Lisdexamfetamine: From Pharmacology to Forensic Implications.
DOI:
https://doi.org/10.48797/sl.2026.426Keywords:
PosterAbstract
Background: Lisdexamfetamine dimesylate (LDX) is a prodrug of d-amphetamine used in the treatment of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD) [1]. Objective: This systematic review aims to provide a comprehensive overview of LDX pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile, and forensic considerations. Methods: A literature search was conducted in PubMed without a limitation period using the keywords “lisdexamfetamine”, “lisdexamfetamine dimesylate”, “LDX”, “ADHD”, “pharmacokinetics”, “pharmacodynamics”, “forensic implications”, “abuse”, “clinical applications”, “clinical efficacy”, and “adverse effects”, either individually or in combination. All types of articles were included. A total of 113 articles were selected. Results: LDX undergoes rapid absorption via peptide transporter 1 (PepT1) in the small intestine, achieving Cmax within 1–2h [2-5], and is hydrolyzed in erythrocytes, by an unidentified aminopeptidase, into d-amphetamine and l-lysine [5, 6]. It is primarily eliminated in the urine (96.4%), with minimal fecal elimination (0.3%) [2]. LDX does not significantly alter the activity of CYP1A2, CYP2D6, and CYP3A4 (7), suggesting low potential for drug-drug interactions. Its stimulant activity results from trace amine-associated receptor 1 activation, monoamine oxidase inhibition, and reverse transport of the vesicular monoamine transporter 2, dopamine transporter, noradrenaline transporter, and serotonin transporter, increasing neurotransmitter levels in the synaptic cleft [1, 8]. Common adverse effects of LDX include dizziness, somnolence, appetite suppression, headache, nausea, and fatigue [9]. Concerns regarding growth suppression arise mainly in the first year of treatment and diminishing thereafter [9, 10]. Although LDX exhibits a lower reinforcing potential than d-amphetamine [11], supra-therapeutic doses may induce similar abuse liability and toxicity. However, its higher lethal dose threshold (five times that of amphetamines) reduces overdose risk [12]. Conclusions: LDX demonstrates established therapeutic benefits in ADHD, often yielding superior outcomes compared with other stimulant medications. In forensic settings, distinguishing between prescribed use and illicit intake remains a significant challenge. Considering its potential applications beyond ADHD, further large-scale investigations are needed to fully define LDX’s pharmacological, toxicological, and clinical profile.
References
1. Quintero J, et al. Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review. Neurol Ther, 2022, 11, 1489–1517, doi:10.1007/s40120-022-00392-2.
2. Krishnan SM, et al. Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers. Clin Drug Investig, 2008, 28, 745-755, doi:10.2165/0044011-200828120-00002.
3. Krishnan SM, et al. Multiple daily-dose pharmacokinetics of lisdexamfetamine dimesylate in healthy adult volunteers. Curr Med Res Opin, 2008, 24, 33-40, doi:10.1185/030079908x242737.
4. Boellner SW, et al. Pharmacokinetics of lisdexamfetamine dimesylate and its active metabolite, d-amphetamine, with increasing oral doses of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: a single-dose, randomized, open-label, crossover study. Clin Ther, 2010, 32, 252-264, doi:10.1016/j.clinthera.2010.02.011.
5. Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat, 2010, 317-327, doi:10.2147/ndt.s9749.
6. Sharman J, et al. Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells. Neuropsychiatr Dis Treat, 2014, 2275-2280, doi:10.2147/NDT.S70382.
7. Ermer J, et al. Lisdexamfetamine Dimesylate Effects on the Pharmacokinetics of Cytochrome P450 Substrates in Healthy Adults in an Open-Label, Randomized, Crossover Study. Drugs R D, 2015, 15, 175-185, doi:10.1007/s40268-015-0090-z.
8. Hutson PH, et al. Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug. Neuropharmacology, 2014, 87, 41-50, doi:10.1016/j.neuropharm.2014.02.014.
9. Coghill DR, et al. A systematic review of the safety of lisdexamfetamine dimesylate. CNS Drugs, 2014, 28, 497-511, doi:10.1007/s40263-014-0166-2.
10. Swanson JM, et al. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry, 2007, 46, 1015-1027, doi:10.1097/chi.0b013e3180686d7e.
11. Ermer JC, et al. Intranasal versus oral administration of lisdexamfetamine dimesylate: a randomized, open-label, two-period, crossover, single-dose, single-centre pharmacokinetic study in healthy adult men. Clin Drug Investig, 2011, 31, 357-370, doi:10.2165/11588190-000000000-00000.
12. Krishnan S, et al. An evaluation of the cytochrome p450 inhibition potential of lisdexamfetamine in human liver microsomes. Drug Metab Dispos, 2007, 35, 180-184, doi:10.1124/dmd.106.011973.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Mariana Silva-Carvalho, Diana Dias da Silva, Daniel José Barbosa, Ricardo Jorge Dinis-Oliveira
This work is licensed under a Creative Commons Attribution 4.0 International License.
In Scientific Letters, articles are published under a CC-BY license (Creative Commons Attribution 4.0 International License), the most open license available. The users can share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as they give appropriate credit, provide a link to the license, and indicate if changes were made (read the full text of the license terms and conditions of use).
The author is the owner of the copyright.
