View source for Chemistry:Methylphenidate

{{Short description|Central nervous system stimulant}}
{{Infobox drug
| Watchedfields      = changed
| verifiedrevid      = 464371569
| image              = Methylphenidate-2D-skeletal.svg
| width              = 200
| alt                = 
| caption            = 
| image2             = Methylphenidate-enantiomers-3D-balls.png
| width2             = 225
| alt2               = 

<!-- Clinical data -->
| pronounce          = {{IPAc-en|ˌ|m|ɛ|θ|əl|ˈ|f|ɛ|n|ɪ|d|eɪ|t|,_|-|ˈ|f|iː|-}}
| tradename          = Ritalin, Concerta, others
| Drugs.com          = {{drugs.com|monograph|methylphenidate-hydrochloride}}
| MedlinePlus        = a682188
| DailyMedID         = Methylphenidate
| pregnancy_AU       = D
| pregnancy_AU_comment = 
| pregnancy_category = 
| dependency_liability = High<ref name="AHFS2018"/>
| addiction_liability = High<ref>{{cite book |vauthors=Bonewit-West K, Hunt SA, Applegate E |date=2012 |title=Today's Medical Assistant: Clinical and administrative procedures |publisher=Elsevier Health Sciences |isbn=9781455701506 |page=571 |url=https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |url-status=live |access-date=20 August 2019 |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728034412/https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571}}</ref>
| routes_of_administration = [[Medicine:Nasal administration|Insufflation]], intravenous, [[Medicine:Oral administration|oral]], [[Medicine:Rectal administration|rectal]], sublingual, [[Medicine:Transdermal|transdermal]]<ref name=AHFS2018/>
| class              = Central nervous system [[Chemistry:Stimulant|stimulant]] & [[Chemistry:Norepinephrine–dopamine reuptake inhibitor|norepinephrine–dopamine reuptake inhibitor]]
| ATC_prefix         = N06
| ATC_suffix         = BA04
| ATC_supplemental   = 

<!-- Legal status -->
| legal_AU           = S8
| legal_AU_comment   = 
| legal_BR           = A3
| legal_CA           = Schedule III
| legal_CA_comment   = <ref>{{cite web | title=Ritalin Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=800 | access-date=11 June 2022 | archive-date=11 June 2022 | archive-url=https://web.archive.org/web/20220611233512/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=800 | url-status=live }}</ref><ref>{{cite web | title=Controlled Drugs and Substances Act | website=Justice Laws Website | date=31 March 2022 | url=https://laws-lois.justice.gc.ca/eng/acts/C-38.8/FullText.html | access-date=11 June 2022 | archive-date=21 August 2021 | archive-url=https://web.archive.org/web/20210821102842/https://laws-lois.justice.gc.ca/eng/acts/c-38.8/fulltext.html | url-status=live }}</ref>
| legal_DE           = Anlage III
| legal_DE_comment   = 
| legal_NZ_comment   = 
| legal_UK           = Class B
| legal_NZ           = Class B
| legal_UK_comment   = 
| legal_US           = Schedule II
| legal_US_comment   = <ref name="Ritalin FDA label">{{cite web | title=Ritalin- methylphenidate hydrochloride tablet | website=DailyMed | date=26 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c0bf0835-6a2f-4067-a158-8b86c4b0668a | access-date=26 March 2022 | archive-date=20 March 2017 | archive-url=https://web.archive.org/web/20170320052349/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c0bf0835-6a2f-4067-a158-8b86c4b0668a | url-status=live }}</ref><ref name="Ritalin LA FDA label">{{cite web | title=Ritalin LA- methylphenidate hydrochloride capsule, extended release | website=DailyMed | date=26 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=effd952d-ac94-47bb-b107-589a4934dcca | access-date=26 March 2022 | archive-date=26 March 2017 | archive-url=https://web.archive.org/web/20170326230529/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=effd952d-ac94-47bb-b107-589a4934dcca | url-status=live }}</ref><ref name="Concerta FDA label">{{cite web | title=Concerta- methylphenidate hydrochloride tablet, extended release | website=DailyMed | date=1 July 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a88218c-5b18-4220-8f56-526de1a276cd | access-date=26 March 2022 | archive-date=26 March 2017 | archive-url=https://web.archive.org/web/20170326230808/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a88218c-5b18-4220-8f56-526de1a276cd | url-status=live }}</ref><ref name="Daytrana FDA label">{{cite web | title=Daytrana- methylphenidate patch | website=DailyMed | date=15 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2c312c31-3198-4775-91ab-294e0b4b9e7f | access-date=26 March 2022 | archive-date=19 March 2022 | archive-url=https://web.archive.org/web/20220319232456/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2c312c31-3198-4775-91ab-294e0b4b9e7f | url-status=live }}</ref>
| legal_EU           = 
| legal_EU_comment   = 
| legal_UN           = P II<!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment   = 
| legal_status       = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability    = Insufflation: approx. 70%
Oral: approx. 30% (range: 11–52%)
| protein_bound      = 10–33%
| metabolism         = [[Biology:Liver|Liver]] (80%) mostly [[Biology:Carboxylesterase 1|CES1A1]]-mediated
| metabolites        = 
| onset              = 
| elimination_half-life = 2–3 hours<ref name="pmid10628897"/>
| duration_of_action = {{ubl
| Instant-release: 3-4 hours
| Extended-release: 6-12 hours
}}
| excretion          = [[Biology:Urine|Urine]] (90%)

<!-- Identifiers -->
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 20748-11-2
| CAS_supplemental   = 
| PubChem            = 4158
| IUPHAR_ligand      = 7236
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00422
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 4015
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 207ZZ9QZ49
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D04999
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 6887
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 796
| NIAID_ChemDB       = 
| PDB_ligand         = 
| synonyms           = MPH<ref name="Hodgkins_2012" />

<!-- Chemical and physical data -->
| IUPAC_name         = Methyl phenyl(piperidin-2-yl)acetate <!-- the locant '2' for acetic acid is not cited -->
| C                  = 14
| H                  = 19
| N                  = 1
| O                  = 2
| SMILES             = COC(=O)C(c1ccccc1)C1CCCCN1
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C14H19NO2/c1-17-14(16)13(11-7-3-2-4-8-11)12-9-5-6-10-15-12/h2-4,7-8,12-13,15H,5-6,9-10H2,1H3
| StdInChI_comment   = 
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = DUGOZIWVEXMGBE-UHFFFAOYSA-N
| density            = 
| density_notes      = 
| melting_point      = 74
| melting_high       = 
| melting_notes      = <ref name="Pubchem properties">{{cite web|title=Methylphenidate|url=https://pubchem.ncbi.nlm.nih.gov/compound/4158 |website=Pubchem|access-date=4 September 2017|archive-date=6 January 2014|archive-url=https://web.archive.org/web/20140106100442/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4158#x27|url-status=live}}</ref>
| boiling_point      = 136
| boiling_notes      = <ref name="Pubchem properties" />
| solubility         = 
| sol_units          = 
| specific_rotation  = 
}}
'''Methylphenidate''', sold under the brand names '''Ritalin''' ({{IPAc-en|ˈ|r|ɪ|t|ə|l|ɪ|n}} {{respell|RIT|ə|lin}}) and '''Concerta''' ({{IPAc-en|k|ə|n|ˈ|s|ɜːr|t|ə}} {{respell|kən|SUR|tə}}) among others, is a [[Biology:Central nervous system|central nervous system]] (CNS) [[Chemistry:Stimulant|stimulant]] used medically to treat [[Medicine:Attention deficit hyperactivity disorder|attention deficit hyperactivity disorder]] (ADHD) and, to a lesser extent, [[Medicine:Narcolepsy|narcolepsy]]. It is a primary medication for ADHD (e.g. in the UK<ref>{{cite web |date=24 December 2021 |title=Attention deficit hyperactivity disorder (ADHD): Treatment |url=https://www.nhs.uk/conditions/attention-deficit-hyperactivity-disorder-adhd/treatment/ |access-date=18 October 2022 |website=National Health Service (NHS)}}</ref>); it may be taken [[Medicine:Oral administration|by mouth]] or applied to the skin, and different formulations have varying durations of effect, commonly ranging from 2–4&nbsp;hours.<ref name=AHFS2018>{{cite web |title=Methylphenidate Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/methylphenidate-hydrochloride.html |website=Drugs.com |publisher=AHFS |access-date=19 December 2018 |archive-url=https://web.archive.org/web/20181219182550/https://www.drugs.com/monograph/methylphenidate-hydrochloride.html |archive-date=19 December 2018 |url-status=live }}</ref>

<!-- Side effects -->
Common adverse reactions of methylphenidate include: [[Chemistry:Euphoria|euphoria]], [[Medicine:Mydriasis|dilated pupils]], [[Medicine:Tachycardia|tachycardia]], [[Medicine:Palpitations|palpitations]], [[Medicine:Headache|headache]], [[Medicine:Insomnia|insomnia]], [[Medicine:Anxiety|anxiety]], hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and [[Medicine:Abdominal pain|abdominal pain]].<ref name="Ritalin FDA label" /> [[Medicine:Drug withdrawal|Withdrawal symptoms]] may include: [[Physics:Chills|chills]], [[Medicine:Depression (mood)|depression]], drowsiness, [[Medicine:Dysphoria|dysphoria]], [[Medicine:Fatigue|exhaustion]], [[Medicine:Headache|headache]], irritability, lethargy, [[Unsolved:Nightmare|nightmare]]s, [[Medicine:Psychomotor agitation|restlessness]], [[Medicine:Suicidal ideation|suicidal thoughts]], and [[Medicine:Weakness|weakness]].<ref name="AHFS2018"/>

<!-- Mechanism of action -->
Methylphenidate is believed to work by blocking the [[Biology:Reuptake|reuptake]] of [[Biology:Dopamine|dopamine]] and [[Biology:Norepinephrine|norepinephrine]] by [[Biology:Neuron|neuron]]s.<ref name="Arn2005">{{cite journal | vauthors = Arnsten AF, Li BM | title = Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions | journal = Biological Psychiatry | volume = 57 | issue = 11 | pages = 1377–1384 | date = June 2005 | pmid = 15950011 | doi = 10.1016/j.biopsych.2004.08.019 | s2cid = 22992765 }}</ref><ref name="St4th">{{cite book | vauthors = Stahl SM |date=11 April 2013 |title=Stahl's Essential Psychopharmacology: Neuroscientific basis and practical applications |publisher=Cambridge University Press |isbn=978-1107686465 |edition=4th}}</ref> It is a [[Biology:Central nervous system|central nervous system]] (CNS) stimulant of the [[Chemistry:Substituted phenethylamine|phenethylamine]] and [[Chemistry:Piperidine|piperidine]] classes.

== Etymology ==
The word methylphenidate is a portmanteau of the chemical name, <u>Methyl</u>-2-<u>phen</u>yl-2-(p<u>i</u>peri<u>d</u>in-2-yl) acet<u>ate</u>.

== Uses ==
Methylphenidate is most commonly used to treat ADHD and narcolepsy.<ref name=drugbank>{{cite web |title=Methylphenidate |url=https://www.drugbank.ca/drugs/DB00422 |website=DrugBank |access-date=30 January 2019 |archive-url=https://web.archive.org/web/20190131040915/https://www.drugbank.ca/drugs/DB00422 |archive-date=31 January 2019 }}</ref>

=== Attention deficit hyperactivity disorder ===
Methylphenidate is used for the treatment of [[Medicine:Attention deficit hyperactivity disorder|attention deficit hyperactivity disorder]].<ref>{{cite journal | vauthors = Fone KC, Nutt DJ | title = Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder | journal = Current Opinion in Pharmacology | volume = 5 | issue = 1 | pages = 87–93 | date = February 2005 | pmid = 15661631 | doi = 10.1016/j.coph.2004.10.001 }}</ref> The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose.<ref name="Huss Duhan Gandhi Chen 2021 p. ">{{cite journal | vauthors = Huss M, Duhan P, Gandhi P, Chen CW, Spannhuth C, Kumar V | title = Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity | journal = Neuropsychiatric Disease and Treatment | volume = 13 | pages = 1741–1751 | date = 2 June 2021 | pmid = 28740389 | pmc = 5505611 | doi = 10.2147/NDT.S130444 | doi-access = free }}</ref> Immediate-release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms.<ref name="Management 2011 pp. 1007–1022">{{cite journal | vauthors = Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, Ganiats TG, Kaplanek B, Meyer B, Perrin J, Pierce K, Reiff M, Stein MT, Visser S | title = ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit / hyperactivity disorder in children and adolescents | journal = Pediatrics | volume = 128 | issue = 5 | pages = 1007–1022 | date = November 2011 | pmid = 22003063 | pmc = 4500647 | doi = 10.1542/peds.2011-2654 }}</ref><ref name=Neinstein-2009>{{cite book | vauthors = Neinstein L | year=2009 | title=Handbook of Adolescent Health Care | publisher=Wolters Kluwer Health / Lippincott Williams & Wilkins | location=Philadelphia, PA | isbn=978-0-7817-9020-8 | oclc=226304727 }}{{rp|722}}</ref> Methylphenidate is not approved for children under six years of age.<ref>{{cite journal | vauthors = Vitiello B | date = October 2001 | title = Psychopharmacology for young children: clinical needs and research opportunities | journal = Pediatrics | volume = 108 | issue = 4 | pages = 983–989 | pmid = 11581454 | doi = 10.1542/peds.108.4.983 | s2cid = 33417584 }}</ref><ref>{{cite journal | vauthors = Hermens DF, Rowe DL, Gordon E, Williams LM | date = May 2006 | title = Integrative neuroscience approach to predict ADHD stimulant response | journal = Expert Review of Neurotherapeutics | volume = 6 | issue = 5 | pages = 753–763 | pmid = 16734523 | doi = 10.1586/14737175.6.5.753 | s2cid = 15971025 }}</ref>

In children over age&nbsp;6 and adolescents, the short-term benefits and cost-effectiveness of methylphenidate are well established.<ref>{{cite journal | vauthors = Gilmore A, Milne R | title = Methylphenidate in children with hyperactivity: review and cost-utility analysis | journal = Pharmacoepidemiology and Drug Safety | volume = 10 | issue = 2 | pages = 85–94 | year = 2001 | pmid = 11499858 | doi = 10.1002/pds.564 | s2cid = 22871134 }}</ref><ref>{{cite journal | vauthors = Mott TF, Leach L, Johnson L | title = Clinical inquiries. Is methylphenidate useful for treating adolescents with ADHD? | journal = The Journal of Family Practice | volume = 53 | issue = 8 | pages = 659–661 | date = August 2004 | pmid = 15298843 | url = http://www.jfponline.com/Pages.asp?AID=1753 | access-date = 30 April 2009 | url-status = dead | df = dmy-all | archive-url = https://web.archive.org/web/20110713105514/http://www.jfponline.com/Pages.asp?AID=1753 | archive-date = 13 July 2011 }}</ref> A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.<ref name="Millichap_3" /><ref name="Long-Term Outcomes Medications">{{cite journal | vauthors = Huang YS, Tsai MH | title = Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge | journal = CNS Drugs | volume = 25 | issue = 7 | pages = 539–554 | date = July 2011 | pmid = 21699268 | doi = 10.2165/11589380-000000000-00000 | s2cid = 3449435 }}</ref><ref name="Millichap">{{cite book | vauthors = Millichap JG | year = 2010 | chapter = Chapter&nbsp;3: Medications for ADHD | veditors = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A physician's guide to ADHD | publisher = Springer | location = New York, NY | isbn = 9781441913968 | pages = 121–123 | edition = 2nd}}</ref>

Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms.<ref name="WebMds Review">{{cite journal | vauthors = Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, Benson RS, Bukstein O, Kinlan J, McClellan J, Rue D, Shaw JA, Stock S | title = Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 41 | issue = 2 Suppl | pages = 26S–49S | date = February 2002 | pmid = 11833633 | doi = 10.1097/00004583-200202001-00003 }}</ref> Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and [[Social:Impulsivity|impulsive]], and have longer [[Medicine:Attention span|attention span]]s.<ref name=Millichap_3>{{cite book | vauthors = Millichap JG | year = 2010 | chapter = Chapter&nbsp;3: Medications for ADHD |veditors = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A physician's guide to ADHD | publisher = Springer | location = New York, NY | isbn = 9781441913968 | pages = 111–113 | edition = 2nd}}</ref> There is evidence to suggest that children diagnosed with ADHD who do not receive treatment will have an increased risk of [[Medicine:Substance use disorder|substance use disorder]]s as adults.<ref name="esmadhd18307377">{{cite journal | vauthors = Faraone SV, Wilens TE | title = Effect of stimulant medications for attention-deficit/hyperactivity disorder on later substance use and the potential for stimulant misuse, abuse, and diversion | journal = The Journal of Clinical Psychiatry | volume = 68 | issue = 11 | pages = 15–22 | year = 2007 | pmid = 18307377 | doi = 10.4088/jcp.1107e28 }}</ref><ref name="dstadhd12509574">{{cite journal | vauthors = Wilens TE, Faraone SV, Biederman J, Gunawardene S | title = Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature | journal = Pediatrics | volume = 111 | issue = 1 | pages = 179–185 | date = January 2003 | pmid = 12509574 | doi = 10.1542/peds.111.1.179 | s2cid = 29956425 | citeseerx = 10.1.1.507.874 }}</ref>

The precise magnitude of improvement in ADHD symptoms and quality of life produced by methylphenidate treatment remains uncertain {{as of|2023|March|lc=yes}}.<ref name="pmid36971690">{{cite journal | vauthors = Storebø OJ, Storm MR, Pereira Ribeiro J, Skoog M, Groth C, Callesen HE, Schaug JP, Darling Rasmussen P, Huus CL, Zwi M, Kirubakaran R, Simonsen E, Gluud C | title = Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD) | url = https://www.researchgate.net/publication/369558291 | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 3 | article-number = CD009885 | date = 27 March 2023 | pages = CD009885 | pmid = 36971690 | pmc = 10042435 | pmc-embargo-date = 27 March 2024 <!--when embargo ends, remove preprint url as well--> | doi = 10.1002/14651858.CD009885.pub3 | quote = the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear }}</ref> Methylphenidate is not included in the World Health Organization Essential Medicines List, as findings by the [[Organization:World Health Organization|World Health Organization]] indicate evidence of benefit versus harm to be unclear in the treatment of ADHD.<ref>{{cite web |title=eEML - Electronic Essential Medicines List |url=https://list.essentialmeds.org/recommendations/1200 |website=list.essentialmeds.org |access-date=26 March 2020 |archive-date=26 March 2020 |archive-url=https://web.archive.org/web/20200326025659/https://list.essentialmeds.org/recommendations/1200 |url-status=live }}</ref> A 2021 systematic review did not find clear evidence for using IR methylphenidate (immediate-release) for adults.<ref name="Cândido Menezes de Padua Golder Junqueira">{{cite journal | vauthors = Cândido RC, Menezes de Padua CA, Golder S, Junqueira DR | title = Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | page = CD013011 | date = January 2021 | pmid = 33460048 | pmc = 8092481 | doi = 10.1002/14651858.cd013011.pub2 | publisher = Wiley }}</ref>

Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a "study drug" by some populations, which may be harmful.<ref name="Abelman 68">{{cite journal | vauthors = Abelman DD | title = Mitigating risks of students use of study drugs through understanding motivations for use and applying harm reduction theory: a literature review | journal = Harm Reduction Journal | volume = 14 | issue = 1 | page = 68 | date = October 2017 | pmid = 28985738 | pmc = 5639593 | doi = 10.1186/s12954-017-0194-6 | doi-access = free }}</ref> This also applies to people who may be experiencing a different issue and are [[Medicine:Medical error|misdiagnosed]] with ADHD.<ref name="Abelman 68"/> People in this category can then experience negative side-effects of the drug, which worsen their condition.<ref name="Abelman 68"/>

=== Narcolepsy ===
[[Medicine:Narcolepsy|Narcolepsy]], a [[Medicine:Chronic condition|chronic]] [[Medicine:Sleep disorder|sleep disorder]] characterized by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing [[Philosophy:Wakefulness|wakefulness]], vigilance, and performance.<ref name="pmid9484423">{{cite journal | vauthors = Fry JM | title = Treatment modalities for narcolepsy | journal = Neurology | volume = 50 | issue = 2 Suppl 1 | pages = S43–S48 | date = February 1998 | pmid = 9484423 | doi = 10.1212/WNL.50.2_Suppl_1.S43 | s2cid = 36824088 }}</ref> Methylphenidate improves measures of [[Medicine:Somnolence|somnolence]] on [[Medicine:Medical test|standardized tests]], such as the [[Biology:Multiple Sleep Latency Test|Multiple Sleep Latency Test]] (MSLT), but performance does not improve to levels comparable to healthy people.<ref name="pmid7701190">{{cite journal | vauthors = Mitler MM | title = Evaluation of treatment with stimulants in narcolepsy | journal = Sleep | volume = 17 | issue = 8 Suppl | pages = S103–S106 | date = December 1994 | pmid = 7701190 | doi = 10.1093/sleep/17.suppl_8.S103 | doi-access = free }}</ref>

=== Other medical uses ===
Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of [[Medicine:Bipolar disorder|bipolar disorder]] and major depressive disorder.<ref name="pmid25312027">{{cite journal | vauthors = Dell'Osso B, Dobrea C, Cremaschi L, Arici C, Altamura AC | title = Wake-promoting pharmacotherapy for psychiatric disorders | journal = Current Psychiatry Reports | volume = 16 | issue = 12 | page = 524 | date = December 2014 | pmid = 25312027 | doi = 10.1007/s11920-014-0524-2 | s2cid = 26314915 }}</ref> It can also improve depression in several groups, including [[Medicine:Stroke|stroke]], [[Medicine:Cancer|cancer]], and HIV-positive patients.<ref name="pmid15079851">{{cite journal | vauthors = Leonard BE, McCartan D, White J, King DJ | title = Methylphenidate: A review of its neuropharmacological, neuropsychological, and adverse clinical effects | journal = Human Psychopharmacology | volume = 19 | issue = 3 | pages = 151–180 | date = April 2004 | pmid = 15079851 | doi = 10.1002/hup.579 | s2cid = 21173346 }}</ref> There is weak evidence in favor of methylphenidate's effectiveness for depression,<ref>{{cite journal | vauthors = Bahji A, Mesbah-Oskui L | title = Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis | journal = Journal of Affective Disorders | volume = 292 | pages = 416–423 | date = September 2021 | pmid = 34144366 | doi = 10.1016/j.jad.2021.05.119 }}</ref> including providing additional benefit in combination with [[Chemistry:Antidepressant|antidepressant]]s.<ref>{{cite journal | vauthors = Pary R, Scarff JR, Jijakli A, Tobias C, Lippmann S | title = A Review of Psychostimulants for Adults With Depression | journal = Federal Practitioner | volume = 32 | issue = Suppl 3 | pages = 30S–37S | date = April 2015 | pmid = 30766117 | pmc = 6375494 }}</ref> In individuals with [[Medicine:Terminal illness|terminal cancer]], methylphenidate can be used to counteract [[Chemistry:Opioid|opioid]]-induced [[Medicine:Somnolence|somnolence]], to increase the [[Biology:Analgesic|analgesic]] effects of opioids, to treat depression, and to improve cognitive function.<ref name=pmid11773187>{{cite journal | vauthors = Rozans M, Dreisbach A, Lertora JJ, Kahn MJ | title = Palliative uses of methylphenidate in patients with cancer: a review | journal = Journal of Clinical Oncology | volume = 20 | issue = 1 | pages = 335–339 | date = January 2002 | pmid = 11773187 | doi = 10.1200/JCO.20.1.335 }}</ref> A 2021 systematic review and meta-analysis found that all studies on geriatric depression reported positive results of methylphenidate use; the review recommended short-term use in combination with [[Chemistry:Citalopram|citalopram]].<ref>{{cite journal | vauthors = Smith KR, Kahlon CH, Brown JN, Britt RB | title = Methylphenidate use in geriatric depression: A systematic review | journal = International Journal of Geriatric Psychiatry | volume = 36 | issue = 9 | pages = 1304–1312 | date = September 2021 | pmid = 33829530 | doi = 10.1002/gps.5536 | s2cid = 233184870 }}</ref> A 2018 review found low-quality evidence supporting its use to treat apathy as seen in [[Medicine:Alzheimer's disease|Alzheimer's disease]], in addition to slight benefits for cognition and cognitive performance.<ref>{{cite journal | vauthors = Ruthirakuhan MT, Herrmann N, Abraham EH, Chan S, Lanctôt KL | title = Pharmacological interventions for apathy in Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 6 | page = CD012197 | date = May 2018 | pmid = 29727467 | pmc = 6494556 | doi = 10.1002/14651858.CD012197.pub2 }}</ref>

===Enhancing performance===

Methylphenidate's efficacy as an [[Chemistry:Performance-enhancing substance|athletic performance enhancer]], [[Chemistry:Nootropic|cognitive enhancer]], aphrodisiac, and [[Chemistry:Euphoriant|euphoriant]] is supported by research.<ref>{{cite web |date=1 June 2018 |series=Attention deficit hyperactivity disorder (ADHD) |title=Treatment |url=https://www.nhs.uk/conditions/attention-deficit-hyperactivity-disorder-adhd/treatment/ |access-date=24 October 2022 |website=nhs.uk |language=en}}</ref><ref>{{cite journal | vauthors = Robison LS, Ananth M, Hadjiargyrou M, Komatsu DE, Thanos PK | title = Chronic oral methylphenidate treatment reversibly increases striatal dopamine transporter and dopamine type&nbsp;1 receptor binding in rats | journal = Journal of Neural Transmission | volume = 124 | issue = 5 | pages = 655–667 | date = May 2017 | pmid = 28116523 | pmc = 5400672 | doi = 10.1007/s00702-017-1680-4 }}</ref><ref name="Unambiguous">{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex | journal = Biological Psychiatry | volume = 77 | issue = 11 | pages = 940–950 | date = June 2015 | pmid = 25499957 | pmc = 4377121 | doi = 10.1016/j.biopsych.2014.09.013 }}</ref><ref name="Cognitive & motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = Journal of Cognitive Neuroscience | volume = 27 | issue = 6 | pages = 1069–1089 | date = June 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | s2cid = 15788121 | url = https://repository.upenn.edu/cgi/viewcontent.cgi?article=1141&context=neuroethics_pubs | access-date = 12 June 2022 | archive-date = 26 May 2022 | archive-url = https://web.archive.org/web/20220526103820/https://repository.upenn.edu/cgi/viewcontent.cgi?article=1141&context=neuroethics_pubs | url-status = live }}</ref><ref name="pmid26813119">{{cite journal | vauthors = Busardò FP, Kyriakou C, Cipolloni L, Zaami S, Frati P | title = From Clinical Application to Cognitive Enhancement: The Example of Methylphenidate | journal = Current Neuropharmacology | volume = 14 | issue = 1 | pages = 17–27 | date = 2016 | pmid = 26813119 | pmc = 4787280 | doi = 10.2174/1570159x13666150407225902 }}</ref><ref name="pmid30657540">{{cite journal | vauthors = Carlier J, Giorgetti R, Varì MR, Pirani F, Ricci G, Busardò FP | title = Use of cognitive enhancers: methylphenidate and analogs | journal = European Review for Medical and Pharmacological Sciences | volume = 23 | issue = 1 | pages = 3–15 | date = January 2019 | pmid = 30657540 | doi = 10.26355/eurrev_201901_16741 | s2cid = 58643522 }}</ref><ref name="pmid33201262">{{cite journal | vauthors = Repantis D, Bovy L, Ohla K, Kühn S, Dresler M | title = Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine | journal = Psychopharmacology | volume = 238 | issue = 2 | pages = 441–451 | date = February 2021 | pmid = 33201262 | pmc = 7826302 | doi = 10.1007/s00213-020-05691-w }}</ref><ref name="Libido2008">{{cite journal | vauthors = Montgomery KA | title = Sexual desire disorders | journal = Psychiatry | volume = 5 | issue = 6 | pages = 50–55 | date = June 2008 | pmid = 19727285 | pmc = 2695750 }}</ref><ref name=":1">{{cite journal | vauthors = Berezanskaya J, Cade W, Best TM, Paultre K, Kienstra C | title = ADHD Prescription Medications and Their Effect on Athletic Performance: A Systematic Review and Meta-analysis | journal = Sports Medicine - Open | volume = 8 | issue = 1 | pages = 5 | date = January 2022 | pmid = 35022919 | pmc = 8755863 | doi = 10.1186/s40798-021-00374-y | doi-access = free }}</ref> However, the manner in which methylphenidate is used for these purposes (high dosages, alternate routes of administration, during sleep deprivation, etc.) can result in severe unintended side effects.<ref>{{cite journal | vauthors = Thoenes MM | title = Heat-related illness risk with methylphenidate use | language = English | journal = Journal of Pediatric Health Care | volume = 25 | issue = 2 | pages = 127–132 | date = 1 March 2011 | pmid = 21320685 | doi = 10.1016/j.pedhc.2010.07.006 }}</ref><ref>{{cite journal | vauthors = Docherty JR, Alsufyani HA | title = Cardiovascular and temperature adverse actions of stimulants | journal = British Journal of Pharmacology | volume = 178 | issue = 13 | pages = 2551–2568 | date = July 2021 | pmid = 33786822 | doi = 10.1111/bph.15465 | s2cid = 232431910 | doi-access = free }}</ref><ref name=":1" />
A 2015 review found that therapeutic doses of [[Chemistry:Amphetamine|amphetamine]] and methylphenidate result in modest improvements in [[Cognition|cognition]], including [[Working memory|working memory]], [[Biology:Episodic memory|episodic memory]], and [[Philosophy:Inhibitory control|inhibitory control]], in normal healthy adults;<ref name=Spencer-Devilbiss-Berridge-2015>{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex | journal = Biological Psychiatry | volume = 77 | issue = 11 | pages = 940–950 | date = June 2015 | pmid = 25499957 | pmc = 4377121 | doi = 10.1016/j.biopsych.2014.09.013}}</ref>{{efn|
The procognitive actions of psychostimulants are only associated with low doses ... cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors.<ref name=Spencer-Devilbiss-Berridge-2015/>
}}<ref name=Ilieva-Hook-Farah-2015>{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = Journal of Cognitive Neuroscience | volume = 27 | issue = 6 | pages = 1069–1089 | date = June 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | url = https://repository.upenn.edu/neuroethics_pubs/130 | access-date = 14 November 2018 | url-status = live | s2cid = 15788121 | archive-url = https://web.archive.org/web/20180919111616/https://repository.upenn.edu/neuroethics_pubs/130/ | archive-date = 19 September 2018 }}</ref>{{efn|
The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.<ref name=Ilieva-Hook-Farah-2015/>
}}
the cognition-enhancing effects of these drugs are known to occur through the [[Biology:Indirect agonist|indirect activation]] of both [[Biology:Dopamine receptor D1|dopamine receptor&nbsp;D<sub>1</sub>]] and [[Biology:Alpha-2 adrenergic receptor|adrenoceptor&nbsp;α<sub>2</sub>]] in the [[Biology:Prefrontal cortex|prefrontal cortex]].<ref name=Spencer-Devilbiss-Berridge-2015/> Methylphenidate and other ADHD stimulants also improve task [[Salience (neuroscience)|saliency]] and increase arousal.<ref name=Malenka_2009/><ref name=Continuum>{{cite journal | vauthors = Wood S, Sage JR, Shuman T, Anagnostaras SG | title = Psychostimulants and cognition: a continuum of behavioral and cognitive activation | journal = Pharmacological Reviews | volume = 66 | issue = 1 | pages = 193–221 | date = January 2014 | pmid = 24344115 | pmc = 3880463 | doi = 10.1124/pr.112.007054 }}</ref> Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks,<ref name=Malenka_2009>{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | year = 2009 | chapter = Chapter&nbsp;13: Higher cognitive function and behavioral control | title = Molecular Neuropharmacology: A foundation for clinical neuroscience | publisher = McGraw-Hill Medical | location = New York, NY | isbn = 9780071481274 | page = 318 | edition = 2nd}}</ref>{{efn|
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.<ref name=Malenka_2009/>
}}<ref name=Continuum/><ref>{{cite journal | vauthors = Agay N, Yechiam E, Carmel Z, Levkovitz Y | title = Non-specific effects of methylphenidate (Ritalin) on cognitive ability and decision-making of ADHD and healthy adults | journal = Psychopharmacology | volume = 210 | issue = 4 | pages = 511–519 | date = July 2010 | pmid = 20424828 | doi = 10.1007/s00213-010-1853-4 | s2cid = 17083986}}</ref> and are used by some students as a study and test-taking aid.<ref name="Abelman 68"/><ref>{{cite web | work = JS Online | vauthors = Twohey M | date = 26 March 2006 | title = Pills become an addictive study aid | access-date = 2 December 2007 | url = http://www.jsonline.com/story/index.aspx?id=410902 | archive-url = https://web.archive.org/web/20070815200239/http://www.jsonline.com/story/index.aspx?id=410902 | archive-date = 15 August 2007}}</ref> Based upon studies of self-reported illicit stimulant use, performance-enhancing use rather than use as a recreational drug, is the primary reason that students use stimulants.<ref name=pmid16999660>{{cite journal | vauthors = Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ | title = Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration | journal = Pharmacotherapy | volume = 26 | issue = 10 | pages = 1501–1510 | date = October 2006 | pmid = 16999660 | pmc = 1794223 | doi = 10.1592/phco.26.10.1501}}</ref>

Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control.<ref name=Malenka_2009/><ref name=Continuum/> Like amphetamine and [[Chemistry:Bupropion|bupropion]], methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system.<ref name=Roelands_2013>{{cite journal | vauthors = Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R | title = Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing | journal = Sports Medicine | volume = 43 | issue = 5 | pages = 301–311 | date = May 2013 | pmid = 23456493 | doi = 10.1007/s40279-013-0030-4 | s2cid = 30392999 }}</ref> Similar to the loss of cognitive enhancement when using large amounts, large doses of methylphenidate can induce [[Medicine:Side effect|side effect]]s that impair athletic performance, such as [[Medicine:Rhabdomyolysis|rhabdomyolysis]] and [[Medicine:Hyperthermia|hyperthermia]].<ref name="Daytrana FDA label" /> While literature suggests it might improve cognition, most authors agree that using the drug as a study aid when an ADHD diagnosis is not present does not actually improve GPA.<ref name="Abelman 68"/> Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.<ref name="Abelman 68"/>

== Contraindications ==
Methylphenidate is contraindicated for individuals with agitation, tics, [[Medicine:Glaucoma|glaucoma]], heart defects or a [[Medicine:Hypersensitivity|hypersensitivity]] to any ingredients contained in methylphenidate pharmaceuticals.<ref name="Daytrana FDA label" />

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks.<ref>{{cite web | url = https://www.drugs.com/pregnancy/methylphenidate.html | title = Methylphenidate: Use During Pregnancy and Breastfeeding | archive-url = https://web.archive.org/web/20180102005138/https://www.drugs.com/pregnancy/methylphenidate.html | archive-date=2 January 2018 | work = Drugs.com }}</ref> Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.<ref>{{cite journal | vauthors = Humphreys C, Garcia-Bournissen F, Ito S, Koren G | title = Exposure to attention deficit hyperactivity disorder medications during pregnancy | journal = Canadian Family Physician | volume = 53 | issue = 7 | pages = 1153–1155 | date = July 2007 | pmid = 17872810 | pmc = 1949295 }}</ref> In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".<ref>{{cite journal | vauthors = Ornoy A | title = Pharmacological Treatment of Attention Deficit Hyperactivity Disorder During Pregnancy and Lactation | journal = Pharmaceutical Research | volume = 35 | issue = 3 | page = 46 | date = February 2018 | pmid = 29411149 | doi = 10.1007/s11095-017-2323-z | s2cid = 3663423 }}</ref>

== Adverse effects ==
[[File:Rational harm assessment of drugs radar plot.svg|thumb|Addiction experts in psychiatry, chemistry, pharmacology, [[Physics:Forensic science|forensic science]], epidemiology, and the police and legal services engaged in [[Delphi method|delphic analysis]] regarding 20&nbsp;popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.<ref>{{cite journal | vauthors = Nutt D, King LA, Saulsbury W, Blakemore C | title = Development of a rational scale to assess the harm of drugs of potential misuse | journal = Lancet | volume = 369 | issue = 9566 | pages = 1047–1053 | date = March 2007 | pmid = 17382831 | doi = 10.1016/S0140-6736(07)60464-4 | s2cid = 5903121 }}</ref>]]
The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, [[Medicine:Anxiety|anxiety]]/nervousness, nausea, and [[Medicine:Insomnia|insomnia]].<ref name="Coghill Banaschewski Zuddas Pelaz p.">{{cite journal |vauthors=Coghill D, Banaschewski T, Zuddas A, Pelaz A, Gagliano A, Doepfner M |date=September 2013 |title=Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies |journal=BMC Psychiatry |publisher=Springer Science and Business Media LLC |volume=13 |issue=1 |page=237 |doi=10.1186/1471-244x-13-237 |pmc=3852277 |pmid=24074240 |doi-access=free }}</ref> Gastrointestinal adverse effects may include [[Medicine:Abdominal pain|abdominal pain]] and weight loss. [[Biology:Nervous system|Nervous system]] adverse effects may include [[Medicine:Akathisia|akathisia]] (agitation/restlessness), irritability, [[Medicine:Dyskinesia|dyskinesia]] (tics), Oromandibular dystonia,<ref>{{cite journal |vauthors=Rissardo JP, Caprara AL |date=2020 |title=Oromandibular dystonia secondary to methylphenidate: A case report and literature review |url=https://go.gale.com/ps/i.do?id=GALE%7CA626978803&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=23832568&p=AONE&sw=w&userGroupName=anon%7E859e3a3c |journal=Int Arch Health Sci |volume=7 |pages=108–111 |doi=10.4103/iahs.iahs_71_19 |doi-broken-date=1 August 2023 |doi-access=free|via=Gale Academic OneFile |access-date=15 November 2021 |archive-date=15 November 2021 |archive-url=https://web.archive.org/web/20211115231245/https://go.gale.com/ps/i.do?id=GALE%7CA626978803&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=23832568&p=AONE&sw=w&userGroupName=anon~859e3a3c|url-status=live}}</ref> lethargy (drowsiness/fatigue), and [[Medicine:Dizziness|dizziness]]. Cardiac adverse effects may include [[Medicine:Palpitations|palpitations]], changes in [[Physics:Blood pressure|blood pressure]], and [[Medicine:Pulse|heart rate]] (typically mild), and [[Medicine:Tachycardia|tachycardia]] (rapid heart rate).<ref name = "Ritalin Rx info">{{cite web | url = http://www.pharma.us.novartis.com/product/pi/pdf/ritalin_la.pdf | title = Ritalin&nbsp;LA (methylphenidate hydrochloride) extended-release capsules | archive-url = https://web.archive.org/web/20110720004745/http://www.pharma.us.novartis.com/product/pi/pdf/ritalin_la.pdf | archive-date=20 July 2011 | publisher = Novartis}}</ref> Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of [[Medicine:Diplopia|diplopia]] and [[Medicine:Mydriasis|mydriasis]].{{Contradictory inline|date=September 2023}}<ref name="De Sousa Kalra 2012 pp. 45–69"/><ref>{{cite journal | vauthors = Jaanus SD | title = Ocular side effects of selected systemic drugs | journal = Optometry Clinics | volume = 2 | issue = 4 | pages = 73–96 | year = 1992 | pmid = 1363080 }}</ref>

Smokers with ADHD who take methylphenidate may increase their [[Chemistry:Nicotine|nicotine]] dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3&nbsp;[[Engineering:Cigarette|cigarette]]s per day.<ref>{{cite journal |vauthors=Bron TI, Bijlenga D, Kasander MV, Spuijbroek AT, Beekman AT, Kooij JJ |date=June 2013 |title=Long-term relationship between methylphenidate and tobacco consumption and nicotine craving in adults with ADHD in a prospective cohort study |journal=European Neuropsychopharmacology |volume=23 |issue=6 |pages=542–554 |doi=10.1016/j.euroneuro.2012.06.004 |pmid=22809706 |s2cid=23148548}}</ref>

There is some evidence of mild reductions in height with prolonged treatment in children.<ref name="pmid23294014">{{cite journal | vauthors = Cortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Dittmann RW, Graham J, Taylor E, Sergeant J | title = Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | volume = 54 | issue = 3 | pages = 227–246 | date = March 2013 | pmid = 23294014 | doi = 10.1111/jcpp.12036 }}</ref> This has been estimated at {{Convert|1|cm||1|abbr=}} or less per year during the first three years with a total decrease of {{Convert|3|cm||1|abbr=}} over 10 years.<ref>{{cite journal | vauthors = Poulton A | title = Growth on stimulant medication; clarifying the confusion: a review | journal = Archives of Disease in Childhood | volume = 90 | issue = 8 | pages = 801–806 | date = August 2005 | pmid = 16040876 | pmc = 1720538 | doi = 10.1136/adc.2004.056952}}</ref><ref>{{cite journal | vauthors = Hinshaw SP, Arnold LE | title = ADHD, Multimodal Treatment, and Longitudinal outcome: Evidence, paradox, and challenge | journal = Wiley Interdisciplinary Reviews. Cognitive Science | volume = 6 | issue = 1 | pages = 39–52 | date = January 2015 | pmid = 25558298 | pmc = 4280855 | doi = 10.1002/wcs.1324 }}</ref>

[[Medicine:Hypersensitivity|Hypersensitivity]] (including skin rash, urticaria, and [[Medicine:Fever|fever]]) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.<ref>{{cite journal | vauthors = Findling RL, Dinh S | title = Transdermal therapy for attention-deficit hyperactivity disorder with the methylphenidate patch (MTS) | journal = CNS Drugs | volume = 28 | issue = 3 | pages = 217–228 | date = March 2014 | pmid = 24532028 | pmc = 3933749 | doi = 10.1007/s40263-014-0141-y }}</ref>

Methylphenidate can worsen [[Medicine:Psychosis|psychosis]] in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms.<ref name=pmid20571380>{{cite journal | vauthors = Kraemer M, Uekermann J, Wiltfang J, Kis B | title = Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature | journal = Clinical Neuropharmacology | volume = 33 | issue = 4 | pages = 204–206 | date = July 2010 | pmid = 20571380 | doi = 10.1097/WNF.0b013e3181e29174 | s2cid = 34956456 }}</ref> It should be used with extreme caution in people with [[Medicine:Bipolar disorder|bipolar disorder]] due to the potential induction of [[Medicine:Mania|mania]] or [[Medicine:Hypomania|hypomania]].<ref>{{cite journal | vauthors = Wingo AP, Ghaemi SN | title = Frequency of stimulant treatment and of stimulant-associated mania / hypomania in bipolar disorder patients | journal = Psychopharmacology Bulletin | volume = 41 | issue = 4 | pages = 37–47 | date = 2008 | pmid = 19015628 }}</ref> There have been very rare reports of [[Medicine:Suicidal ideation|suicidal ideation]], but some authors claim that evidence does not support a link.<ref name=pmid23294014/> Logorrhea is occasionally reported and visual [[Unsolved:Hallucination|hallucination]]s are very rarely reported.<ref name="De Sousa Kalra 2012 pp. 45–69">{{cite journal | vauthors = de Sousa A, Kalra G | title = Drug therapy of attention deficit hyperactivity disorder: current trends | journal = Mens Sana Monographs | volume = 10 | issue = 1 | pages = 45–69 | date = January 2012 | pmid = 22654382 | pmc = 3353606 | doi = 10.4103/0973-1229.87261 | doi-broken-date = 27 January 2024 | doi-access = free }}</ref> [[Medicine:Priapism|Priapism]] is a very rare adverse event that can be potentially serious.<ref name=FDA>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm378876.htm |title=Methylphenidate ADHD medications: Drug safety communication – risk of long-lasting erections |website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) |date=17 December 2013 |access-date=17 December 2013 |archive-url=https://web.archive.org/web/20131217225515/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm378876.htm|archive-date=17 December 2013|url-status=dead}}</ref>

U.S. Food and Drug Administration-commissioned studies in 2011 indicate that in children, young adults, and adults, there is no association between serious adverse [[Medicine:Cardiovascular disease|cardiovascular events]] (sudden death, [[Medicine:Myocardial infarction|heart attack]], and [[Medicine:Stroke|stroke]]) and the medical use of methylphenidate or other ADHD stimulants.<ref>{{cite web | title=FDA drug safety communication: Safety review update of medications used to treat attention-ceficit / hyperactivity disorder (ADHD) in children and young adults | date=20 December 2011 | url=https://www.fda.gov/Drugs/DrugSafety/ucm277770.htm | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | access-date=4 November 2013 | archive-url=https://web.archive.org/web/20131030042927/https://www.fda.gov/Drugs/DrugSafety/ucm277770.htm | archive-date=30 October 2013 | url-status=live }}

{{cite journal | vauthors = Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA | title = ADHD drugs and serious cardiovascular events in children and young adults | journal = The New England Journal of Medicine | volume = 365 | issue = 20 | pages = 1896–1904 | date = November 2011 | pmid = 22043968 | pmc = 4943074 | doi = 10.1056/NEJMoa1110212 }}

{{cite web | title=FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults | date=15 December 2011 | url=https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm | work=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | access-date=4 November 2013 | archive-url=https://web.archive.org/web/20131030064843/https://www.fda.gov/Drugs/DrugSafety/ucm279858.htm | archive-date=30 October 2013 | url-status=live }}

{{cite journal | vauthors = Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV | title = ADHD medications and risk of serious cardiovascular events in young and middle-aged adults | journal = JAMA | volume = 306 | issue = 24 | pages = 2673–2683 | date = December 2011 | pmid = 22161946 | pmc = 3350308 | doi = 10.1001/jama.2011.1830 }}
</ref>

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.<ref>{{cite journal | vauthors = Gordon N | title = Attention deficit hyperactivity disorder: Possible causes and treatment | journal = International Journal of Clinical Practice | volume = 53 | issue = 7 | pages = 524–528 | year = 1999 | doi = 10.1111/j.1742-1241.1999.tb11794.x | pmid = 10692738 | s2cid = 27462347 }}</ref>

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low.<ref name=Cochrane2018 />

The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.<ref name=Cochrane2018>{{cite journal | vauthors = Storebø OJ, Pedersen N, Ramstad E, Kielsholm ML, Nielsen SS, Krogh HB, Moreira-Maia CR, Magnusson FL, Holmskov M, Gerner T, Skoog M, Rosendal S, Groth C, Gillies D, Buch Rasmussen K, Gauci D, Zwi M, Kirubakaran R, Håkonsen SJ, Aagaard L, Simonsen E, Gluud C | title = Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies | journal = The Cochrane Database of Systematic Reviews | volume = 5 | page = CD012069 | date = May 2018 | issue = 5 | pmid = 29744873 | pmc = 6494554 | doi = 10.1002/14651858.CD012069.pub2 | type = Systematic Review }}</ref>{{efn|
"Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children" "Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events."<ref name=Cochrane2018/>
}}

=== Overdose ===
The symptoms of a moderate acute overdose on methylphenidate primarily arise from [[Biology:Central nervous system|central nervous system]] overstimulation; these symptoms include: [[Medicine:Vomiting|vomiting]], nausea, [[Medicine:Psychomotor agitation|agitation]], tremors, hyperreflexia, muscle twitching, [[Chemistry:Euphoria|euphoria]], confusion, hallucinations, [[Medicine:Delirium|delirium]], [[Medicine:Hyperthermia|hyperthermia]], sweating, flushing, headache, [[Medicine:Tachycardia|tachycardia]], heart palpitations, cardiac arrhythmias, [[Medicine:Hypertension|hypertension]], [[Medicine:Mydriasis|mydriasis]], and dryness of [[Biology:Mucous membrane|mucous membrane]]s.<ref name="Daytrana FDA label"/><ref name="MPH INCHEM"/> A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, [[Medicine:Convulsion|convulsion]]s, [[Medicine:Paranoia|paranoia]], [[Biology:Stereotypy|stereotypy]] (a repetitive movement disorder), [[Medicine:Rhabdomyolysis|rhabdomyolysis]], [[Medicine:Coma|coma]], and [[Medicine:Circulatory collapse|circulatory collapse]].<ref name="Daytrana FDA label"/><ref name="MPH INCHEM">{{cite web |vauthors=Heedes G, Ailakis J |title=Methylphenidate hydrochloride (PIM 344) |url=http://www.inchem.org/documents/pims/pharm/pim344.htm |website=INCHEM |publisher=International Programme on Chemical Safety| access-date=23 June 2015 |archive-url=https://web.archive.org/web/20150623102325/http://www.inchem.org/documents/pims/pharm/pim344.htm |archive-date=23 June 2015 |url-status=live}}</ref><ref name="ADHD toxidrome">{{cite journal | vauthors = Spiller HA, Hays HL, Aleguas A | title = Overdose of drugs for attention-deficit hyperactivity disorder: Clinical presentation, mechanisms of toxicity, and management | journal = CNS Drugs | volume = 27 | issue = 7 | pages = 531–543 | date = July 2013 | pmid = 23757186 | doi = 10.1007/s40263-013-0084-8 | s2cid = 40931380 | doi-access = free }}</ref>{{efn|
The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. ... However, fatalities are rare with appropriate care.<ref name="ADHD toxidrome"/>
}}
A methylphenidate overdose is rarely fatal with appropriate care.<ref name="ADHD toxidrome"/> Following injection of methylphenidate tablets into an [[Biology:Artery|artery]], severe toxic reactions involving [[Medicine:Abscess|abscess]] formation and [[Biology:Necrosis|necrosis]] have been reported.<ref name=pmid21984207>{{cite journal | vauthors = Bruggisser M, Bodmer M, Liechti ME | title = Severe toxicity due to injected but not oral or nasal abuse of methylphenidate tablets | journal = Swiss Medical Weekly | volume = 141 | page = w13267 | year = 2011 | pmid = 21984207 | doi = 10.4414/smw.2011.13267 | doi-access = free }}</ref>

Treatment of a methylphenidate overdose typically involves the administration of [[Chemistry:Benzodiazepine|benzodiazepine]]s, with [[Chemistry:Antipsychotic|antipsychotic]]s, α-adrenoceptor agonists and [[Chemistry:Propofol|propofol]] serving as second-line therapies.<ref name="ADHD toxidrome"/>

[[File:Add Wize Methylphenidate Warning.jpg|thumb|Packaging of a formulation of methylphenidate advises against crushing the tablets. It is placed under Schedule&nbsp;X of the Indian drug scheduling system. Schedule&nbsp;X medications typically hold abusable medications such as barbiturates or stimulants such as amphetamines.]]

===Addiction and dependence===
Methylphenidate is a stimulant with an addiction liability and dependence liability similar to [[Chemistry:Amphetamine|amphetamine]]. It has moderate liability among addictive drugs;<ref name=pmid15014637>{{cite journal | vauthors = Morton WA, Stockton GG | title = Methylphenidate Abuse and Psychiatric Side Effects | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 2 | issue = 5 | pages = 159–164 | date = October 2000 | pmid = 15014637 | pmc = 181133 | doi = 10.4088/PCC.v02n0502 }}</ref><ref name="MPH - addiction"/> accordingly, [[Medicine:Addiction|addiction]] and [[Medicine:Psychological dependence|psychological dependence]] are possible and likely when methylphenidate is used at high doses as a recreational drug.<ref name="MPH - addiction"/> When used above the medical dose range, stimulants are associated with the development of [[Medicine:Stimulant psychosis|stimulant psychosis]].<ref>{{cite journal | vauthors = Auger RR, Goodman SH, Silber MH, Krahn LE, Pankratz VS, Slocumb NL | title = Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: A case-control study | journal = Sleep | volume = 28 | issue = 6 | pages = 667–672 | date = June 2005 | pmid = 16477952 | doi = 10.1093/sleep/28.6.667 | doi-access = free }}</ref>

==== Biomolecular mechanisms ====
Methylphenidate has the potential to induce [[Chemistry:Euphoria|euphoria]] due to its pharmacodynamic effect (i.e., [[Chemistry:Dopamine reuptake inhibitor|dopamine reuptake inhibition]]) in the brain's [[Philosophy:Reward system|reward system]]. At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system; consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an [[Medicine:Addiction|addiction]].<ref name="MPH - addiction">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | year = 2009 | chapter = Chapter&nbsp;15: Reinforcement and addictive disorders | title = Molecular Neuropharmacology: A foundation for clinical neuroscience | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 368 | edition = 2nd}}</ref>

== Interactions ==
Methylphenidate may inhibit the metabolism of [[Chemistry:Vitamin K antagonist|vitamin K anticoagulants]], certain [[Chemistry:Anticonvulsant|anticonvulsant]]s, and some antidepressants ([[Chemistry:Tricyclic antidepressant|tricyclic antidepressant]]s, and [[Chemistry:Selective serotonin reuptake inhibitor|selective serotonin reuptake inhibitor]]s). [[Medicine:Concomitant drug|Concomitant administration]] may require dose adjustments, possibly assisted by monitoring of [[Biology:Blood plasma|plasma]] drug concentrations.<ref name="Concerta FDA label"/> There are several case reports of methylphenidate inducing [[Medicine:Serotonin syndrome|serotonin syndrome]] with concomitant administration of antidepressants.<ref>{{cite journal | vauthors = Ishii M, Tatsuzawa Y, Yoshino A, Nomura S | title = Serotonin syndrome induced by augmentation of SSRI with methylphenidate | journal = Psychiatry and Clinical Neurosciences | volume = 62 | issue = 2 | page = 246 | date = April 2008 | pmid = 18412855 | doi = 10.1111/j.1440-1819.2008.01767.x | s2cid = 5659107 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Türkoğlu S | title = Serotonin syndrome with sertraline and methylphenidate in an adolescent | journal = Clinical Neuropharmacology | volume = 38 | issue = 2 | pages = 65–66 | date = 2015 | pmid = 25768857 | doi = 10.1097/WNF.0000000000000075 | s2cid = 38523209 }}</ref><ref>{{cite journal | vauthors = Park YM, Jung YK | title = Manic switch and serotonin syndrome induced by augmentation of paroxetine with methylphenidate in a patient with major depression | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 34 | issue = 4 | pages = 719–720 | date = May 2010 | pmid = 20298736 | doi = 10.1016/j.pnpbp.2010.03.016 | s2cid = 31984813 }}</ref><ref>{{cite journal | vauthors = Bodner RA, Lynch T, Lewis L, Kahn D | title = Serotonin syndrome | journal = Neurology | volume = 45 | issue = 2 | pages = 219–223 | date = February 1995 | pmid = 7854515 | doi = 10.1212/wnl.45.2.219 | s2cid = 35190429 }}</ref>

When methylphenidate is coingested with [[Chemistry:Ethanol|ethanol]], a metabolite called [[Chemistry:Ethylphenidate|ethylphenidate]] is formed via hepatic [[Chemistry:Transesterification|transesterification]],<ref>{{cite journal | vauthors = Patrick KS, González MA, Straughn AB, Markowitz JS | title = New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder | journal = Expert Opinion on Drug Delivery | volume = 2 | issue = 1 | pages = 121–143 | date = January 2005 | pmid = 16296740 | doi = 10.1517/17425247.2.1.121 | s2cid = 25026467 }}</ref><ref name=pmid10820132>{{cite journal | vauthors = Markowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS | title = Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol | journal = Drug Metabolism and Disposition | volume = 28 | issue = 6 | pages = 620–624 | date = June 2000 | pmid = 10820132 }}</ref> not unlike the hepatic formation of [[Chemistry:Cocaethylene|cocaethylene]] from [[Biology:Cocaine#Metabolism and excretion|cocaine]] and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.<ref name=pmid10440465>{{cite journal | vauthors = Markowitz JS, Logan BK, Diamond F, Patrick KS | title = Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion | journal = Journal of Clinical Psychopharmacology | volume = 19 | issue = 4 | pages = 362–366 | date = August 1999 | pmid = 10440465 | doi = 10.1097/00004714-199908000-00013 }}</ref><ref name=pmid10820132/>

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.<ref name=pmid17339864>{{cite journal | vauthors = Patrick KS, Straughn AB, Minhinnett RR, Yeatts SD, Herrin AE, DeVane CL, Malcolm R, Janis GC, Markowitz JS | title = Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics | journal = Clinical Pharmacology and Therapeutics | volume = 81 | issue = 3 | pages = 346–353 | date = March 2007 | pmid = 17339864 | pmc = 3188424 | doi = 10.1038/sj.clpt.6100082 }}</ref>

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of [[Chemistry:Beta-adrenergic agonist|β-adrenergic agonists]] with methylphenidate may increase the risk of liver toxicity.<ref>{{cite journal | vauthors = Roberts SM, DeMott RP, James RC | title = Adrenergic modulation of hepatotoxicity | journal = Drug Metabolism Reviews | volume = 29 | issue = 1–2 | pages = 329–353 | year = 1997 | pmid = 9187524 | doi = 10.3109/03602539709037587 }}</ref>

== Pharmacology ==

=== Pharmacodynamics ===
{| class="wikitable" style="float:right;margin-left:5px; text-align:center;"
|+ Binding profile<ref name=pmid18480678>{{cite journal | vauthors = Markowitz JS, Patrick KS | title = Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: Does chirality matter? | journal = Journal of Clinical Psychopharmacology | volume = 28 | issue = 3 Suppl 2 | pages = S54–S61 | date = June 2008 | pmid = 18480678 | doi = 10.1097/JCP.0b013e3181733560 }}</ref><ref name=pmid17218796>{{cite journal | vauthors = Williard RL, Middaugh LD, Zhu HJ, Patrick KS | title = Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity | journal = Behavioural Pharmacology | volume = 18 | issue = 1 | pages = 39–51 | date = February 2007 | pmid = 17218796 | doi = 10.1097/fbp.0b013e3280143226 | s2cid = 20232871 }}</ref><ref name=pmid17201613>{{cite journal | vauthors = Markowitz JS, DeVane CL, Pestreich LK, Patrick KS, Muniz R | title = A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study | journal = Journal of Child and Adolescent Psychopharmacology | volume = 16 | issue = 6 | pages = 687–698 | date = December 2006 | pmid = 17201613 | doi = 10.1089/cap.2006.16.687 | s2cid = 22895177 }}</ref>
|-
! [[Biology:Neurotransmitter transporter|Neurotransmitter<br/>transporter]]
! Measure<br />(units)
! {{abbr|dl-MPH|d,l-threo-methylphenidate or racemic methylphenidate}}
! {{abbr|d-MPH|d-threo-methylphenidate or dexmethylphenidate}}
! {{abbr|l-MPH|l-threo-methylphenidate or levomethylphenidate}}
|-
|rowspan="2"| [[Biology:Dopamine transporter|DAT]]
| [[Chemistry:Dissociation constant|K<sub>i</sub>]] ({{abbrlink|nM|nanomolar}})
| 121
| 161
| 2250
|-
| [[Chemistry:IC50|IC<sub>50</sub>]] ({{abbr|nM|nanomolar}})
| 20
| 23
| 1600
|-
|rowspan="2"| [[Biology:Norepinephrine transporter|NET]]
| K<sub>i</sub> (nM)
| 788
| 206
| >10000
|-
| IC<sub>50</sub> (nM)
| 51
| 39
| 980
|-
|rowspan="2"| [[Biology:Serotonin transporter|SERT]]
| K<sub>i</sub> (nM)
| >10000
| >10000
| >6700
|-
| IC<sub>50</sub> (nM)
|style="text-align:center;"| <nowiki>—</nowiki>
| >10000
| >10000
|-
! GPCR
! Measure<br/>(units)
! {{abbr|dl-MPH|d,l-threo-methylphenidate or racemic methylphenidate}}
! {{abbr|d-MPH|d-threo-methylphenidate or dexmethylphenidate}}
! {{abbr|l-MPH|l-threo-methylphenidate or levomethylphenidate}}
|-
|rowspan="2"| [[Biology:5-HT1A receptor|5-HT<sub>1A</sub>]]
| [[Chemistry:Dissociation constant|K<sub>i</sub>]] ({{abbrlink|nM|nanomolar}})
| 5000
| 3400
| >10000
|-
| [[Chemistry:IC50|IC<sub>50</sub>]] ({{abbr|nM|nanomolar}})
| 10000
| 6800
| >10000
|-
|rowspan="2"| [[Biology:5-HT2B receptor|5-HT<sub>2B</sub>]]
| K<sub>i</sub> (nM)
| >10000
| 4700
| >10000
|-
| IC<sub>50</sub> (nM)
| >10000
| 4900
| >10000
|}

Methylphenidate primarily acts as a [[Chemistry:Norepinephrine–dopamine reuptake inhibitor|norepinephrine–dopamine reuptake inhibitor]] (NDRI). It is a [[Chemistry:2-Benzylpiperidine|benzylpiperidine]] and [[Biology:Phenethylamine|phenethylamine]] [[Chemistry:Derivative|derivative]] which also shares part of its basic structure with [[Biology:Catecholamine|catecholamine]]s.

Methylphenidate is a psychostimulant and increases the activity of the [[Biology:Central nervous system|central nervous system]] through inhibition on reuptake of the neurotransmitters [[Biology:Norepinephrine|norepinephrine]] and [[Biology:Dopamine|dopamine]]. As models of ADHD suggest, it is associated with functional impairments in some of the brain's neurotransmitter systems, particularly those involving dopamine in the [[Chemistry:Mesocortical pathway|mesocortical]] and [[Chemistry:Mesolimbic pathway|mesolimbic]] pathways and norepinephrine in the [[Biology:Prefrontal cortex|prefrontal cortex]] and locus coeruleus.<ref name=Malenka_2009_03/> Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the [[Biology:Synapse|synapse]] increase and last longer, respectively. Therefore, methylphenidate is called a norepinephrine–dopamine reuptake inhibitor.<ref name=pmid10440465/> By increasing the effects of norepinephrine and dopamine, methylphenidate increases the activity of the central nervous system and produces effects such as increased alertness, reduced fatigue, and improved attention.<ref name=Malenka_2009_03>{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE | year = 2009 | chapter = Chapter&nbsp;6: Widely projecting systems: Monoamines, acetylcholine, and orexin |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A foundation for clinical neuroscience | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 154–157 | edition = 2nd}}</ref><ref name=steele>{{cite journal | vauthors = Steele M, Weiss M, Swanson J, Wang J, Prinzo RS, Binder CE | title = A randomized, controlled effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in attention deficit-hyperactivity disorder | journal = The Canadian Journal of Clinical Pharmacology | volume = 13 | issue = 1 | pages = e50–e62 | year = 2006 | pmid = 16456216 | url = http://www.cjcp.ca/pdf/CJCP_05-012_e50.pdf | url-status = dead | archive-url = http://webarchive.nationalarchives.gov.uk/20111215210932/http%3A//www.cjcp.ca/CJCP_05%2D012_e50%2Dr101628 | archive-date = 15 December 2011 }}</ref>

Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE).<ref name="Heal DJ, Pierce DM 2006 713–38">{{cite journal | vauthors = Heal DJ, Pierce DM | title = Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system | journal = CNS Drugs | volume = 20 | issue = 9 | pages = 713–738 | year = 2006 | pmid = 16953648 | doi = 10.2165/00023210-200620090-00002 | s2cid = 39535277 }}</ref> Methylphenidate binds to and blocks [[Biology:Dopamine transporter|dopamine transporter]]s (DAT) and [[Biology:Norepinephrine transporter|norepinephrine transporter]]s (NET).<ref>{{cite journal | vauthors = Iversen L | title = Neurotransmitter transporters and their impact on the development of psychopharmacology | journal = British Journal of Pharmacology | volume = 147 | issue = Suppl 1 | pages = S82–S88 | date = January 2006 | pmid = 16402124 | pmc = 1760736 | doi = 10.1038/sj.bjp.0706428 }}</ref> Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that methylphenidate amplifies [[Medicine:Basal|basal]] dopamine activity, leading to nonresponse in those with low basal DA activity.<ref>{{cite journal | vauthors = Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ | title = Mechanism of action of methylphenidate: insights from PET imaging studies | journal = Journal of Attention Disorders | volume = 6 | issue = Suppl 1 | pages = S31–S43 | date = 1 January 2002 | pmid = 12685517 | doi = 10.1177/070674370200601s05 | s2cid = 9132302 }}</ref> On average, methylphenidate elicits a 3–4 times increase in dopamine and norepinephrine in the [[Biology:Striatum|striatum]] and [[Biology:Prefrontal cortex|prefrontal cortex]].<ref name="Hodgkins_2012">{{cite journal | vauthors = Hodgkins P, Shaw M, Coghill D, Hechtman L | title = Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options | journal = European Child & Adolescent Psychiatry | volume = 21 | issue = 9 | pages = 477–492 | date = September 2012 | pmid = 22763750 | pmc = 3432777 | doi = 10.1007/s00787-012-0286-5 }}</ref> [[Physics:Magnetic resonance imaging|Magnetic resonance imaging]] (MRI) studies suggest that long-term treatment with ADHD stimulants (specifically, [[Chemistry:Amphetamine|amphetamine]] and methylphenidate) decreases abnormalities in [[Biology:Human brain|brain]] structure and function found in subjects with ADHD.<ref name="Neuroplasticity 1">{{cite journal | vauthors = Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K | title = Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects | journal = JAMA Psychiatry | volume = 70 | issue = 2 | pages = 185–198 | date = February 2013 | pmid = 23247506 | doi = 10.1001/jamapsychiatry.2013.277 | doi-access = free }}</ref><ref name="Neuroplasticity 2">{{cite journal | vauthors = Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J | title = Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies | journal = The Journal of Clinical Psychiatry | volume = 74 | issue = 9 | pages = 902–917 | date = September 2013 | pmid = 24107764 | pmc = 3801446 | doi = 10.4088/JCP.12r08287 }}</ref><ref name="Neuroplasticity 3">{{cite journal | vauthors = Frodl T, Skokauskas N | title = Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects | journal = Acta Psychiatrica Scandinavica | volume = 125 | issue = 2 | pages = 114–126 | date = February 2012 | pmid = 22118249 | doi = 10.1111/j.1600-0447.2011.01786.x | s2cid = 25954331 | doi-access = free }}</ref>{{efn|
Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.<ref name="Neuroplasticity 3"/>
}}

Both [[Chemistry:Amphetamine|amphetamine]] and methylphenidate are predominantly [[Chemistry:Dopaminergic|dopaminergic]] drugs, yet their [[Chemistry:Mechanism of action|mechanisms of action]] are distinct. Methylphenidate acts as a norepinephrine–dopamine reuptake inhibitor, while amphetamine is both a releasing agent and [[Chemistry:Reuptake inhibitor|reuptake inhibitor]] of dopamine and norepinephrine. Methylphenidate's mechanism of action in the release of dopamine and norepinephrine is fundamentally different from most other [[Chemistry:Substituted phenethylamine|phenethylamine derivatives]], as methylphenidate is thought to increase neuronal [[Biology:Action potential#Neural firing rate|firing rate]],<ref name=pmid15303308>{{cite journal | vauthors = Viggiano D, Vallone D, Sadile A | title = Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling | journal = Neural Plasticity | volume = 11 | issue = 1–2 | pages = 97–114 | year = 2004 | pmid = 15303308 | pmc = 2565441 | doi = 10.1155/NP.2004.97 | doi-access = free }}</ref><ref>{{cite web | title = Focalin XR | url = https://www.rxlist.com/focalin-xr-drug.htm#description | work = RxList | access-date = 5 February 2020 | archive-date = 6 August 2020 | archive-url = https://web.archive.org/web/20200806185517/https://www.rxlist.com/focalin-xr-drug.htm#description | url-status = live }}</ref><ref>{{cite web | url = http://www.medicines.org.uk/emc/medicine/8380 | title = Concerta XL 18 mg – 54 mg prolonged release tablets | archive-url = https://web.archive.org/web/20171017010139/http://www.medicines.org.uk/emc/medicine/8380 | archive-date = 17 October 2017 | work = eMC}}</ref> whereas [[Chemistry:Amphetamine|amphetamine]] reduces firing rate, but causes [[Biology:Monoamine neurotransmitter|monoamine]] release by reversing the flow of the monoamines through [[Biology:Monoamine transporter|monoamine transporter]]s via a diverse set of mechanisms, including [[Biology:TAAR1|TAAR1]] activation and modulation of VMAT2 function, among other mechanisms.<ref name=Miller>{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–176 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref><ref name="E Weihe">{{cite journal | vauthors = Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Annals of the New York Academy of Sciences | volume = 1216 | issue = 1 | pages = 86–98 | date = January 2011 | pmid = 21272013 | pmc = 4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | bibcode = 2011NYASA1216...86E }}</ref>{{efn|
VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.<ref name="E Weihe"/>
}}<ref name="Amphetamine VMAT2 pH gradient">{{cite journal | vauthors = Sulzer D, Cragg SJ, Rice ME | title = Striatal dopamine neurotransmission: regulation of release and uptake | journal = Basal Ganglia | volume = 6 | issue = 3 | pages = 123–148 | date = August 2016 | pmid = 27141430 | pmc = 4850498 | doi = 10.1016/j.baga.2016.02.001}}</ref>{{efn|
Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.<ref name="Amphetamine VMAT2 pH gradient"/>
}}
The difference in mechanism of action between methylphenidate and amphetamine results in methylphenidate inhibiting amphetamine's effects on monoamine transporters when they are co-administered.<ref name=Miller/>{{better source needed|date=December 2022 |reason=need a better source for this statement - the cited source (Miller) discusses methylphenidate and methamphetamine, rather than amphetamine; the mechanism by which methylphenidate interacts with meth is the same for amph though}}

Methylphenidate has both [[Biology:Dopamine transporter|dopamine transporter]] and [[Biology:Norepinephrine transporter|norepinephrine transporter]] binding affinity, with the dextromethylphenidate [[Chemistry:Enantiomer|enantiomer]]s displaying a prominent affinity for the [[Biology:Norepinephrine transporter|norepinephrine transporter]].<ref>{{cite journal | vauthors = Liu F, Minami H, Silva RR | title = Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder | journal = Neuropsychiatric Disease and Treatment | volume = 2 | issue = 4 | pages = 467–473 | date = December 2006 | pmid = 19412495 | pmc = 2671958 | doi = 10.2147/nedt.2006.2.4.467 | doi-access = free }}</ref> Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the [[Chemistry:Serotonin|serotonergic]] [[Biology:5-HT1A receptor|5HT<sub>1A</sub>]] and [[Biology:5-HT2B receptor|5HT<sub>2B</sub>]] subtypes, though direct binding to the [[Biology:Serotonin transporter|serotonin transporter]] was not observed.<ref name=pmid17201613/> A later study confirmed the d-threo-methylphenidate ([[Chemistry:Dexmethylphenidate|dexmethylphenidate]]) binding to the 5HT<sub>1A</sub> receptor, but no significant activity on the 5HT<sub>2B</sub> receptor was found.<ref>{{cite journal | vauthors = Markowitz JS, DeVane CL, Ramamoorthy S, Zhu HJ | title = The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor | journal = Die Pharmazie | volume = 64 | issue = 2 | pages = 123–125 | date = February 2009 | pmid = 19322953 }}</ref>

There exist some paradoxical findings that oppose the notion that methylphenidate acts as silent antagonist of the DAT (DAT inhibitor).<ref name="Volkow_1996" /> 80% occupancy of the DAT is necessary for methylphenidate's euphoriant effect, but re-administration of methylphenidate beyond this level of DAT occupancy has been found to produce similarly potent euphoriant effects (despite DAT occupancy being unchanged with repeated administration).<ref name="Volkow_1996">{{cite journal |vauthors=Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Ding YS, Logan J, Dewey SL, Hitzemann R, Lieberman J |date=September 1996 |title=Relationship between psychostimulant-induced "high" and dopamine transporter occupancy |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=93 |issue=19 |pages=10388–10392 |bibcode=1996PNAS...9310388V |doi=10.1073/pnas.93.19.10388 |pmc=38394 |pmid=8816810 |doi-access=free}}</ref> By contrast, other DAT inhibitors such as [[Chemistry:Bupropion|bupropion]] have not been observed to exhibit this effect.<ref>{{cite journal |vauthors=Shoptaw S, Heinzerling KG, Rotheram-Fuller E, Steward T, Wang J, Swanson AN, De La Garza R, Newton T, Ling W |date=August 2008 |title=Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence |journal=Drug and Alcohol Dependence |volume=96 |issue=3 |pages=222–232 |doi=10.1016/j.drugalcdep.2008.03.010 |pmc=3652530 |pmid=18468815}}</ref> These observations have prompted the hypothesis that methylphenidate may act as a "DAT inverse agonist" or "negative allosteric modifier of the DAT" by reversing the direction of the dopamine efflux by the DAT at higher dosages.<ref>{{cite journal |vauthors=Heal DJ, Gosden J, Smith SL |date=December 2014 |title=Dopamine reuptake transporter (DAT) "inverse agonism" – a novel hypothesis to explain the enigmatic pharmacology of cocaine |journal=Neuropharmacology |volume=87 |pages=19–40 |doi=10.1016/j.neuropharm.2014.06.012 |pmid=24953830 |s2cid=4660652}}</ref>

Methylphenidate may [[Biology:Neuroprotection|protect neurons]] from the neurotoxic effects of [[Medicine:Parkinson's disease|Parkinson's disease]] and [[Chemistry:Methamphetamine|methamphetamine]] use disorder.<ref name=Volz2008>{{cite journal | vauthors = Volz TJ | title = Neuropharmacological mechanisms underlying the neuroprotective effects of methylphenidate | journal = Current Neuropharmacology | volume = 6 | issue = 4 | pages = 379–385 | date = December 2008 | pmid = 19587858 | pmc = 2701286 | doi = 10.2174/157015908787386041 }}</ref> The hypothesized mechanism of neuroprotection is through inhibition of methamphetamine–DAT interactions, and through reducing cytosolic dopamine, leading to decreased production of dopamine-related [[Biology:Reactive oxygen species|reactive oxygen species]].<ref name=Volz2008/>

The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.<ref name="Heal DJ, Pierce DM 2006 713–38"/> The studied maximized daily dosage of OROS methylphenidate appears to be 144&nbsp;mg/day.<ref name="Drugs.com 2018">{{cite web | title=Concerta | website=Drugs.com | date=1 October 2018 | url=https://www.drugs.com/pro/concerta.html | access-date=11 March 2019 | archive-url=https://web.archive.org/web/20180929171112/https://www.drugs.com/pro/concerta.html | archive-date=29 September 2018 | url-status=live }}</ref>

=== Pharmacokinetics ===
Methylphenidate taken by mouth has a [[Chemistry:Bioavailability|bioavailability]] of 11–52% with a duration of action around 2–4&nbsp;hours for instant-release (i.e. Ritalin), 3–8&nbsp;hours for sustained-release (i.e. Ritalin SR), and 8–12&nbsp;hours for extended-release (i.e. Concerta). The [[Biology:Biological half-life|half-life]] of methylphenidate is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours.<ref name=pmid10628897>{{cite journal | vauthors = Kimko HC, Cross JT, Abernethy DR | title = Pharmacokinetics and clinical effectiveness of methylphenidate | journal = Clinical Pharmacokinetics | volume = 37 | issue = 6 | pages = 457–470 | date = December 1999 | pmid = 10628897 | doi = 10.2165/00003088-199937060-00002 | s2cid = 397390 }}</ref> Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65&nbsp;L/kg.<ref name="Ritalin LA FDA label"/>

Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.<ref name=pmid10628897/>

The oral [[Chemistry:Bioavailability|bioavailability]] and speed of absorption for immediate-release methylphenidate is increased when administered with a meal.<ref>{{cite journal | vauthors = Chan YP, Swanson JM, Soldin SS, Thiessen JJ, Macleod SM, Logan W | title = Methylphenidate hydrochloride given with or before breakfast: II.&nbsp;Effects on plasma concentration of methylphenidate and ritalinic acid | journal = Pediatrics | volume = 72 | issue = 1 | pages = 56–59 | date = July 1983 | pmid = 6866592 | doi = 10.1542/peds.72.1.56 | s2cid = 28806553 | url = https://escholarship.org/uc/item/9gv7p39v | access-date = 12 December 2021 | archive-date = 17 December 2021 | archive-url = https://web.archive.org/web/20211217003134/https://escholarship.org/uc/item/9gv7p39v | url-status = live }}</ref> The effects of a high fat meal on the observed [[Medicine:Cmax (pharmacology)|C<sub>max</sub>]] differ between some extended-release formulations, with combined IR/ER and OROS formulations showing reduced C<sub>max</sub> levels<ref>{{cite web | title=Cotempla XR-ODT- methylphenidate tablet, orally disintegrating | website=DailyMed | date=1 July 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=33f70f58-c871-42c8-8adb-345caeafefcd | access-date=25 May 2022 | archive-date=26 May 2022 | archive-url=https://web.archive.org/web/20220526063140/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=33f70f58-c871-42c8-8adb-345caeafefcd | url-status=live }}</ref> while liquid-based extended-release formulations showed increased C<sub>max</sub> levels when administered with a high-fat meal, according to some researchers.<ref>{{cite web | title=Quillivant XR- methylphenidate hydrochloride suspension, extended release | website=DailyMed | date=30 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c2dc2109-44a6-4797-b04e-18761dd9d45a | access-date=26 May 2022 | archive-date=26 May 2022 | archive-url=https://web.archive.org/web/20220526063140/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c2dc2109-44a6-4797-b04e-18761dd9d45a | url-status=live }}</ref> A 2003 study, however, showed no difference between a high-fat meal administration and a fasting administration of oral methylphenidate.<ref>{{cite journal | vauthors = Lee L, Kepple J, Wang Y, Freestone S, Bakhtiar R, Wang Y, Hossain M | title = Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce | journal = Biopharmaceutics & Drug Disposition | volume = 24 | issue = 6 | pages = 233–243 | date = September 2003 | pmid = 12973820 | doi = 10.1002/bdd.358 | s2cid = 29609987 }}</ref>

Methylphenidate is metabolized into [[Chemistry:Ritalinic acid|ritalinic acid]] by [[Biology:Carboxylesterase 1|CES1A1]] enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate.<ref name=pmid15082749>{{cite journal | vauthors = Sun Z, Murry DJ, Sanghani SP, Davis WI, Kedishvili NY, Zou Q, Hurley TD, Bosron WF | title = Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 2 | pages = 469–476 | date = August 2004 | pmid = 15082749 | doi = 10.1124/jpet.104.067116 | s2cid = 24233422 }}</ref> 97% of the metabolised drug is excreted in the urine, and between 1 and 3% is excreted in the faeces. A small amount, less than 1%, of the drug is excreted in the urine in its unchanged form.<ref name="Ritalin LA FDA label"/>

== Chemistry ==
{{see also|List of methylphenidate analogues}}Despite the claim made by some urban legends, it is not a [[Biology:Cocaine|cocaine]] derivative nor analog; cocaine is a [[Medicine:Local anesthetic|local anesthetic]] and ligand channel blocker with SNDRI action, while methylphenidate is an [[Chemistry:Norepinephrine–dopamine reuptake inhibitor|NDRI]] with 2–3&nbsp;fold selectivity for the [[Biology:Dopamine transporter|dopamine transporter]] (DAT) over the [[Biology:Norepinephrine transporter|norepinephrine transporter]] (NET). Cocaine is also more potent in [[Biology:Serotonin transporter|serotonin transporter]]s (SERTs) than NDRI sites.<ref>{{cite book |url=https://books.google.com/books?id=Yu9eBwAAQBAJ&pg=PA651 |title=Neuropathology of Drug Addictions and Substance Misuse |vauthors=Preedy VR |date=2016 |publisher=Academic Press |isbn=9780128006771 |volume=3: General processes and mechanisms, prescription medications, caffeine and areca, polydrug misuse, emerging addictions, and non-drug addictions |page=651 |access-date=19 December 2018 |archive-url=https://web.archive.org/web/20210829151101/https://books.google.com/books?id=Yu9eBwAAQBAJ&pg=PA651 |archive-date=29 August 2021 |url-status=live}}</ref><ref name="Systematic 2014 - Amph, MPH, Modafinil">{{cite journal |vauthors=Bagot KS, Kaminer Y |date=April 2014 |title=Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: A systematic review |journal=Addiction |volume=109 |issue=4 |pages=547–557 |doi=10.1111/add.12460 |pmc=4471173 |pmid=24749160}}</ref>

Four [[Chemistry:Isomer|isomer]]s of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects.<ref name="Heal DJ, Pierce DM 2006 713–38"/><ref>{{cite journal | vauthors = Froimowitz M, Patrick KS, Cody V | title = Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT | journal = Pharmaceutical Research | volume = 12 | issue = 10 | pages = 1430–1434 | date = October 1995 | pmid = 8584475 | doi = 10.1023/A:1016262815984 | s2cid = 26097197 }}</ref> The erythro [[Chemistry:Diastereomer|diastereomer]]s are ''pressor'' amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1&nbsp;mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as [[Chemistry:Dexmethylphenidate|dexmethylphenidate]], d-MPH, or d-threo-methylphenidate. A review on the synthesis of [[Physics:Enantiopure drug|enantiomerically pure]] (2''R'',2'''R'')-(+)-''threo''-methylphenidate hydrochloride has been published.<ref name=Prashad>{{cite journal | doi =10.1002/1615-4169(200107)343:5<379::AID-ADSC379>3.0.CO;2-4| vauthors = Prashad M | year = 2001 | title = Approaches to the Preparation of Enantiomerically Pure (2R,2{{prime}}R)-(+)-threo-Methylphenidate Hydrochloride | journal = Adv. Synth. Catal. | volume = 343 | issue = 5 | pages = 379–392 }}</ref>

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|image1=Methylphenidate axten.png
|width1=750
|caption1=Method 1: Methylphenidate preparation elucidated by Axten ''et al.'' (1998)<ref>{{cite journal | doi = 10.1021/jo982214t | title = A Stereoselective Synthesis ofdl-threo-Methylphenidate: Preparation and Biological Evaluation of Novel Analogues | year = 1998 |vauthors=Axten JM, Krim L, Kung HF, Winkler JD | journal = The Journal of Organic Chemistry | volume = 63 | issue = 26 | pages = 9628–9629 }}</ref> via Bamford-Stevens reaction.
|alt1=Methylphenidate synthesis graphic

|image2=Methylphenidate classic2.png
|width2=750
|caption2=Method 2: Classic methylphenidate synthesis<ref name=erowid>{{cite journal | vauthors = Singh S | title = Chemistry, design, and structure-activity relationship of cocaine antagonists | journal = Chemical Reviews | volume = 100 | issue = 3 | pages = 925–1024 | date = March 2000 | pmid = 11749256 | doi = 10.1021/cr9700538 }}</ref>
|alt2=Methylphenidate synthesis graphic
}}

=== Detection in biological fluids ===

The concentration of methylphenidate or [[Chemistry:Ritalinic acid|ritalinic acid]], its major [[Biology:Metabolite|metabolite]], may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.<ref>{{cite book |veditors=Baselt R |year=2011 |title=Disposition of Toxic Drugs and Chemicals in Man |edition=9th |publisher=Biomedical Publications |place=Seal Beach, CA |pages=1091–1093}}</ref>

== History ==
Methylphenidate was first [[Chemistry:Chemical synthesis|synthesized]] in 1944 and was approved for medical use in the United States in 1955.<ref name=Lang2010>{{cite journal | vauthors = Lange KW, Reichl S, Lange KM, Tucha L, Tucha O | date = December 2010 | title = The history of attention deficit hyperactivity disorder | journal = Attention Deficit and Hyperactivity Disorders | volume = 2 | issue = 4 | pages = 241–255 | pmid = 21258430 | pmc = 3000907 | doi = 10.1007/s12402-010-0045-8 }}</ref><ref name=pmid27409720>{{cite journal | vauthors = Wenthur CJ | title = Classics in chemical neuroscience: Methylphenidate | journal = ACS Chem Neurosci | volume = 7 | issue = 8 | pages = 1030–1040 | date = August 2016 | pmid = 27409720 | doi = 10.1021/acschemneuro.6b00199 | url = }}</ref><ref name="Panizzon1944">{{cite journal| author = Panizzon L | title = La preparazione di piridile piperidil-arilacetonitrili e di alcuni prodotti di trasformazione (Parte Ia) | journal = Helvetica Chimica Acta | volume = 27 | pages = 1748–1756 | year = 1944 | doi = 10.1002/hlca.194402701222}}</ref> It was synthesized by chemist Leandro Panizzon and sold by Swiss company CIBA (now [[Company:Novartis|Novartis]]).<ref name=Lang2010/> He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure.<ref>{{cite book |vauthors=Myers RL |date=1 January 2007 |title=The 100&nbsp;Most Important Chemical Compounds: A reference guide |publisher=ABC-CLIO |isbn=9780313337581 |page=178 |url=https://books.google.com/books?id=a4DuGVwyN6cC&q=named+ritalin+after+his+wife&pg=PA178 |url-status=live |via=Google Books |access-date=24 September 2016 |archive-url=https://web.archive.org/web/20170202064317/https://books.google.com/books?id=a4DuGVwyN6cC&pg=PA178&lpg=PA178&dq=named+ritalin+after+his+wife#v=onepage&q=named%20ritalin%20after%20his%20wife&f=false |archive-date=2 February 2017}}</ref> Methylphenidate was not reported to be a stimulant until 1954.<ref name=pmid16953648>{{cite journal | vauthors = Heal DJ, Pierce DM | date = 2006 | title = Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system | journal = CNS Drugs | volume = 20 | issue = 9 | pages = 713–738 | pmid = 16953648 | doi = 10.2165/00023210-200620090-00002 | s2cid = 39535277}}</ref><ref name=pmid13164273>{{cite journal | vauthors = Meier R, Gross F, Tripod J | date = May 1954 | title = Ritalin, eine neuartige synthetische Verbindung mit spezifischer zentralerregender Wirkungskomponente | language = de | trans-title = Ritalin, a new synthetic compound with specific analeptic components | journal = Klinische Wochenschrift | volume = 32 | issue = 19–20 | pages = 445–450 | pmid = 13164273 | doi = 10.1007/BF01466968 | s2cid = 24516999 }}</ref> The drug was introduced for medical use in the United States in 1957.<ref name=pmid24344115>{{cite journal | vauthors = Wood S, Sage JR, Shuman T, Anagnostaras SG | date = 2014 | title = Psychostimulants and cognition: A continuum of behavioral and cognitive activation | journal = Pharmacol Rev | volume = 66 | issue = 1 | pages = 193–221 | pmid = 24344115 | pmc = 3880463 | doi = 10.1124/pr.112.007054}}</ref> Originally, it was marketed as a [[Physics:Mixture|mixture]] of two racemates, 80% (±)-erythro and 20% (±)-threo, under the brand name Centedrin.<ref name=pmid16953648/> Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer.<ref name=pmid16953648/><ref>{{cite patent | country = US | number = 2507631 | inventor = Hartmann, M.; Panizzon, L. | gdate = 16 May 1950 | title = Pyridine and piperidine compounds and process of making same | assign1 = CIBA Pharmaceutical Products, Inc}}</ref><ref>{{cite patent | country = US | number = 2838519 | inventor = Rouietscji, R. | gdate = 10 June 1958 | title = Process for the conversion of stereoisomers | assign1 = CIBA Pharmaceutical Products, Inc}}</ref><ref>{{cite patent | country = US | number = 2957880 |inventor = Rouietscji,  R. | gdate = 25 October 1960 | title = Process for the conversion of stereoisomers | assign1 = CIBA Pharmaceutical Products, Inc}}</ref> The erythro isomer was eliminated, and now modern formulations of methyphenidate contain only the threo isomer in a 50:50&nbsp;mixture of ''d''- and ''l''-isomers.<ref name=pmid16953648/>

Methylphenidate was first used to allay [[Chemistry:Barbiturate|barbiturate]]-induced coma, narcolepsy and depression.<ref name=Meyers-2007>{{cite book | vauthors = Myers RL |date=August 2007 |title=The 100&nbsp;Most Important Chemical Compounds: A reference guide |publisher=ABC-CLIO |isbn=978-0-313-33758-1 |url=https://archive.org/details/100mostimportant0000myer |url-access=registration |access-date=10 September 2010 |page=[https://archive.org/details/100mostimportant0000myer/page/178 178] |quote=...&nbsp;named ritalin after his wife&nbsp;...}}</ref> It was later used to treat memory deficits in the elderly.<ref>{{cite book | vauthors = Stolerman I | year = 2010 | title = Encyclopedia of Psychopharmacology | publisher = Springer | location = Berlin, DE / London, UK | isbn = 978-3540686989 | page = 763}}</ref> Beginning in the 1960s, it was used to treat children with ADHD based on earlier work, starting with the studies by American psychiatrist Charles Bradley<ref>{{cite report |vauthors = McCrossin S |year = 1995 |title=Ritalin and attention deficit disorder: History of its use, effects, and side effects |url=http://www.crossinology.com/pdf/RITALINus.pdf |access-date=22 July 2014 |url-status=dead |archive-url=https://web.archive.org/web/20120824105824/http://www.crossinology.com/pdf/RITALINus.pdf |archive-date=24 August 2012 }}</ref> on the use of psychostimulant drugs, such as Benzedrine, with then called "maladjusted children".<ref name=Bradley_1950>{{cite journal | vauthors = Bradley C | date = January 1950 | title = Benzedrine and dexedrine in the treatment of children's behavior disorders | journal = Pediatrics | volume = 5 | issue = 1 | pages = 24–37 | pmid = 15404645 | doi = 10.1542/peds.5.1.24 | s2cid = 45655000 }}</ref> Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.<ref>{{cite report | vauthors = Woodworth T |date=16 May 2000 |title=DEA Congressional Testimony |publisher=U.S. [[Organization:Drug Enforcement Administration|Drug Enforcement Administration]] |url=http://www.dea.gov/pubs/cngrtest/ct051600.htm |access-date=2 November 2007 |url-status=dead |archive-url=https://web.archive.org/web/20071012061712/http://www.dea.gov/pubs/cngrtest/ct051600.htm |archive-date=12 October 2007 }}</ref>

In 2000, Alza Corporation received US FDA approval to market Concerta, an extended-release form of methylphenidate.<ref name="Concerta FDA label"/><ref>{{cite web | title=Drug Approval Package: Concerta (methylphenidate HCI) NDA #21-121 | date=24 December 1999 | website=fda.gov | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-121_Concerta.cfm | access-date=26 March 2022 | url-status=live | archive-url=https://web.archive.org/web/20220327053311/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-121_Concerta.cfm | archive-date=27 March 2022}}</ref><ref>{{cite web | title = Newly Approved Drug Therapies (637) Concerta, Alza | website = CenterWatch | url = http://www.centerwatch.com/drug-information/fda-approvals/drug-details.aspx?DrugID=637 | url-status = dead | access-date = 30 April 2011 | archive-url = https://web.archive.org/web/20101216171133/http://centerwatch.com/drug-information/fda-approvals/drug-details.aspx?DrugID=637 | archive-date = 16 December 2010}}</ref>

It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012.<ref name=PJ2015>{{cite journal |title=Narcotics monitoring board reports 66% increase in global consumption of methylphenidate |journal=The Pharmaceutical Journal|publisher=Royal Pharmaceutical Society |url=https://www.pharmaceutical-journal.com/news-and-analysis/news-in-brief/narcotics-monitoring-board-reports-66-increase-in-global-consumption-of-methylphenidate/20068042.article?firstPass=false |access-date=19 December 2018 |date=4 March 2015|volume=294|issue=7853|doi= 10.1211/PJ.2015.20068042 |archive-url=https://web.archive.org/web/20181219230236/https://www.pharmaceutical-journal.com/news-and-analysis/news-in-brief/narcotics-monitoring-board-reports-66-increase-in-global-consumption-of-methylphenidate/20068042.article?firstPass=false |archive-date=19 December 2018 |url-status=live }}</ref> In 2021, it was the 43rd most commonly prescribed medication in the United States, with more than 15{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title=Methylphenidate - Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/Methylphenidate | access-date=14 January 2024 }}</ref> It is available as a generic medication.<ref name="AHFS2018"/>

==Society and culture==
=== Names ===
<gallery widths="180px" heights="180px">
Ritalin Methylphenidat.jpg | Swiss "Ritalin" brand methylphenidate.
Add Wize Methylphenidate.jpg | Indian "AddWize" branded instant-release and extended-release formulations costing US$1.9 for a strip of instant-release and US$2.9 for a strip of AddWize extended-release.
Methylphenidate Formulations.jpg | Clockwise from top: Concerta 18&nbsp;mg, Medikinet 5&nbsp;mg, Methylphenidat TAD 10&nbsp;mg, Ritalin 10&nbsp;mg, Medikinet&nbsp;XL 30&nbsp;mg.
</gallery>
Methylphenidate is sold in the majority of countries worldwide.<ref name=":0">{{cite report |vauthors=Moscibrodzki P, Katz C |date=8 December 2018 |title=Application for inclusion to the 22nd&nbsp;expert committee on the selection and use of essential medicines: Methylphenidate hydrochloride |publisher=[[Organization:World Health Organization|World Health Organization]] |url=https://www.who.int/selection_medicines/committees/expert/22/applications/s24_methylphenidate.pdf |access-date=16 November 2019 |archive-date=6 August 2020 |archive-url=https://web.archive.org/web/20200806210756/https://www.who.int/selection_medicines/committees/expert/22/applications/s24_methylphenidate.pdf |url-status=live}}</ref>{{rp|8–9}} Brand names for methylphenidate include Ritalin (in honor of Rita, the wife of the molecule discoverer), Rilatine (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta,<ref name="Concerta FDA label"/> Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Konsenidat, Equasym, Foquest,<ref>{{cite report |title=Foquest: Methylphenidate hydrochloride controlled release capsules |series=Product Monograph |type=vers.&nbsp;E |date=1 March 2019 |publisher=Purdue Pharma |place=Pickering, Ontario, Canada |via=caddra.ca |id=Submission Control Nr&nbsp;214860 |url=https://www.caddra.ca/wp-content/uploads/FOQUEST-Product-Monograph-E-01Mar2019.pdf |access-date=14 December 2022}}</ref> Methylin, Penid, Phenida, Prohiper, and Tradea.<ref name=":0"/>{{rp|8–9}}

=== Available forms ===
The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade in both an immediate-release and an extended-release form. There is some evidence that dexmethylphenidate has better bioavailability and a longer duration of action than methylphenidate.<ref>{{cite journal | vauthors = Liu F, Minami H, Silva RR | title = Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder | journal = Neuropsychiatric Disease and Treatment | volume = 2 | issue = 4 | pages = 467–473 | date = December 2006 | pmid = 19412495 | pmc = 2671958 | doi = 10.2147/nedt.2006.2.4.467 | doi-access = free }}</ref>

==== Immediate-release ====
<gallery widths="250px" heights="150px">
Structural formula for Concerta.jpg | [[Chemistry:Structural formula|Structural formula]] for the substance among Ritalin tablet series. (Ritalin, Ritalin LA, Ritalin SR.) The volume of distribution was 2.65±1.11 L/kg for d-methylphenidate and 1.80±0.91 L/kg for l-methylphenidate subsequent to swallow of Ritalin tablet.<ref name="Ritalin FDA label"/>
Structural formula for Concerta.jpg | Structural formula for the substance inside Concerta tablet. Following administration of Concerta, plasma concentrations of the l-isomer were approximately&nbsp;{{sfrac|1|40}} the plasma concentrations of the d-isomer.<ref name="Concerta FDA label"/> Note that the substance is the same as for Concerta - the differences lies in other aspects of the individual pills.
</gallery>
Methylphenidate was originally available as an immediate-release racemic mixture formulation under the Novartis brand name Ritalin, although a variety of generics are available, some under other brand names. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, Tranquilyn, and Rubifen.{{citation needed|date=May 2022}}

==== Extended-release ====
Extended-release methylphenidate products include:
{| border="1" class="wikitable" style="width:575px;"<!-- Note that a modified version of this table is in use on https://en.wikipedia.org/wiki/Attention_deficit_hyperactivity_disorder_management#Methylphenidate -->
|-
! Brand name(s)
! Generic name(s)<ref>
{{cite web |title=Education / training |series=Clinical resources |website=Illinois DocAssist |publisher=University of Illinois |place=Chicago, IL |url=http://www.psych.uic.edu/docassist/ClinicalResources.html |url-status=dead |access-date=26 July 2012 |archive-url=https://web.archive.org/web/20130101125300/http://www.psych.uic.edu/docassist/ClinicalResources.html |archive-date=1 January 2013 |quote=Ritalin‑SR, methylphenidate&nbsp;SR, Methylin&nbsp;ER, and Metadate&nbsp;ER are the same formulation and have the same drug delivery system}}
</ref><ref>
</ref><ref>
{{cite press release |title=New product: Sandoz methylphenidate&nbsp;SR 20&nbsp;mg |publisher=Sandoz Canada Inc |url=http://www.rxbriefcase.com/rxNow/Archive/Sandoz/506_Methylphenidate%20SR%20launch%20Fax_EN.pdf |url-status=live |access-date=26 July 2012 |date=5 May 2009 |quote=An alternative to Ritalin‑SR from Novartis |archive-url=https://web.archive.org/web/20121203062249/http://www.rxbriefcase.com/rxNow/Archive/Sandoz/506_Methylphenidate%20SR%20launch%20Fax_EN.pdf |archive-date=3 December 2012}}
</ref><ref name=usfda-drugdb>
</ref>
! Duration
! Dosage<br/>form
|-
| Aptensio&nbsp;XR&nbsp;(US);<br/>Biphentin&nbsp;(CA)
| {{No2|Currently unavailable}}
| 12&nbsp;hours<ref name=pmid19881943>
{{cite journal | vauthors = Hosenbocus S, Chahal R | title = A review of long-acting medications for ADHD in Canada | journal = Journal of the Canadian Academy of Child and Adolescent Psychiatry | volume = 18 | issue = 4 | pages = 331–339 | date = November 2009 | pmid = 19881943 | pmc = 2765387 }}
</ref><ref>
{{cite web |url=http://www.aptensioxr.com/resources/full-prescribing-information.pdf |title=Aptensio XR Prescribing Information |access-date=15 April 2017 |archive-url=https://web.archive.org/web/20170202000406/http://www.aptensioxr.com/resources/full-prescribing-information.pdf |archive-date=2 February 2017 |url-status=live}}</ref>
|style="text-align:center;"| [[Medicine:Modified-release dosage|{{abbr|XR|extended-release}}]]<br />capsule
|-
| Concerta&nbsp;(US/CA/AU);<br/>Concerta&nbsp;XL&nbsp;(UK)
| methylphenidate&nbsp;ER (US/CA);{{efn|group=lower-roman|US generic manufactured by [[Company:Actavis|Actavis]]; CA generics manufactured by Pharmascience and Apotex.}}<br/>methylphenidate&nbsp;ER‑C (CA){{efn|group=lower-roman|Manufactured by [[Company:Teva Pharmaceutical Industries|Teva]].}}
| 12&nbsp;hours<ref name=Moses>{{cite web |vauthors = Moses S |date=26 July 2009 |title=Methylphenidate |website=Family Practice Notebook |url=http://www.fpnotebook.com/peds/Pharm/Mthylphndt.htm |access-date=7 August 2012 |url-status=live |archive-url=https://web.archive.org/web/20120914020554/http://www.fpnotebook.com/Peds/Pharm/Mthylphndt.htm |archive-date=14 September 2012}}</ref>
|style="text-align:center;"| [[Medicine:Osmotic-controlled release oral delivery system|{{abbr|OROS|Osmotic [Controlled] Release Oral [Delivery] System}}]]<br/>tablet
|-
| Quillivant&nbsp;XR&nbsp;(US)
| {{No2|Currently unavailable}}
| 12&nbsp;hours<ref name=Moses/>
|style="text-align:center;"| oral<br/>[[Chemistry:Suspension|suspension]]
|-
| Daytrana&nbsp;(US)
| methylphenidate film, extended release;transdermal (US){{efn|group=lower-roman|Manufactured by Mylan Tech Viatris}}
| 11&nbsp;hours<ref>{{cite web |title=Daytrana transdermal |url=http://www.webmd.com/drugs/2/drug-144192/daytrana+transdermal/details |publisher=WebMD |access-date=11 June 2015 |archive-url=https://web.archive.org/web/20150611051920/http://www.webmd.com/drugs/2/drug-144192/daytrana+transdermal/details |archive-date=11 June 2015 |url-status=live}}</ref>
|style="text-align:center;"| [[Medicine:Transdermal patch|transdermal<br />patch]]
|-
| Metadate&nbsp;CD&nbsp;(US);<br/>Equasym&nbsp;XL (UK)
| methylphenidate&nbsp;ER&nbsp;(US){{efn|group=lower-roman|Manufactured by Impax, [[Company:Mallinckrodt|Mallinckrodt]], and [[Company:Teva Pharmaceutical Industries|Teva]].}}
| 8–10&nbsp;hours<ref name=Moses/>
|style="text-align:center;"| [[Medicine:Modified-release dosage|{{abbr|CD/XL|controlled-delivery/extended-release}}]]<br />capsule
|-
| QuilliChew&nbsp;ER (US)
| {{No2|Currently unavailable}}
| 8&nbsp;hours<ref>{{cite press release |title=Quillichew ER (methylphenidate HCl extended-release chewable tablets CII) |website=Pfizer Medical Information (pfizermedicalinformation.com) |publisher=Pfizer |place=U.S. |url=https://www.pfizermedicalinformation.com/en-us/quillichew-er |url-status=dead |access-date=16 April 2017 |archive-url=https://web.archive.org/web/20170416125833/https://www.pfizermedicalinformation.com/en-us/quillichew-er |archive-date=16 April 2017}}</ref>
|style="text-align:center;"| chewable<br/>tablet
|-
| Ritalin&nbsp;LA&nbsp;(US/AU);<br />Medikinet&nbsp;XL&nbsp;(UK)
| methylphenidate&nbsp;ER&nbsp;(US){{efn|group=lower-roman|Manufactured by Barr and Mayne.}}
| 8&nbsp;hours<ref name=Moses/>
|style="text-align:center;"| [[Medicine:Modified-release dosage|{{abbr|ER|extended-release}}]]<br/>capsule
|-
| Ritalin&nbsp;SR&nbsp;(US/CA/UK);<br/>Rubifen&nbsp;SR&nbsp;(NZ)
| Metadate&nbsp;ER&nbsp;(US);{{efn|group=lower-roman|Manufactured by UCB.}}<br/>Methylin&nbsp;ER&nbsp;(US);{{efn|group=lower-roman|Manufactured by [[Company:Mallinckrodt|Mallinckrodt]].}}<br/>methylphenidate&nbsp;SR&nbsp;(US/CA){{efn|group=lower-roman|US generics manufactured by County Line Pharmaceuticals and Abhai; CA generic manufactured by Apotex.}}
| 5–8&nbsp;hours<ref name=Moses/>
|style="text-align:center;"| {{abbr|CR|controlled-release}}<br/>tablet
|-
|colspan="4"| {{notelist|colwidth=12em|group=lower-roman}}
|}

Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the dosage strength in milligrams. Approximately 22% of the dose is immediate-release,<ref>{{cite web | url = http://pediatrics.about.com/cs/adhd/a/concerta.htm | title = Concerta for Kids with ADHD | archive-url = https://web.archive.org/web/20110107153016/http://pediatrics.about.com/cs/adhd/a/concerta.htm | archive-date= 7 January 2011 | work = Pediatrics.about.com | date = 1 April 2003}}</ref> and the remaining 78% of the dose is released over 10–12&nbsp;hours post-ingestion, with an initial increase over the first 6–7&nbsp;hours, and subsequent decline in the released drug.<ref>{{cite web | url = http://www.rxlist.com/concerta-drug.htm | title = Concerta (methylphenidate extended-release tablets) |series=Drug information: User reviews, side effects, drug interactions, and dosage | work = RxList | archive-url = https://web.archive.org/web/20110326160650/http://www.rxlist.com/concerta-drug.htm |archive-date=26 March 2011 | access-date = 30 April 2011}}</ref>

Ritalin&nbsp;LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. Ritalin&nbsp;LA<ref name="Ritalin Rx info"/> provides two standard doses – half the total dose being released immediately and the other half released four hours later. In total, each capsule is effective for about eight hours.

Metadate&nbsp;CD capsules contain two types of beads: 30% are immediate-release, and the other 70% are evenly sustained release.<ref>{{cite web | url = http://adhd.emedtv.com/metadate-cd/metadate-cd.html | title = Metadate&nbsp;CD | archive-url = https://web.archive.org/web/20110710185835/http://adhd.emedtv.com/metadate-cd/metadate-cd.html | archive-date=10 July 2011 }}</ref>

Medikinet Retard/CR/Adult/Modified Release tablets are an extended-release oral capsule form of methylphenidate. It delivers 50% of the dosage as IR MPH and the remaining 50% in 3–4 hours.<ref>{{cite journal | vauthors = Coghill D, Banaschewski T, Zuddas A, Pelaz A, Gagliano A, Doepfner M | title = Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies | journal = BMC Psychiatry | volume = 13 | pages = 237 | date = September 2013 | pmid = 24074240 | pmc = 3852277 | doi = 10.1186/1471-244X-13-237 | doi-access = free }}</ref><ref>{{cite web |title=UK Report on Ritalin |url=https://mhraproductsproduction.blob.core.windows.net/docs/4781baf366b1fafd0ea203962ccb54faadcdcfcc |access-date=9 January 2024 |page=9}}</ref>

====Skin patch====
A methylphenidate [[Medicine:Transdermal patch|skin patch]] is sold under the brand name Daytrana in the United States. It was developed and marketed by Noven Pharmaceuticals and approved in the US in 2006.<ref name="Daytrana FDA label"/> It is also referred to as methylphenidate [[Medicine:Transdermal|transdermal]] system (MTS). It is approved as a once-daily treatment in children with ADHD aged 6–17&nbsp;years. It is mainly prescribed as a second-line treatment when oral forms are not well tolerated, or if people have difficulty with compliance. Noven's original FDA submission indicated that it should be used for 12&nbsp;hours. When the FDA rejected the submission, they requested evidence that a shorter time period was safe and effective; Noven provided such evidence, and it was approved for a 9-hour period.<ref>{{cite report |title=Methylphenidate transdermal system (MTS) |date=24 October 2005 |type=safety summary |id={{nowrap|NDA No. 21-514}}, Appendix&nbsp;3 |publisher=Noven Pharmaceuticals |via=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] |url=http://www.fda.gov/ohrms/dockets/AC/05/briefing/2005-4195B1_01_04-Noven-Appendix-3.pdf |url-status=dead |access-date=17 January 2022 |archive-url=https://web.archive.org/web/20070930004912/http://www.fda.gov/ohrms/dockets/AC/05/briefing/2005-4195B1_01_04-Noven-Appendix-3.pdf |archive-date=30 September 2007}}</ref>

Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-[[Chemistry:Isomer|isomer]] is extensively metabolized. By circumventing this first-pass metabolism, the relative concentrations of ℓ-threo-methylphenidate are much higher with transdermal administration (50–60% of those of [[Chemistry:Dexmethylphenidate|dexmethylphenidate]] instead of about 14–27%).<ref>{{cite journal | vauthors = Heal DJ, Pierce DM | title = Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system | journal = CNS Drugs | volume = 20 | issue = 9 | pages = 713–738 | year = 2006 | pmid = 16953648 | doi = 10.2165/00023210-200620090-00002 | s2cid = 39535277 }}

{{cite journal | vauthors = Anderson VR, Scott LJ | title = Methylphenidate transdermal system: In attention-deficit hyperactivity disorder in children | journal = Drugs | volume = 66 | issue = 8 | pages = 1117–1126 | year = 2006 | pmid = 16789796 | doi = 10.2165/00003495-200666080-00007 | s2cid = 46975783 }}</ref><!-- SPC of Ritalin states: "Owing to extensive first-pass metabolism the absolute bioavailability was 22±8 % for the d-enantiomer and 5±3 % for the l-enantiomer." (Summary of Product Characteristics last updated on the eMC: 05/02/2010) -->

A 39&nbsp;nanograms/mL peak serum concentration of methylphenidate has been found to occur between 7.5–10.5&nbsp;hours after administration.<ref name="Daytrana FDA label"/> However, the onset to peak effect is 2&nbsp;hours, and the clinical effects remain up to 2&nbsp;hours after the patch has been removed. The absorption is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9&nbsp;hours after application (onto normal, unexposed to heat and uninflamed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug.<ref name="Daytrana FDA label"/>

====Parenteral formulation====
When it was released in the United States, methylphenidate was available from CIBA in a parenteral form for use by medical professionals. It came in 10mL multiple-dose vials containing 100&nbsp;mg methylphenidate HCl and 100&nbsp;mg lactose in lyophilized (freeze-dried) form. It was also available as single-dose ampoules containing 20&nbsp;mg methylphenidate HCl. Instructions were to reconstitute with 10mL sterile solvent (water). The indication was 10 to 20&nbsp;mg (1.0mL from MDV's, up to one full single-use ampoule) to produce a focused, talkative state that could help certain patients breakdown the resistance to therapy. Parenteral methylphenidate was discontinued out of a concern for the actual benefit and of inducing a psychic dependence. This is not truth serum in the normal sense, as it does not impair the ability to control the flow of information like a barbiturate agent (Pentothal©) or similar might.{{citation needed | date = May 2023}}

=== Cost ===
[[File:Ritalin Pill.jpg|thumb|Ritalin 10 mg tablet]]

Brand-name and [[Social:Generic drug|generic]] formulations are available.<ref name=AHFS2018/>

=== Legal status ===
[[File:Ritalin.jpg|thumb|250px|Legal warning printed on Ritalin packaging]]Internationally, methylphenidate is a Schedule&nbsp;II drug under the [[Medicine:Convention on Psychotropic Substances|Convention on Psychotropic Substances]].<ref>{{cite report |url=http://www.incb.org/pdf/e/list/green.pdf |title=Green List: Annex to the annual statistical report on psychotropic substances (form&nbsp;P) |date=August 2003 |publisher=International Narcotics Board |edition=23rd |id={{small|(1.63&nbsp;MB)}} |access-date=2 March 2006 |archive-url=https://web.archive.org/web/20120831222336/http://www.incb.org/pdf/e/list/green.pdf |archive-date=31 August 2012 |url-status=dead |place=Vienna International Centre, Austria}}</ref>
{| class="wikitable"
|{{legend|#55B23A|Legal}}
|{{legend|#FA8128|Controlled Substance}}
|{{legend|#C4C9CD|Illegal}}
|}
{| class="wikitable sortable"
!Country/Territory
!
! class="unsortable" |Status
! class="unsortable" |Notes
|-
|{{flag|Australia}}
| style="background:#FA8128;" |
|"Schedule&nbsp;8" controlled substance. Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment.
|<ref>{{cite web |date=27 November 2014 |title=Poisons Standard 2012 as amended made under paragraph 52D(2)(a) of the Therapeutic Goods Act 1989 |url=https://www.comlaw.gov.au/Details/F2015C00043 |url-status=live |archive-url=https://web.archive.org/web/20150701012941/https://www.comlaw.gov.au/Details/F2015C00043 |archive-date=1 July 2015 |access-date=28 June 2015 |publisher=Therapeutic Goods Administration}}</ref>
|-
|{{flag|Canada}}
| style="background:#FA8128;" |
|Schedule III of the Controlled Drugs and Substances Act and is illegal to possess without a prescription, with unlawful possession punishable by up to three years imprisonment, or (via summary conviction) by up to one year imprisonment and/or fines of up to two thousand dollars. Unlawful possession for the purpose of trafficking is punishable by up to ten years imprisonment, or (via summary conviction) by up to eighteen months imprisonment.
|<ref>{{cite report |url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/ |title=Controlled Drugs and Substances Act |date=25 April 2017 |publisher=Department of Justice, Government of Canada |id=S.C.&nbsp;1996, c.&nbsp;19 |access-date=26 April 2017 |archive-url=https://web.archive.org/web/20110403004630/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/ |archive-date=3 April 2011 |url-status=live |series=Laws}}</ref>
|-
| {{flag|Fiji}}
| style="background:#C4C9CD;" |
|Schedule 1 Illicit Drug under the Illicit Drugs Control Act 2004
|<ref>{{cite web |title=FIJI ISLANDS ILLICIT DRUGS CONTROL ACT 2004 |url=https://www.health.gov.fj/wp-content/uploads/2018/02/Fiji-Illicit-Drug-Act-2004.pdf |url-status=dead |archive-url=https://web.archive.org/web/20180713134828/http://www.health.gov.fj/wp-content/uploads/2018/02/Fiji-Illicit-Drug-Act-2004.pdf |archive-date=13 July 2018 |access-date=5 August 2023 |website=health.gov.fj}}</ref>
|-
|{{flag|France}}
| style="background:#FA8128;" |
|Covered by the "narcotics" schedule, prescription and distribution conditions are restricted, with hospital or city specialist-only (pediatrician for children, psychiatrist or neurologist for adults) prescription for the initial treatment and yearly consultations.<ref>{{cite news |title=TDAH : la prescription de méthylphénidate peut désormais être initiée en villexxxxxxxxx |url=https://www.vidal.fr/actualites/27908-tdah-la-prescription-de-methylphenidate-peut-desormais-etre-initiee-en-villexxxxxxxxx.html |work=VIDAL |language=fr}}</ref>

|-
|{{flag|Hong Kong}}
| style="background:#FA8128;" |
|Controlled under the schedule&nbsp;1 of the Dangerous Drugs Ordinance (cap.&nbsp;134).
|<ref>{{cite web |title=Dangerous Drugs Ordinance |url=https://www.elegislation.gov.hk/hk/cap134?xpid=ID_1438402701417_001 |url-status=live |archive-url=https://web.archive.org/web/20210828171921/https://www.elegislation.gov.hk/checkconfig/success.jsp |archive-date=28 August 2021 |access-date=20 March 2019 |website=Hong Kong e-Legislation |id=1438402701417-001}}</ref>
|-
|{{flag|India}}
| style="background:#FA8128;" |
|Methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule, 1945. It is dispensed only by physician's prescription. Legally, 2&nbsp;grams of methylphenidate is classified as a small quantity, and 50&nbsp;grams as a large or commercial quantity.
|<ref>{{cite report |url=http://www.mohfw.nic.in/showfile.php?lid=3036 |title=The Drugs and Cosmetics Rules |date=15 August 2013 |publisher=Government of India |pages=729–730 |access-date=5 December 2016 |archive-url=https://web.archive.org/web/20160808040545/http://mohfw.nic.in/showfile.php?lid=3036 |archive-date=8 August 2016 |url-status=live |orig-date=1945 |series=Ministry of Health & Family Welfare}}</ref><ref name="NCB">{{cite report |url=http://narcoticsindia.nic.in/upload/download/document_idd8a4e572d866aa45da78418d9d2ff9f9.pdf |title=Drug Law Enforcement Field Officers' Hand Book |date=26 February 2014 |publisher=Government of India |page=145 |access-date=5 December 2016 |archive-url=https://web.archive.org/web/20170305004634/http://narcoticsindia.nic.in/upload/download/document_idd8a4e572d866aa45da78418d9d2ff9f9.pdf |archive-date=5 March 2017 |url-status=dead <!-- checked 2022-12-14 --> |vauthors=Mehta R |series=Narcotics Control Bureau, Ministry of Home Affairs}}</ref>
|-
|{{flag|New Zealand}}
| style="background:#FA8128;" |
|In New Zealand, methylphenidate is a 'class B2 controlled substance'. Unlawful possession is punishable by six-month prison sentence and distribution by a 14-year sentence.
|
|-
|{{flag|Russia}}
| style="background:#C4C9CD;" |
|List&nbsp;I controlled psychotropic substance without recognized medical value. The Constant Committee for Drug Control of the Russian Ministry of Health has put methylphenidate and its derivatives on the National List of Narcotics, Psychotropic Substances and Their Precursors, and the Government banned methylphenidate for any use on 25 October 2014.
|<ref>{{cite web |title=Decree of the Government of Russian Federation on 25&nbsp;October 2014 |url=http://government.ru/media/files/AXPVbdY3sc4.pdf |url-status=live |archive-url=https://web.archive.org/web/20150326231624/http://government.ru/media/files/AXPVbdY3sc4.pdf |archive-date=26 March 2015 |access-date=17 October 2019 |id=No.&nbsp;1102}}</ref>
|-
|{{flag|Sweden}}
| style="background:#FA8128;" |
|List&nbsp;II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.
|<ref name="Narkotikastrafflag">{{cite web |title=Narkotikastrafflag (1968:64) |url=https://lagen.nu/1968:64 |url-status=live |archive-url=https://web.archive.org/web/20131006112822/https://lagen.nu/1968:64 |archive-date=6 October 2013 |access-date=15 January 2014 |publisher=Ministry of Justice}}</ref>
|-
| {{flag|United Kingdom}}
| style="background:#FA8128;" |
|Controlled 'Class&nbsp;B' substance. Possession without prescription carries a sentence up to 5&nbsp;years or an unlimited fine, or both; supplying methylphenidate is 14&nbsp;years or an unlimited fine, or both.
|<ref name="ABC">{{cite report |title=Misuse of Drugs Act (c.&nbsp;38) |publisher=Office of Public Sector Information |access-date=15 June 2009 |archive-url=https://web.archive.org/web/20210828171920/https://www.legislation.gov.uk/ukpga/1971/38/schedule/2/2003-04-01?timeline=true |archive-date=28 August 2021 |url-status=live |year=1971 |section=Schedule&nbsp;2: Controlled Drugs |section-url=http://www.statutelaw.gov.uk/content.aspx?LegType=All+Legislation&title=The+Misuse+of+Drugs+Act+1971&searchEnacted=0&extentMatchOnly=0&confersPower=0&blanketAmendment=0&sortAlpha=0&TYPE=QS&PageNumber=1&NavFrom=0&parentActiveTextDocId=1367412&ActiveTextDocId=1367471&filesize=1699}}</ref>
|-
| {{flag|United States}}
| style="background:#FA8128;" |
|Classified as a Schedule II [[Chemistry:Controlled substance|controlled substance]], the designation used for substances that have a recognized medical value but present a high potential for misuse.
|<ref name=":3">{{cite web |last=Finlator |first=John |date=28 October 1971 |title=Phenmetrazine and its salts, and Methylphenidate |url=https://isomerdesign.com/Cdsa/FR/36FR20686.pdf |url-status=live |archive-url=https://web.archive.org/web/20220303023153/http://isomerdesign.com/Cdsa/FR/36FR20686.pdf |archive-date=3 March 2022 |access-date=16 January 2023 |website=Isomer Design |publisher=Bureau of Narcotics and Dangerous Drugs}}</ref>
|}

=== Controversy ===
Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. The prescription of psychostimulant medication to children to reduce ADHD symptoms has been a major point of criticism.<ref name=pmid17949504>{{cite journal | vauthors = Lakhan SE, Hagger-Johnson GE | date = October 2007 | title = The impact of prescribed psychotropics on youth | journal = Clinical Practice and Epidemiology in Mental Health | volume = 3 | issue = 1 | page = 21 | pmid = 17949504 | pmc = 2100041 | doi = 10.1186/1745-0179-3-21 | doi-access = free }}</ref>{{request quotation | date=June 2015}} The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,<ref name=nih.gov-nida-29.htm>{{cite news |title = New research helps explain ritalin's low abuse potential when taken as prescribed |date = 29 September 1998 |website = NIH.gov |url = http://www.nih.gov/news/pr/sept98/nida-29.htm |access-date = 30 April 2011 |archive-url = https://web.archive.org/web/20100528060023/http://www.nih.gov/news/pr/sept98/nida-29.htm |archive-date=28 May 2010}}</ref> according to which abuse is statistically very low and "stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life".<ref name=drugabuse.gov-ADHDFacts>{{cite web | title = Stimulant ADHD medications: Methylphenidate and amphetamines |series = NIDA InfoFacts |website = Drugabuse.gov | url = http://www.drugabuse.gov/InfoFacts/ADHD.html | access-date = 30 April 2011 | archive-url = https://web.archive.org/web/20100326223023/http://www.drugabuse.gov/infofacts/ADHD.html | archive-date=26 March 2010}}</ref> A study found that ADHD medication was not associated with an increased risk of cigarette use, and in fact, stimulant treatments such as Ritalin seemed to lower this risk.<ref>{{cite journal | vauthors = Schoenfelder EN, Faraone SV, Kollins SH | date = June 2014 | title = Stimulant treatment of ADHD and cigarette smoking: A meta-analysis | journal = Pediatrics | volume = 133 | issue = 6 | pages = 1070–1080 | pmid = 24819571 | pmc = 4531271 | doi = 10.1542/peds.2014-0179 }}</ref> People treated with stimulants such as methylphenidate during childhood were less likely to have [[Medicine:Substance use disorder|substance use disorder]]s in adulthood.<ref>{{cite journal | vauthors = Wilens TE, Faraone SV, Biederman J, Gunawardene S | title = Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature | journal = Pediatrics | volume = 111 | issue = 1 | pages = 179–185 | date = January 2003 | pmid = 12509574 | doi = 10.1542/peds.111.1.179 | s2cid = 29956425 }}</ref>

Among countries with the highest rates of use of methylphenidate medication is Iceland,<ref>{{cite journal | vauthors = Karlstad Ø, Zoëga H, Furu K, Bahmanyar S, Martikainen JE, Kieler H, Pottegård A | title = Use of drugs for ADHD among adults-a multinational study among 15.8 million adults in the Nordic countries | journal = European Journal of Clinical Pharmacology | volume = 72 | issue = 12 | pages = 1507–1514 | date = December 2016 | pmid = 27586399 | pmc = 5110707 | doi = 10.1007/s00228-016-2125-y }}</ref> where research shows that the drug was the most commonly used substance among people who inject drugs.<ref>{{cite journal | vauthors = Bjarnadottir GD, Haraldsson HM, Rafnar BO, Sigurdsson E, Steingrimsson S, Johannsson M, Bragadottir H, Magnusson A | title = Prevalent intravenous abuse of methylphenidate among treatment-seeking patients with substance abuse disorders: a descriptive population-based study | journal = Journal of Addiction Medicine | volume = 9 | issue = 3 | pages = 188–194 | date = 29 November 2016 | pmid = 25748561 | pmc = 4450903 | doi = 10.1097/ADM.0000000000000115 }}</ref> The study involved 108 people who inject drugs and 88% of them had injected methylphenidate within the last 30 days and for 63% of them, methylphenidate was the most preferred substance.

Treatment of ADHD by way of methylphenidate has led to legal actions, including malpractice suits regarding [[Philosophy:Informed consent|informed consent]], inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems.<ref>{{cite journal | vauthors = Ouellette EM | title = Legal issues in the treatment of children with attention deficit hyperactivity disorder | journal = Journal of Child Neurology | volume = 6 | issue = Suppl | pages = S68–S75 | year = 1991 | pmid = 2002217 | doi = 10.1177/0883073891006001S08 | s2cid = 1773939 }}</ref>

== Research ==
Methylphenidate may be effective as a treatment for [[Philosophy:Apathy|apathy]] in [[Medicine:Alzheimer's disease|Alzheimer's disease]].<ref>{{cite journal | vauthors = Theleritis C, Siarkos K, Katirtzoglou E, Politis A | title = Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities | journal = Journal of Geriatric Psychiatry and Neurology | volume = 30 | issue = 1 | pages = 26–49 | date = January 2017 | pmid = 28248559 | doi = 10.1177/0891988716678684 | s2cid = 24642197 }}</ref>

===Replacement therapy===
Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon [[Chemistry:Methamphetamine|methamphetamine]].<ref>{{cite journal | vauthors = Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J | title = Pharmacotherapy of methamphetamine addiction: an update | journal = Substance Abuse | volume = 29 | issue = 3 | pages = 31–49 | year = 2008 | pmid = 19042205 | pmc = 2597382 | doi = 10.1080/08897070802218554 }}</ref> Methylphenidate and [[Chemistry:Amphetamine|amphetamine]] have been investigated as a chemical replacement for the treatment of cocaine addiction.<ref name=pmid9408812>{{cite journal | vauthors = Grabowski J, Roache JD, Schmitz JM, Rhoades H, Creson D, Korszun A | title = Replacement medication for cocaine dependence: methylphenidate | journal = Journal of Clinical Psychopharmacology | volume = 17 | issue = 6 | pages = 485–488 | date = December 1997 | pmid = 9408812 | doi = 10.1097/00004714-199712000-00008 }}</ref><ref>{{cite web|publisher= US National Institute on Drug Addiction|date=1 February 2019|accessdate=11 February 2023 |title=Understanding drug abuse and addiction: What science says |url=https://nida.nih.gov/publications/teaching-addiction-science/understanding-drug-abuse-addiction-what-science-says}}</ref> Its effectiveness in treatment of cocaine, psychostimulant addiction or psychological dependence has not been proven.<ref>{{cite journal | vauthors = Shearer J | title = The principles of agonist pharmacotherapy for psychostimulant dependence | journal = Drug and Alcohol Review | volume = 27 | issue = 3 | pages = 301–308 | date = May 2008 | pmid = 18368612 | doi = 10.1080/09595230801927372 | doi-access = free }}</ref>

== Footnotes ==
{{notelist}}

== References ==
{{reflist}}

== External links ==

{{Stimulants}}
{{ADHD pharmacotherapies|state=expanded}}
{{Drug use}}
{{Monoamine reuptake inhibitors}}
{{Sigma receptor modulators}}
{{Phenethylamines}}

[[Category:2-Benzylpiperidines]]
[[Category:Carboxylate esters]]
[[Category:CYP2D6 inhibitors]]
[[Category:Euphoriants]]
[[Category:Methyl esters]]
[[Category:Nootropics]]
[[Category:Norepinephrine–dopamine reuptake inhibitors]]
[[Category:Sigma agonists]]
[[Category:Stimulants]]
[[Category:Vasoconstrictors]]
[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Methylphenidate}}