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Cited by 475Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorSubstance Abuse Treatment and Outcomes

Variables That Affect the Clinical Use and Abuse of Methylphenidate in the Treatment of ADHD

Volkow, Nora D., Swanson, James M.·2003·American Journal of Psychiatry
DOI 10.1176/appi.ajp.160.11.1909
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Abstract

OBJECTIVE: Methylphenidate, the most common treatment for attention deficit hyperactivity disorder (ADHD), increases extracellular dopamine in the brain, which is associated with its reinforcing as well as its therapeutic effects. The authors evaluated variables that distinguish these two properties. METHOD: The brain imaging and clinical literatures were analyzed to identify variables that contribute to the abuse liability as well as to the clinical efficacy of methylphenidate. RESULTS: Four variables were identified. 1) Dose--there is a threshold for methylphenidate-induced dopamine increases to be perceived as reinforcing and to produce therapeutic effects. 2) Pharmacokinetics--the reinforcing effects of methylphenidate are associated with rapid changes in serum concentrations and presumably fast dopamine increases (as achieved with intravenous injection or insufflation), whereas the therapeutic effects are associated with slowly ascending serum concentrations and presumably smoothly rising dopamine levels (as achieved with oral administration). 3) Individual differences--sensitivity to methylphenidate varies across individuals and sets a threshold for blood and brain levels required for reinforcing effects (drug liking) and for therapeutic effects (symptom reduction). 4) Context--the effects of methylphenidate are modulated by different settings in abuse (rituals of self-administration and powerful conditioning) and in clinical use (external demands of low activity and focused attention). CONCLUSIONS: Reinforcing effects occur when methylphenidate elicits large and fast dopamine increases that mimic those of phasic dopamine cell firing, whereas therapeutic effects occur when methylphenidate elicits slow, steady-state dopamine increases that mimic those of tonic firing. Thus, the characteristics of clinical use (low doses administered orally and titrated for therapeutic effects) constrain methylphenidate's abuse.

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  • Stimulant medications raise dopamine concentration in the nucleus accumbens, a brain region implicated in substance abuse and the proposed neural mechanism for ADHD treatment.

    “One reason for the persistent concern for subsequent substance abuse derives from the fact that stimulant medications increase dopamine concentration in the nucleus accumbens (a brain region implicated in substance abuse and the proposed neural mechanism for ADHD treatment) (Wise, 2002; Volkow & Swanson, 2003).”

    From Stimulant <scp>ADHD</scp> medication and risk for substance abuse (2014) · cites this paper as Volkow & Swanson, 2003

  • In the Volkow study, intravenous methylphenidate could not be distinguished from cocaine by cocaine addicts, whereas oral methylphenidate could be distinguished.

    “In the Volkow study it was found that intravenous methylphenidate could not be distinguished from cocaine by cocaine addicts, whereas this was not the case for oral methylphenidate.”

    From European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD (2010) · cites this paper as [257]

  • During oral clinical use, methylphenidate elicits slow steady-state dopamine increases in the brain that mimic tonic neuron firing, rather than rapid dopamine changes associated with reinforcing drug-like effects.

    “In contrast, during oral clinical use, methylphenidate elicits slow steady-state dopamine increases in the brain which mimic those of tonic neuron firing, rather than rapid dopamine changes associated with reinforcing drug-like effects [257].”

    From European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD (2010) · cites this paper as [257]

  • Abuse potential of stimulants relates to the route of administration, with rapid rise in dopamine levels following injection or snorting.

    “Abuse potential has been studied by Nora Volkow (Director of the National Institute of Drug Abuse, USA) who showed that abuse potential relates to the route of administration, with rapid rise in dopamine levels following injection or snorting of stimulants.”

    From European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD (2010) · cites this paper as [257]

  • The literature supports the view that stimulant treatment for ADHD either has no impact on risk for substance abuse, or may even lower the risk of substance abuse by reducing the early onset of substance abuse in adolescents.

    “Despite concerns that pharmacotherapy with stimulant medication may be a risk factor for substance abuse, the literature supports the view that stimulant treatment for ADHD either has no impact in risk for substance abuse, or may even lower the risk of substance abuse by reducing the early onset of substance abuse in adolescents [206,254,257-259].”

    From European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD (2010) · cites this paper as [257]

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Authors
Volkow, N. D., & Swanson, J. M.
Affiliations
National Institutes of Health (US)
ORCID
Venue
American Journal of Psychiatry
Publisher
American Psychiatric Association Publishing
Published
2003-11-01
Volume
160
Issue
11
Pages
1909-1918
ISSN
  • 0002-953X (ISSN-L)
  • 1535-7228
DOI
10.1176/appi.ajp.160.11.1909
OpenAlex
W2127294790
Cited by
475
References
60
Citations by year
2026: 12 · 2025: 16 · 2024: 14 · 2023: 10 · 2022: 7 · 2021: 7 · 2020: 31 · 2019: 15 · 2018: 14 · 2017: 15 · 2016: 21 · 2015: 19 · 2014: 32 · 2013: 29 · 2012: 23
FWCI
14.12
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Drug Abuse (DA 00280, K20DA000280, DA7092-01)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords
methylphenidate, attention deficit hyperactivity disorder, drug abuse liability, reinforcement effect, dopamine, pharmacokinetics, threshold dose, self-administration, clinical efficacy, oral versus intravenous administration
MeSH terms
Attention Deficit Disorder with Hyperactivity, Brain, Cocaine, Delayed-Action Preparations, Dopamine, Dose-Response Relationship, Drug, Extracellular Space, Humans, Injections, Intravenous, Membrane Glycoproteins, Methylphenidate, Nerve Tissue Proteins, Reinforcement, Psychology, Self Medication, Treatment Outcome, Substance-Related Disorders, Membrane Transport Proteins, Membrane Transport Modulators, Dopamine Plasma Membrane Transport Proteins

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