Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder

David J. Heal, Jane Gosden, Sharon L. Smith

Research output: Chapter or section in a book/report/conference proceedingChapter or section


In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of D-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release D-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, D-amphetamine and D-threo-methylphenidate, and also their potential for misuse and abuse.

Original languageEnglish
Title of host publicationAdvances in Pharmacology
PublisherElsevier Academic Press Inc
Publication statusE-pub ahead of print - 25 Oct 2023
Externally publishedYes

Publication series

NameAdvances in Pharmacology
ISSN (Print)1054-3589
ISSN (Electronic)1557-8925

Bibliographical note

Funding Information:
The authors and DevelRx Ltd received no financial or material support from any agency in the public, commercial, or not-for-profit sectors when preparing this review. David Heal, Sharon Smith and Jane Gosden are shareholders and employees of DevelRx Ltd. DevelRx is a consultancy company which advises the pharmaceutical industry on the discovery and development of CNS drugs. The opinions expressed in this review are exclusively those of the authors and have not been influenced by any public, commercial, or not-for-profit organization.


  • ADHD
  • Attention-deficit hyperactivity disorder
  • Binge-eating disorder
  • Lisdexamfetamine
  • Prodrugs
  • Serdexmethylphenidate
  • Stimulant

ASJC Scopus subject areas

  • Pharmacology


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