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Cited by 634Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorNeuroethics, Human Enhancement, Biomedical Innovations

The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities

Open access
Faraone, Stephen V.·2018·Neuroscience & Biobehavioral Reviews
DOI 10.1016/j.neubiorev.2018.02.001PMC PMC8063758
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Abstract

Psychostimulants, including amphetamines and methylphenidate, are first-line pharmacotherapies for individuals with attention-deficit/hyperactivity disorder (ADHD). This review aims to educate physicians regarding differences in pharmacology and mechanisms of action between amphetamine and methylphenidate, thus enhancing physician understanding of psychostimulants and their use in managing individuals with ADHD who may have comorbid psychiatric conditions. A systematic literature review of PubMed was conducted in April 2017, focusing on cellular- and brain system-level effects of amphetamine and methylphenidate. The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function. Amphetamine actions include dopamine and norepinephrine transporter inhibition, vesicular monoamine transporter 2 (VMAT-2) inhibition, and monoamine oxidase activity inhibition. Methylphenidate actions include dopamine and norepinephrine transporter inhibition, agonist activity at the serotonin type 1A receptor, and redistribution of the VMAT-2. There is also evidence for interactions with glutamate and opioid systems. Clinical implications of these actions in individuals with ADHD with comorbid depression, anxiety, substance use disorder, and sleep disturbances are discussed.

Integrity signals

Registry

Crossref · 10.1016/j.neubiorev.2018.02.001

Cites

269 of 269 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

53 of 121 cited sources checked · 26 supported · 1 flagged · accuracy not yet measured

  • Interpretationcitation

    The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity.

    “The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function.”
    • Also stated in: § Discussion · plain
      “the primary central nervous system effects of AMP and MPH within the brain include increased catecholamine availability in striatal and cortical regions”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [44] Avelar AJ, Juliano SA, Garris PA. Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem. 2013; 125(3): 373– 85. 23406303 PMC3633730 source

      The Introduction describes amphetamine’s actions on dopamine signaling, and the Discussion section “DAT Inhibitors and Vesicular DA Release” identifies methylphenidate as a dopamine-transporter inhibitor that augments dopamine release (page numbers unavailable). These passages support a dopaminergic effect for both drugs, but do not establish that increasing both dopamine and norepinephrine activity is their primary pharmacologic effect. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [52] Covey DP, Juliano SA, Garris PA. Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine. PLoS One. 2013; 8(5): e60763. 23671560 PMC3643976 source

      The Introduction and Results section on phasic dopamine signaling report that amphetamine increases dopamine signaling. The paper does not establish the corresponding claim for methylphenidate or increased norepinephrine activity; methylphenidate appears in the supplied evidence only in a reference. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [58] Easton N, Steward C, Marshall F, Fone K, Marsden C. Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology. 2007; 52(2): 405– 14. 17020775 source
    • cites [59] Finnema SJ, Hughes ZA, Haaparanta-Solin M, Stepanov V, Nakao R, Varnas K, Amphetamine decreases alpha2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain. Int J Neuropsychopharmacol. 2015; 18(3): 1– 10. PMC4360244 25522417 source

      The Results (Rat Brain Microdialysis; page not provided) report that amphetamine increased norepinephrine and dopamine concentrations in rat striatum, and the Discussion describes its elevation of both neurotransmitters. The cited paper does not establish the corresponding claim about methylphenidate, so it supports only the amphetamine portion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [60] Floor E, Meng L. Amphetamine releases dopamine from synaptic vesicles by dual mechanisms. Neurosci Lett. 1996; 215(1): 53– 6. 8880752 source
  • Premisecitation

    Amphetamine's effect on synaptic dopamine and norepinephrine is mediated by inhibition of dopamine and norepinephrine transporters, reducing reuptake.

    “This effect is mediated by inhibition of DA transporters (DAT) and NE transporters (NET) (44, 52, 58), which reduces the reuptake of these molecules from the synapse.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [44] Avelar AJ, Juliano SA, Garris PA. Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem. 2013; 125(3): 373– 85. 23406303 PMC3633730 source

      The Introduction says amphetamine inhibits the dopamine transporter, and the Discussion (“DAT Inhibitors and Vesicular DA Release”; page unavailable) reports that it inhibits dopamine uptake. The paper does not address norepinephrine-transporter inhibition or norepinephrine reuptake. It also identifies enhanced vesicular dopamine release as another important mechanism, so it does not support attributing the whole effect solely to reduced reuptake. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [52] Covey DP, Juliano SA, Garris PA. Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine. PLoS One. 2013; 8(5): e60763. 23671560 PMC3643976 source

      The Results section ('Psychostimulant effects on vesicular dopamine release and dopamine uptake'; page not provided) reports that amphetamine significantly decreased dopamine uptake in both striatal regions, and the Introduction links amphetamine to inhibited dopamine uptake. The cited paper does not establish the claim about norepinephrine transporters (NET) or reduced norepinephrine reuptake. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [58] Easton N, Steward C, Marshall F, Fone K, Marsden C. Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology. 2007; 52(2): 405– 14. 17020775 source
  • Premisecitation

    Psychostimulants are first-line pharmacotherapy for ADHD in children, adolescents, and adults because they have greater efficacy than nonstimulants.

    “Psychostimulants, including amphetamines and methylphenidate, are first-line pharmacotherapies for individuals with attention-deficit/hyperactivity disorder (ADHD).”
    • Also stated in: § Introduction · plain
      “stimulants are considered first-line therapy in children, adolescents, and adults with ADHD because of their greater efficacy (25-30).”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [25] Atkinson M, Hollis C. NICE guideline: attention deficit hyperactivity disorder. Arch Dis Child Educ Pract Ed. 2010; 95(1): 24– 7. 20145015 source
    • cites [26] Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement and Management, Wolraich M, Brown L, Brown RT, DuPaul G, ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011; 128(5): 1007– 22. 22003063 PMC4500647 source

      The Medication discussion (INTRODUCTION; page unavailable) says stimulants are highly effective for most children and reports a larger effect size than for nonstimulants. But this is a guideline for children and adolescents, not adults, and its Special Circumstances discussion recommends behavioral therapy first for preschool-aged children. It therefore does not support an unqualified first-line claim for all individuals with ADHD. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [27] Rostain AL. Attention-deficit/hyperactivity disorder in adults: evidence-based recommendations for management. Postgrad Med. 2008; 120(3): 27– 38. 18824823 source
    • cites [28] Bolea-Alamanac B, Nutt DJ, Adamou M, Asherson P, Bazire S, Coghill D, Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014; 28(3): 179– 203. 24526134 source
    • cites [29] Kooij SJ, Bejerot S, Blackwell A, Caci H, Casas-Brugue M, Carpentier PJ, European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry. 2010; 10: 67. 20815868 PMC2942810 source
    • cites [30] Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines, Third Edition. Toronto, ON, Canada: CADDRA, 2011.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    Amphetamine increases dopamine release across multiple brain regions in healthy humans, including dorsal and ventral striatum, substantia nigra, and cortex.

    “Reductions in ligand binding in PET (130-132, 134, 136, 144-146, 148-154, 157, 159, 161, 162, 164) and SPECT (140, 142, 143, 156) studies in healthy humans indicate that AMP increases DA release across multiple brain regions, including the dorsal and ventral striatum, substantia nigra, and regions of the cortex.”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [130] Boileau I, Dagher A, Leyton M, Welfeld K, Booij L, Diksic M, Conditioned dopamine release in humans: a positron emission tomography [11C]raclopride study with amphetamine. J Neurosci. 2007; 27(15): 3998– 4003. 17428975 PMC6672545 source

      The Results section ('Effect of amphetamine and amphetamine-predictive cues on [¹¹C]raclopride BP'; page not available) reports reduced ligand binding after amphetamine in healthy volunteers’ ventral striatum and dorsal putamen, supporting those regions of the claim. The PET acquisition protocol lists the measured regions; it does not report amphetamine-induced dopamine release in the substantia nigra or cortex. The cerebellar cortex was used as a reference region, not reported as a site of increased release. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [131] Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Li R, Ansari MS, Dopaminergic network differences in human impulsivity. Science. 2010; 329(5991): 532. 20671181 PMC3161413 source

      The paper reports PET evidence of amphetamine-induced dopamine release in the striatum of healthy volunteers (Abstract; page unavailable). It does not establish release in the cortex or substantia nigra: its substantia nigra/ventral tegmental area finding concerns D2/D3 receptor availability. The passages also do not distinguish dorsal from ventral striatal release. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [132] Cardenas L, Houle S, Kapur S, Busto UE. Oral D-amphetamine causes prolonged displacement of [11C]raclopride as measured by PET. Synapse. 2004; 51(1): 27– 31. 14579423 source
    • cites [134] Cropley VL, Innis RB, Nathan PJ, Brown AK, Sangare JL, Lerner A, Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans. Synapse. 2008; 62(6): 399– 408. 18361438 source
    • cites [136] Drevets WC, Gautier C, Price JC, Kupfer DJ, Kinahan PE, Grace AA, Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry. 2001; 49(2): 81– 96. 11164755 source
  • Premisecitation

    The procognitive effects of methylphenidate in a working memory task are blocked by the α2 adrenergic antagonist idazoxan.

    “Further evidence for the interaction of MPH with α2 adrenergic receptors comes from data indicating that the procognitive effects of MPH in a working memory task are blocked by the α2 adrenergic antagonist idazoxan (115).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [115] Gamo NJ, Wang M, Arnsten AF. Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry. 2010; 49(10): 1011– 23. 20855046 PMC2999884 source
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    Methylphenidate directly interacts with adrenergic receptors, and through α2 adrenergic receptor activation it stimulates cortical excitability.

    “Multiple studies have demonstrated that MPH also directly interacts with adrenergic receptors (109, 115, 119, 120). Through activation of α2 adrenergic receptors, MPH has been demonstrated to stimulate cortical excitability (109).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [109] Andrews GD, Lavin A. Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors. Neuropsychopharmacology. 2006; 31(3): 594– 601. 15999146 PMC5509071 source
    • cites [115] Gamo NJ, Wang M, Arnsten AF. Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry. 2010; 49(10): 1011– 23. 20855046 PMC2999884 source

      The Conclusions describe MPH’s effects on α2 adrenoceptors as indirect, contrary to the claim of direct receptor interaction. The Discussion says MPH’s cellular actions could not be documented; the reported increase in prefrontal neuronal firing followed α2A receptor stimulation, not a demonstrated effect of MPH on cortical excitability. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [119] Markowitz JS, DeVane CL, Ramamoorthy S, Zhu HJ. The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor. Pharmazie. 2009; 64(2): 123– 5. 19322953 source

  • May combine two claims.

    Premisecitation

    Amphetamine increases synaptic extracellular dopamine and norepinephrine levels.

    “The main mechanism of action of AMP is to increase synaptic extracellular DA and NE levels (44, 52, 59, 60, 67, 68, 71, 78, 80, 85, 87, 94, 105, 107, 128).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [44] Avelar AJ, Juliano SA, Garris PA. Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem. 2013; 125(3): 373– 85. 23406303 PMC3633730 source

      The Introduction (page unavailable) describes amphetamine’s effects on dopamine signaling, including dopamine release and inhibition of its uptake. The Discussion (page unavailable) also describes amphetamine-induced increases in extracellular dopamine signals. Neither passage supports the attributed increase in norepinephrine, which this paper does not examine. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [52] Covey DP, Juliano SA, Garris PA. Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine. PLoS One. 2013; 8(5): e60763. 23671560 PMC3643976 source

      The Introduction (page unavailable) says amphetamine enhances dopamine signaling through transporter reversal, reduced uptake, and increased vesicular release. The Discussion also describes increases in extracellular dopamine transients. Our copy does not establish an increase in norepinephrine, so it supports only the dopamine part of the claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [59] Finnema SJ, Hughes ZA, Haaparanta-Solin M, Stepanov V, Nakao R, Varnas K, Amphetamine decreases alpha2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain. Int J Neuropsychopharmacol. 2015; 18(3): 1– 10. PMC4360244 25522417 source

  • May combine two claims.

    Premisecitation

    In healthy adults, amphetamine increases BOLD signal variability and exerts an equalizing effect on ventral striatum activity during incentive processing.

    “In fMRI studies in healthy adults, AMP increased BOLD signal variability (137) and exerted an “equalizing” effect on ventral striatum activity during incentive processing (141).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [137] Garrett DD, Nagel IE, Preuschhof C, Burzynska AZ, Marchner J, Wiegert S, Amphetamine modulates brain signal variability and working memory in younger and older adults. Proc Natl Acad Sci U S A. 2015; 112(24): 7593– 8. 26034283 PMC4475975 source

      The citation to this paper is attached to the BOLD-variability claim, not the separate ventral-striatum claim. The Discussion (page unavailable) reports that amphetamine increased BOLD signal variability in older adults, but says younger adults showed a mix of increases and decreases, with no net group change. The unqualified claim about healthy adults therefore overgeneralizes the finding. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [141] Knutson B, Bjork JM, Fong GW, Hommer D, Mattay VS, Weinberger DR. Amphetamine modulates human incentive processing. Neuron. 2004; 43(2): 261– 9. 15260961 source

  • May combine two claims.

    Premisecitation

    Methylphenidate increases activation of parietal and prefrontal cortices and increases deactivation of insula and posterior cingulate cortex during visual attention and working memory tasks.

    “Using fMRI, it has been shown that MPH increases activation of the parietal and prefrontal cortices and increases deactivation of the insula and posterior cingulate cortex during visual attention and working memory tasks (180).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [180] Tomasi D, Volkow ND, Wang GJ, Wang R, Telang F, Caparelli EC, Methylphenidate enhances brain activation and deactivation responses to visual attention and working memory tasks in healthy controls. Neuroimage. 2011; 54(4): 3101– 10. 21029780 PMC3020254 source

  • May combine two claims.

    Premisecitation

    In high-functioning, drug-naive young adults with ADHD, resting-state fMRI revealed altered connectivity in orbitofrontal-temporal-occipital and frontal-amygdala-occipital networks compared with matched controls, and these abnormalities were not related to developmental delays, impaired cognition, or pharmacotherapy.

    “In high-functioning, drug-naive young adults with ADHD, resting-state fMRIs revealed altered connectivity in the orbitofrontal-temporal-occipital and frontal-amygdala-occipital networks (relating to inattentive and hyperactive/impulsive symptoms, respectively) compared with matched controls; these abnormalities were not related to developmental delays, impaired cognition, or use of pharmacotherapy”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [205] Cocchi L, Bramati IE, Zalesky A, Furukawa E, Fontenelle LF, Moll J, Altered functional brain connectivity in a non-clinical sample of young adults with attention-deficit/hyperactivity disorder. J Neurosci. 2012; 32(49): 17753– 61. 23223295 PMC6621678 source

  • May combine two claims.

    Premisecitation

    In a PET study in adults with ADHD, decreased dopamine transporter and D2/D3 receptor availability in the nucleus accumbens and midbrain was reported compared with individuals without ADHD, and reduced availability was significantly correlated with lower indices of motivation only in those with ADHD.

    “In another PET study in adults with ADHD, decreased DAT and D2/D3 receptor availability in the nucleus accumbens and midbrain compared with individuals without ADHD was reported, and reduced availability of DAT and D2/D3 receptor availability was significantly correlated with lower indices of motivation only in those with ADHD (217).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [217] Volkow ND, Wang GJ, Newcorn JH, Kollins SH, Wigal TL, Telang F, Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Mol Psychiatry. 2011; 16(11): 1147– 54. 20856250 PMC3010326 source

  • May combine two claims.

    Premisecitation

    In a PET study, more pronounced reductions in amphetamine-induced reductions in striatal [11C]raclopride binding were associated with worse response inhibition, and those with ADHD had the highest-magnitude reductions.

    “In a PET study of treatment-naive men with ADHD and men without ADHD, more pronounced reductions in AMP-induced reductions in striatal [11C]raclopride binding were associated with worse response inhibition, and those with ADHD had the highest-magnitude reductions and AMP-induced reductions in striatal [11C]raclopride binding (209).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [209] Cherkasova MV, Faridi N, Casey KF, O'Driscoll GA, Hechtman L, Joober R, Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD. Neuropsychopharmacology. 2014; 39(6): 1498– 507. 24378745 PMC3988554 source

  • May combine two claims.

    Premisecitation

    Decreased levels of activation are observed in the precuneus of adolescents with ADHD compared with individuals without ADHD, but there is a significantly greater increase in precuneus activation following fluoxetine administration in adolescents with ADHD compared with controls.

    “Functionally, it has been reported that decreased levels of activation are observed in the precuneus of adolescents with ADHD compared with individuals without ADHD; however, there is a significantly greater increase in the activation of the precuneus following the administration of fluoxetine in adolescents with ADHD compared with controls (226).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [226] Chantiluke K, Barrett N, Giampietro V, Brammer M, Simmons A, Murphy DG, Inverse effect of fluoxetine on medial prefrontal cortex activation during reward reversal in ADHD and autism. Cereb Cortex. 2015; 25(7): 1757– 70. 24451919 PMC4459282 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a study of 126 cocaine-dependent adults with ADHD, extended-release mixed amphetamine salts produced significantly greater reductions in ADHD symptoms and higher abstinence from cocaine use than placebo.

    “In a study that examined the efficacy of extended-release mixed AMP salts in the treatment of ADHD symptoms and cocaine abuse in 126 cocaine-dependent adults with ADHD (250), significantly greater reductions in ADHD symptoms and higher abstinence from cocaine use were observed with extended-release mixed AMP salts than placebo.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [250] Levin FR, Mariani JJ, Specker S, Mooney M, Mahony A, Brooks DJ, Extended-Release Mixed Amphetamine Salts vs Placebo for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cocaine Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2015; 72(6): 593– 602. 25887096 PMC4456227 source

  • May combine two claims.

    Premisecitation

    In a self-controlled case series analysis, treatment with methylphenidate was associated with an increased overall risk of arrhythmia and with an increased risk of myocardial infarction from 1 week to 2 months after treatment initiation in children and adolescents with ADHD.

    “In a self-controlled case series analysis, treatment with MPH was associated with an increased overall risk of arrhythmia and with an increased risk of myocardial infarction from 1 week to 2 months after treatment initiation in children and adolescents with ADHD (260).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [260] Shin JY, Roughead EE, Park BJ, Pratt NL. Cardiovascular safety of methylphenidate among children and young people with attention-deficit/hyperactivity disorder (ADHD): nationwide self controlled case series study. BMJ. 2016; 353: i2550. 27245699 PMC4887614 source

  • May combine two claims.

    Premisecitation

    In a study of MPH in children with ADHD, 23% of participants without preexisting sleep problems developed sleep problems while taking MPH, whereas 68.5% of those with preexisting sleep problems no longer experienced sleep problems after taking MPH.

    “For example, in a study of MPH in children with ADHD, 23% of participants without preexisting sleep problems developed sleep problems while taking MPH, whereas 68.5% of those with preexisting sleep problems no longer experienced sleep problems after taking MPH (254).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [254] Becker SP, Froehlich TE, Epstein JN. Effects of methylphenidate on sleep functioning in children with attention-deficit/hyperactivity disorder. J Dev Behav Pediatr. 2016; 37(5): 395– 404. 27011002 PMC4887346 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    In a systematic review of 14 studies, no study assessed the relationship between psychostimulant treatment and neuroinflammation, so the relevance of preclinical models of neuroinflammation to psychostimulant treatment in individuals with ADHD is unknown.

    “In a systematic review of 14 studies (266), no study assessed the relationship between psychostimulant treatment and neuroinflammation so the relevance of preclinical models of neuroinflammation to psychostimulant treatment in individuals with ADHD is unknown.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [266] Anand D, Colpo GD, Zeni G, Zeni CP, Teixeira AL. Attention-Deficit/Hyperactivity Disorder and inflammation: what does current knowledge tell us? A systematic review. Front Psychiatry. 2017; 8: 228. 29170646 PMC5684106 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxidative stress has been implicated in the lower brain volumes seen in ADHD patients.

    “Oxidative stress has also been implicated in the lower brain volumes seen in ADHD patients (268).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [268] Hess JL, Akutagava-Martins GC, Patak JD, Glatt SJ, Faraone SV. Why is there selective subcortical vulnerability in ADHD? Clues from postmortem brain gene expression data. Mol Psychiatry. 2017. PMC6985986 29180674 source

  • May combine two claims.

    Premisecitation

    Methylphenidate directly inhibits dopamine and norepinephrine transporters, has agonist activity at the 5-HT1A receptor, and redistributes VMAT-2.

    “The direct effects of MPH include inhibition of the DAT and NET (113, 114, 118, 120, 123, 128), an affinity for and agonist activity at the 5-HT1A receptor (119, 120), and redistribution of VMAT-2 (88, 125).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [113] Dresel SH, Kung MP, Huang X, Plossl K, Hou C, Shiue CY, In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates. Eur J Nucl Med. 1999; 26(4): 342– 7. 10199939 source
    • cites [114] Federici M, Geracitano R, Bernardi G, Mercuri NB. Actions of methylphenidate on dopaminergic neurons of the ventral midbrain. Biol Psychiatry. 2005; 57(4): 361– 5. 15705351 source
    • cites [118] Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS. Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci. 1996; 58(12): 231– 9. 8786705 source

  • May combine two claims.

    Premisecitation

    Amphetamine also inhibits VMAT-2, increasing vesicular dopamine release and causing reverse transport of cytosolic dopamine via DAT.

    “AMP also increases vesicular DA release via inhibition of the vesicular monoamine transporter 2 (VMAT-2), which releases DA from vesicular storage, and the concomitant release of cytosolic DA via reverse transport by the DAT (58, 88, 99).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [58] Easton N, Steward C, Marshall F, Fone K, Marsden C. Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology. 2007; 52(2): 405– 14. 17020775 source
    • cites [88] Riddle EL, Hanson GR, Fleckenstein AE. Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2. Eur J Pharmacol. 2007; 571(1): 25– 8. 17618619 PMC2581712 source
    • cites [99] Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci. 1995; 15(5 Pt 2): 4102– 8. 7751968 PMC6578196 source

  • May combine two claims.

    Premisecitation

    Amphetamine inhibits monoamine oxidase activity, decreasing cytosolic monoamine breakdown.

    “Furthermore, AMP inhibits monoamine oxidase (MAO) activity (79, 90), which decreases cytosolic monoamine breakdown.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Miller HH, Shore PA, Clarke DE. In vivo monoamine oxidase inhibition by d-amphetamine. Biochem Pharmacol. 1980; 29(10): 1347– 54. 6901611 source
    • cites [90] Robinson JB. Stereoselectivity and isoenzyme selectivity of monoamine oxidase inhibitors. Enantiomers of amphetamine, N-methylamphetamine and deprenyl. Biochem Pharmacol. 1985; 34(23): 4105– 8. 3933519 source

  • May combine two claims.

    Premisereasoning

    Methylphenidate elevates extracellular dopamine and norepinephrine levels.

    “As a consequence of these interactions, MPH elevates extracellular DA and NE levels (58, 71, 94, 107).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [58] Easton N, Steward C, Marshall F, Fone K, Marsden C. Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology. 2007; 52(2): 405– 14. 17020775 source
    • cites [71] Kuczenski R, Segal DS. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem. 1997; 68(5): 2032– 7. 9109529 source
    • cites [94] Schiffer WK, Volkow ND, Fowler JS, Alexoff DL, Logan J, Dewey SL. Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse. 2006; 59(4): 243– 51. 16385551 source

  • May combine two claims.

    Premisecitation

    The effects of amphetamine on regional cerebral blood flow are dose-dependent: lower doses decrease blood flow in frontal and temporal cortices and striatum, while higher doses increase blood flow in anterior cingulate cortex, caudate nucleus, putamen, and thalamus.

    “The effects of AMP on regional CBF appear to be dependent on the dose, with lower doses decreasing rates of blood flow in the frontal and temporal cortices and in the striatum (163) and higher doses increasing blood flow in the anterior cingulate cortex, caudate nucleus, putamen, and thalamus (160).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Wolkin A, Angrist B, Wolf A, Brodie J, Wolkin B, Jaeger J, Effects of amphetamine on local cerebral metabolism in normal and schizophrenic subjects as determined by positron emission tomography. Psychopharmacology (Berl). 1987; 92(2): 241– 6. 3110848 source
    • cites [160] Vollenweider FX, Maguire RP, Leenders KL, Mathys K, Angst J. Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography (PET). Psychiatry Res. 1998; 83(3): 149– 62. 9849724 source

  • May combine two claims.

    Premisecitation

    Methylphenidate reduces regional cerebral blood flow in the prefrontal cortex and increases it in the thalamus and precentral gyrus.

    “MPH has also been shown to reduce regional CBF in the prefrontal cortex and increase regional CBF in the thalamus and precentral gyrus (176).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Schweitzer JB, Lee DO, Hanford RB, Zink CF, Ely TD, Tagamets MA, Effect of methylphenidate on executive functioning in adults with attention-deficit/hyperactivity disorder: normalization of behavior but not related brain activity. Biol Psychiatry. 2004; 56(8): 597– 606. 15476690 source

  • May combine two claims.

    Interpretationcitation

    The correlation between medication exposure and striatal dopamine transporter density accounted for 48% of variance across studies, suggesting higher density in ADHD was a neuroadaptive response to stimulant exposure.

    “As the correlation between medication exposure and striatal DAT density accounted for 48% of the variance across studies (202), it was suggested that the higher striatal DAT density in individuals with ADHD was a neuroadaptive response to stimulant exposure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Fusar-Poli P, Rubia K, Rossi G, Sartori G, Balottin U. Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis. Am J Psychiatry. 2012; 169(3): 264– 72. 22294258 source

  • May combine two claims.

    Premisecitation

    Two SPECT studies and one PET study showed that adults with ADHD had higher dopamine transporter concentrations than adults without ADHD, and the SPECT studies reported that methylphenidate reduced DAT availability in adults with ADHD.

    “Two SPECT studies and 1 PET study showed that adults with ADHD had higher DAT concentrations than adults without ADHD (210-212), with the SPECT studies further reporting that MPH reduced DAT availability in adults with ADHD (210, 211).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [210] Dresel S, Krause J, Krause KH, LaFougere C, Brinkbaumer K, Kung HF, Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med. 2000; 27(10): 1518– 24. 11083541 source
    • cites [211] Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K. Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography. Neurosci Lett. 2000; 285(2): 107– 10. 10793238 source
    • cites [212] Spencer TJ, Biederman J, Madras BK, Dougherty DD, Bonab AA, Livni E, Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane. Biol Psychiatry. 2007; 62(9): 1059– 61. 17511972 PMC2715944 source

  • May combine two claims.

    Premisecitation

    A PET study in young male adults with ADHD reported dysfunctional dopamine metabolism in the putamen, amygdala, and dorsal midbrain relative to healthy controls regardless of treatment status, and a history of methylphenidate treatment resulted in down-regulation of dopamine turnover.

    “Also, a PET study in young male adults with ADHD has also reported dysfunctional DA metabolism in the putamen, amygdala, and dorsal midbrain relative to healthy controls regardless of treatment status (naive vs previously treated with MPH) and that a history of MPH treatment resulted in a down-regulation of DA turnover (218).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Ludolph AG, Kassubek J, Schmeck K, Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults: a 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study. Neuroimage. 2008; 41: 718– 27. 18424180 source

  • May combine two claims.

    Premisecitation

    Increased methylation of the serotonin transporter is associated with worse clinical presentation and reduced cortical thickness in children with ADHD.

    “Regarding the 5-HT systems, it has been reported that increased methylation of the 5-HT transporter is associated with worse clinical presentation and reduced cortical thickness in children with ADHD (224).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] Park S, Lee JM, Kim JW, Cho DY, Yun HJ, Han DH, Associations between serotonin transporter gene (SLC6A4) methylation and clinical characteristics and cortical thickness in children with ADHD. Psychol Med. 2015; 45(14): 3009– 17. 26017091 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    At present, there are no published neuroimaging studies of endogenous opioid or acetylcholine systems in individuals with ADHD.

    “At present, there are no published neuroimaging studies of endogenous opioid or ACH systems in individuals with ADHD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The effects of stimulants on anxiety can be complex, with acute administration of methylphenidate reducing anxiety in adults and chronic treatment during early life increasing anxiety during adulthood.

    “In practice, the effects of stimulants on anxiety can be complex, with acute administration of MPH reducing anxiety in adults and chronic treatment during early life increasing anxiety during adulthood (228).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Sanchez-Perez AM, Garcia-Aviles A, Albert Gasco H, Sanjuan J, Olucha-Bordonau FE. [ Effects of methylphenidate on anxiety]. Rev Neurol. 2012; 55(8): 499– 506. 23055432

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 2008 meta-analysis of 3 short-term trials reported statistically significant improvements favoring monotherapy with psychostimulants compared with placebo for depressive symptoms.

    “Although one meta-analysis published in 2008 based on 3 short-term trials reported statistically significant improvements favoring monotherapy with psychostimulants compared with placebo for depressive symptoms (232), a systematic review of augmentation therapy for MDD published in 2009 based on MPH (2 studies) and modafinil (2 studies) reported that neither augmentation strategy was clinically”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Candy M, Jones L, Williams R, Tookman A, King M. Psychostimulants for depression. Cochrane Database Syst Rev. 2008(2): CD006722. 18425966 source

  • May combine two claims.

    Premisecitation

    In a meta-analysis of 9 articles, the use of psychostimulant medication was associated with longer sleep latency, worse sleep efficiency, and shorter sleep duration.

    “In a meta-analysis of 9 articles, the use of psychostimulant medication was associated with longer sleep latency, worse sleep efficiency, and shorter sleep duration (255).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255] Kidwell KM, Van Dyk TR, Lundahl A, Nelson TD. Stimulant medications and sleep for youth with ADHD: a meta-analysis. Pediatrics. 2015; 136(6): 1144– 53. 26598454 source
27 of 27

  • The paper relies on this without support.

    Findings about amphetamine and methylphenidate mechanisms from preclinical models and healthy human volunteers can be generalized to individuals with ADHD.

    “The literature search included both animal and human studies.”
    “In healthy human volunteers, AMP has been reported to potentiate amygdalar activity in response to the processing of angry and fearful facial expressions (139).”

  • The paper relies on this without support.

    Important studies were not missed despite the review searching only PubMed.

    “Although it is a limitation of the review that the only database searched was PubMed, it is unlikely that important studies were not captured.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The increase of DA promotes dopaminergic transmission by regulating (inhibiting) VMAT2, SERT (with weaker affinity), and MAOA and MAOB.

    “The increase of DA promotes the dopaminergic transmission by regulating (inhibiting) other proteins: VMAT2, whose inhibition induces the DA liberation from vesicular storage and the concomitant release of cytosolic DA via DAT reverse transport [33, 187], SERT (with weaker affinity), and MAOA and MAOB [153].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [33]

    The Results > Preclinical Studies passage says amphetamine inhibits VMAT-2, releasing vesicular dopamine and enabling reverse transport through DAT; it also says amphetamine inhibits monoamine oxidase activity. It does not specify weaker affinity for SERT or inhibition of both MAO-A and MAO-B. The passage describes these actions as contributing to increased dopamine, rather than increased dopamine causing the inhibition. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Stimulants affect striato-cortical regions by modulating norepinephrine and dopamine (Faraone, 2018).

    “These stimulants affect striato-cortical regions by modulating norepinephrine and dopamine (Faraone, 2018).”

    From Are prediction error modifications domain specific in autism but domain general in ADHD? (2025) · cites this paper as Faraone, 2018

  • Stimulants are generally used as first-line pharmacologic treatment owing to higher efficacy in symptomatology reduction compared to nonstimulant medications in all age groups.

    “Stimulants have generally been used as first-line pharmacologic treatment owing to a higher efficacy in symptomatology reduction compared to nonstimulant medications in all groups of age (children, adolescents and adults) [17, 33, 34].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [33]

  • Deficiencies in catecholamines such as NE and DA or dysregulation of such NTs are among the causing physiological alterations that have been reported to explain ADHD development.

    “Deficiencies in catecholamines such as NE and DA [75, 79, 80] or dysregulation of such NTs, which are essential for normal brain function, including executive and attentional functions [33], are among the causing physiological alterations that have been reported to explain ADHD development.”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [33]

  • Methylphenidate increases central dopamine and norepinephrine activity, improving executive/attentional functioning and emotion regulation.

    “Methylphenidate increases central dopamine and norepinephrine activity, which improves executive and attentional functioning and emotion regulation [173]”

    From Toward a neurocircuit-based taxonomy to guide treatment of obsessive-compulsive disorder (2021) · cites this paper as [173]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • An ADHD imaging study conflicts with the stated exclusion rule

    Minor

    The methods say imaging studies of people with psychiatric disorders were excluded, yet the review cites reference 176 for a neuroimaging finding. Its title identifies its participants as adults with ADHD.

  • A SPECT study is classified as a PET study

    Minor

    The passage groups reference 165 among PET studies, but the cited study's title identifies its method as single-photon emission tomography (SPECT).

2 of 2

Cites

Flagged first, then by citations

4 of the 273 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Sanchez-Perez, 2012, [Effects of methylphenidate on anxiety], Rev. Neurol., 55, 499

Cited by

Sorted by citations

Related

Authors
Faraone, S. V.
Affiliations
SUNY Upstate Medical University (US)
Corresponding author
Faraone, Stephen V.
ORCID
Faraone, Stephen V.
Venue
Neuroscience & Biobehavioral Reviews
Publisher
Elsevier BV
Published
2018-04
Volume
87
Pages
255-270
ISSN
0149-7634 (ISSN-L)
DOI
10.1016/j.neubiorev.2018.02.001
PMC
PMC8063758
OpenAlex
W2794227021
Semantic Scholar
b5d58c2662fc5ea542bd5146daeab197a9a284e4
Cited by
631
References
273
Citations by year
2026: 55 · 2025: 106 · 2024: 102 · 2023: 98 · 2022: 87 · 2021: 81 · 2020: 52 · 2019: 39 · 2018: 10
FWCI
7.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience & Biobehavioral Reviews (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • K. G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (602805)
  • European Union’s Horizon 2020 (667302)
  • NIMH (5R01MH101519, U01 MH109536-01)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neuroethics, Human Enhancement, Biomedical Innovations
Keywords
amphetamine, methylphenidate, attention deficit hyperactivity disorder, psychostimulants, dopamine transporter inhibition, norepinephrine reuptake inhibition, vesicular monoamine transporter 2, monoamine oxidase inhibition, 5-HT1A receptor, opioid interaction, comorbid depression, anxiety comorbidity, substance use disorders, sleep disorders, executive function, attention
MeSH terms
Amphetamine, Central Nervous System Stimulants, Animals, Attention Deficit Disorder with Hyperactivity, Mental Disorders, Brain, Humans, Methylphenidate, Comorbidity, Adrenergic Uptake Inhibitors, Dopamine Uptake Inhibitors

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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