The neuropharmacology of ADHD drugs in vivo: Insights on efficacy and safety
Abstract
Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.
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LDX modulates seven human protein targets: it activates TAAR1 and inhibits SLC18A2, DAT, NET, SERT, MAOA, and MAOB.
“LDX has been reported to modulate with pharmacological action of seven human protein targets (Table 2). On the one hand, it acts as activator of TAAR1. On the other hand, six protein targets are inhibited by LDX: synaptic vesicular amine transporter (SLC18A2), DAT (SLC6A3), NET (SLC6A2), SERT (SLC6A4) and amine oxidase [flavin-containing] (MAO) A and B [153–157].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [156]
MPH and LDX have similar targets and act in the same way: both promote the inhibition of DAT and NET.
“MPH and LDH have similar targets and act in the same way: both promote the inhibition of DAT and NET [153, 156, 157].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [156]
All of these targets are involved in presynaptic signalling, and LDX therefore has a role in regulating three main NT pathways: DA, NE and serotonin.
“All of these targets are involved in the presynaptic signalling, and LDX therefore has a role in regulating three main NT pathways: DA, NE and serotonin.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [156]
LDX inhibits DAT and NET transporters leading to an increase in DA and NE levels in the synaptic cleft.
“LDX inhibits DAT and NET transporters leading to an increase in DA and NE levels in the synaptic cleft [153, 156, 157].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [156]
MPH preferentially blocks the reuptake of catecholamines, including dopamine and norepinephrine, in both the striatum and prefrontal cortex.
“a psychostimulant that preferentially blocks the reuptake of catecholamines, including dopamine (DA) and norepinephrine (NE), in both the striatum and prefrontal cortex (Mehta et al., 2000, 2004; Schiffer et al., 2006; Heal et al., 2009).”
From The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD (2015) · cites this paper as Heal et al., 2009
D-amphetamine is the major pharmacological ingredient in dextroamphetamine and lisdexamfetamine dimesylate, and both are believed to exert their therapeutic actions by enhancing the function of noradrenaline and DA.
“D-amphetamine is the major pharmacological ingredient in dextroamphetamine and lisdexamfetamine dimesylate, and both are believed to exert their therapeutic actions by enhancing the function of noradrenaline and DA [498].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [498]
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- Authors
- Heal, D. J., Cheetham, S. C., & Smith, S. L.
- Affiliations
- RenaSci (United Kingdom) (GB)
- Corresponding author
- Heal, D.J.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 57
- Issue
- 7-8
- Pages
- 608-618
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2077614189
- Cited by
- 198
- References
- 115
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 10 · 2023: 9 · 2022: 9 · 2021: 5 · 2020: 10 · 2019: 1 · 2018: 10 · 2017: 9 · 2016: 16 · 2015: 17 · 2014: 13 · 2013: 23 · 2012: 22
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shire
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- attention deficit hyperactivity disorder, psychostimulants, d-amphetamine, methylphenidate, atomoxetine, dopamine efflux, noradrenaline efflux, intracerebral microdialysis, drug safety, abuse liability, lisdexamfetamine, prodrugs, monoamine oxidase inhibition
- MeSH terms
- Atomoxetine Hydrochloride, Amphetamine, Central Nervous System Stimulants, Animals, Attention Deficit Disorder with Hyperactivity, Brain, Catecholamines, Humans, Methylphenidate, Propylamines, Stereoisomerism, Dopamine Agents, Adrenergic Uptake Inhibitors, Substance-Related Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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