is limited. We conducted the first systematic review of empirical studies focussing on tolerance/tachyphylaxis to ADHD medication to clarify their potential clinical relevance.

Methods: as registered on PROSPERO (CRD42024594759), we searched Pubmed, OVID, (Including Psychinfo and Medline) and Web of Knowledge up to 1 September 2024, and assessed the risk of bias using NIH Quality Assessment tools.
Results: The identified 17 studies were either interventional or observational, and varied greatly in design and duration. Four investigated tachyphylaxis, 9 tolerance to the subjective and behavioural effects, and 4 tolerance to cardiovascular effects. We found preliminary evidence of tachyphylaxis to the affective or behavioural effects of stimulants, as well as tolerance to the subjective effects of d-amphetamine, such as drug liking and excitation, in neurotypical volunteers in the short-term. Conversely, there was little or no evidence for tolerance to the therapeutic or cardiovascular effects of ADHD medication in clinical settings in the longer-term. Quality was rated as low in most studies due to small sample sizes and methodological limitations.

Conclusion: overall, these results do not support the hypothesis that tolerance commonly develops to the therapeutic effects of ADHD medication, although robustly designed longitudinal studies are needed to provide more conclusive evidence. Clinicians may consider other potential explanations for reduced therapeutic effects over time, including natural fluctuations of symptoms, limited compliance, life events, and co-occurrent mental health conditions.

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Identifiers

ORCID for Valeria Parlatini: orcid.org/0000-0002-4754-2494

ORCID for Samuele Cortese: orcid.org/0000-0001-5877-8075

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