The DOI matches its Crossref record; 270 of the 273 references it cites were found in a registry or an index; 53 of the 121 sources its claims cite were checked for support.
The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities
Open accessAbstract
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.
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Claims the paper makes
29 No full text of the sources · 18 Partly supported · 16 Supported · 5 Own interpretation · 2 Supported so far · 2 No basis given · 1 Not supported · 1 Couldn’t confirm · 1 Sources not found · 1 Not checked yet · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Abstract
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [60] Floor E, Meng L. Amphetamine releases dopamine from synaptic vesicles by dual mechanisms. Neurosci Lett. 1996; 215(1): 53– 6. 8880752 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Discussion · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Abstract
What the sources say
- Not checked — no full text of the sourcecites [25] Atkinson M, Hollis C. NICE guideline: attention deficit hyperactivity disorder. Arch Dis Child Educ Pract Ed. 2010; 95(1): 24– 7. 20145015 source
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [27] Rostain AL. Attention-deficit/hyperactivity disorder in adults: evidence-based recommendations for management. Postgrad Med. 2008; 120(3): 27– 38. 18824823 source
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
The ‘Pharmacotherapy for adult ADHD in Europe’ section identifies methylphenidate and dexamphetamine as first-choice medications for children and adults with ADHD. This supports the citing sentence’s attribution that these psychostimulants are first-line treatments. The verbatim citing sentence does not make a comparative-efficacy claim. (LLM, conf=0.93)
- Not matchedcites [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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Supportedcites [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 Results (Behavioral Data, “Methylphenidate”) report that methylphenidate improved working-memory performance and that idazoxan reversed this improvement. The Methods (Behavioral Methods) identify idazoxan as an α2-adrenoceptor antagonist. (LLM, conf=0.94)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Methylphenidate has also been shown to increase striatal DA availability, as measured by reductions in ligand binding potential in PET studies (165, 166, 170, 178, 179, 181, 182, 187, 190, 191), with evidence to indicate that this effect is related to binding to the DAT (185, 186, 188).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
What the sources say
- Partly supportedcites [165] Booij J, Korn P, Linszen DH, van Royen EA. Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography. Eur J Nucl Med. 1997; 24(6): 674– 7. 9169577 sourceExperimental — accuracy not yet measured
The Results report that methylphenidate significantly reduced striatal radioligand uptake, and the Discussion reports a similar reduction in a human raclopride PET study. But this paper’s own measurement used [123I]IBZM single-photon emission tomography (SPET), not PET, so it does not itself provide the PET evidence implied by the citation. (LLM, conf=0.86)
- Supportedcites [166] Clatworthy PL, Lewis SJ, Brichard L, Hong YT, Izquierdo D, Clark L, Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory. J Neurosci. 2009; 29(15): 4690– 6. 19369539 PMC6665353 source
The Introduction explains that drug-induced increases in extracellular dopamine reduce PET radioligand binding. The Results section, “Regional displacement of [11C]-raclopride” (page unavailable), reports methylphenidate-related displacement and a significant drug effect on binding potential. The separate DAT statement is attributed to other citations, not this paper. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [170] Montgomery AJ, Asselin MC, Farde L, Grasby PM. Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET. J Cereb Blood Flow Metab. 2007; 27(2): 369– 77. 16685253 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“NE systems have been implicated as key targets for MPH, with MPH dose-dependently blocking the NET in the thalamus and other NET-rich regions; the estimated occupancy of the NET at therapeutic doses of 0.35 to 0.55 mg/kg MPH is 70% to 80% (168).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
What the sources say
- Supportedcites [168] Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, van Dyck CH, Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry. 2010; 68(9): 854– 60. 20691429 PMC3742016 source
The Results (NET Occupancy: ED50 and IC50) report dose-dependent NET occupancy across NET-rich regions, including the thalamus, and estimate a global ED50 of 0.14 mg/kg. The Discussion (MPH Occupancy of NET) calculates that clinical doses of 0.35–0.55 mg/kg per dose produce 70–80% NET occupancy. (LLM, conf=0.94)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A meta-analysis of 24 task-related fMRI studies coupled with functional decoding based on the BrainMap database reported hypoactivation in the left putamen, inferior frontal gyrus, temporal pole, and right caudate of individuals with ADHD (204).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Supportedcites [204] Cortese S, Castellanos FX, Eickhoff CR, D'Acunto G, Masi G, Fox PT, Functional Decoding and Meta-analytic Connectivity Modeling in Adult Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry. 2016; 80(12): 896– 904. 27569542 PMC5108674 source
The Methods describe an ALE meta-analysis of 24 task-based fMRI studies in adults with ADHD, followed by functional decoding using the BrainMap database. The Results (ALE meta-analysis; page unavailable) report hypoactivation in the left putamen, left inferior frontal gyrus, left temporal pole, and right caudate compared with controls. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A meta-analysis of 1713 persons with ADHD and 1529 controls found volumetric reductions in the accumbens, amygdala, caudate, hippocampus, and putamen (201).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Structural Alterations in ADHD
What the sources say
- Partly supportedcites [201] Hoogman M, Bralten J, Hibar DP, Mennes M, Zwiers MP, Schweren LS, Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry. 2017; 4(4): 310– 9. 28219628 PMC5933934 sourceExperimental — accuracy not yet measured
The Discussion reports 1713 participants with ADHD and 1529 controls, and the Results report significantly smaller volumes in all five named regions in the mega-analysis. However, the Results distinguish that analysis from the case-control meta-analysis, in which the accumbens and hippocampus differences were not significant. Calling the five-region finding a meta-analysis result therefore overstates the source. (LLM, conf=0.88)
plaincorrelationaln = 1,713- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Furthermore, studies have shown significant correlations between global clinical improvement in ADHD symptoms following MPH treatment and striatal DAT availability (213, 214), and the MPH-induced increases in DA availability in the ventral striatum are associated with improved ADHD symptomology in adults with ADHD (215).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Not checked — no full text of the sourcecites [213] Krause J, la Fougere C, Krause KH, Ackenheil M, Dresel SH. Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD. Eur Arch Psychiatry Clin Neurosci. 2005; 255(6): 428– 31. 16091862 source
- Not checked — no full text of the sourcecites [214] la Fougere C, Krause J, Krause KH, Josef Gildehaus F, Hacker M, Koch W, Value of 99mTc-TRODAT-1 SPECT to predict clinical response to methylphenidate treatment in adults with attention deficit hyperactivity disorder. Nucl Med Commun. 2006; 27(9): 733– 7. 16894328 source
- Supportedcites [215] Volkow ND, Wang GJ, Tomasi D, Kollins SH, Wigal TL, Newcorn JH, Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci. 2012; 32(3): 841– 9. 22262882 PMC3350870 source
In the citing sentence, this source is citation 215, attached to the ventral-striatum claim; the DAT-availability claim is attached to citations 213 and 214. The Results section reports that methylphenidate-induced dopamine increases in the ventral striatum were significantly correlated with reduced inattention symptoms after long-term treatment in adults with ADHD. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 25
- Probably not a substantial claim. 3
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Not checked — no full text of the sourcecites [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
- Disputedcites [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 sourceExperimental — accuracy not yet measured
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.
- Not checked — no full text of the sourcecites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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 Discussion states that amphetamine elevates synaptic norepinephrine and dopamine and describes the transport processes involved. The Results (Rat Brain Microdialysis) also report significant increases in both neurotransmitters after amphetamine administration in rat striatum. Page numbers are not provided in our copy. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
What the sources say
- Supportedcites [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
The Discussion states that MPH increased activation in parietal and frontal regions and increased deactivation in the insula and posterior cingulate during both working-memory and visual-attention tasks. The Abstract specifies that these were fMRI findings in healthy men receiving MPH compared with unmedicated controls. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Supportedcites [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
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Supportedcites [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
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Supportedcites [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
The Abstract reports greater amphetamine-induced decreases in striatal [11C]raclopride binding in the ADHD group than in healthy controls. It also reports that, across groups, larger changes in binding were associated with poorer response-inhibition performance. The citing sentence's repeated word “reductions” appears to be a wording error, not a different finding. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Co-occurring Psychiatric Conditions and ADHD
What the sources say
- Supportedcites [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
The Design, Setting, and Participants passage reports 126 adults with ADHD and cocaine use disorder. Results > ADHD Outcome reports significantly greater mean reductions in ADHD ratings at both doses than with placebo; Results > Cocaine Use Outcome reports significantly higher cocaine abstinence at both doses. Participants also received cognitive behavioral therapy. (LLM, conf=0.94)
plaindirectn = 126- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Other Safety Concerns
What the sources say
- Supportedcites [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
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Co-occurring Psychiatric Conditions and ADHD
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Other Safety Concerns
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Oxidative stress has also been implicated in the lower brain volumes seen in ADHD patients (268).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Other Safety Concerns
What the sources say
- Supportedcites [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
The Discussion reports that oxidative-stress pathway expression correlated with ADHD-associated volumetric loss and proposes oxidative stress as one possible contributor to reduced brain volumes. It qualifies this as a hypothesis, with significant correlations in children but not adults; the claim’s word “implicated” reflects that uncertainty. (LLM, conf=0.90)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Furthermore, AMP inhibits monoamine oxidase (MAO) activity (79, 90), which decreases cytosolic monoamine breakdown.”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Not checked — no full text of the sourcecites [79] Miller HH, Shore PA, Clarke DE. In vivo monoamine oxidase inhibition by d-amphetamine. Biochem Pharmacol. 1980; 29(10): 1347– 54. 6901611 source
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“As a consequence of these interactions, MPH elevates extracellular DA and NE levels (58, 71, 94, 107).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Preclinical Studies
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“MPH has also been shown to reduce regional CBF in the prefrontal cortex and increase regional CBF in the thalamus and precentral gyrus (176).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Structural Alterations in ADHD
What the sources say
- Not checked — no full text of the sourcecites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
What the sources say
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“At present, there are no published neuroimaging studies of endogenous opioid or ACH systems in individuals with ADHD.”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Functional Alterations in ADHD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Co-occurring Psychiatric Conditions and ADHD
What the sources say
- Not matchedcites [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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Co-occurring Psychiatric Conditions and ADHD
What the sources say
- Not checked — no full text of the sourcecites [232] Candy M, Jones L, Williams R, Tookman A, King M. Psychostimulants for depression. Cochrane Database Syst Rev. 2008(2): CD006722. 18425966 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Discussion > Co-occurring Psychiatric Conditions and ADHD
What the sources say
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Methods
“A publication was excluded if it did not specifically focus on the mechanism of action or pharmacologic effects of AMP or MPH or if it was an imaging study in individuals who were other than healthy (ie, studies in those with psychiatric disorders were not included).”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > References
“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.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > Results > Human Neuroimaging Studies
“Methylphenidate has also been shown to increase striatal DA availability, as measured by reductions in ligand binding potential in PET studies (165, 166, 170, 178, 179, 181, 182, 187, 190, 191)”
§ The Pharmacology of Amphetamine and Methylphenidate: Relevance to the Neurobiology of Attention-Deficit/Hyperactivity Disorder and Other Psychiatric Comorbidities > References
“165. Booij J, Korn P, Linszen DH, van Royen EA. Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography.”
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Metadata
- 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)
- 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
- hybrid
- doi.org
- 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
- Social Sciences › Arts and Humanities › Philosophy › 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.
A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-05 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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