Original synthesis to sit alongside the encyclopedia article below. Not part of Wikipedia; verify facts on Wikipedia when precision matters.
Methylphenidate (Chinese: 哌甲酯) is a prescription central nervous system stimulant, widely recognized as a first-line clinical treatment for attention deficit hyperactivity disorder (ADHD) and narcolepsy, with well-documented efficacy for reducing core ADHD symptoms including inattention, hyperactivity and impulsive behavior at standard therapeutic doses.
Key moments
1944Chemist Leandro Panizzon first synthesized methylphenidate at Swiss pharmaceutical firm Ciba, naming its original flagship brand Ritalin after his wife Marguerite "Rita" Panizzon
1955Methylphenidate received formal regulatory approval for clinical prescription use in the United States
1980sGlobal prescription rates for methylphenidate began sharp growth as formal clinical recognition of ADHD expanded across pediatric and adult care systems
1990s to 2000sExtended-release formulations such as Concerta launched, enabling convenient once-daily dosing that eliminated the need for midday dose administration for school-age children and working adults
Pharmacological Profile and Clinical Effects
Methylphenidate acts by blocking the reuptake transporters for dopamine and norepinephrine in the brain's prefrontal cortex, raising local concentrations of these neurotransmitters to improve executive function, working memory, and impulse regulation for patients with ADHD. Contrary to common public misconceptions, it produces a paradoxical calming, focusing effect for people with ADHD at prescribed doses, rather than the euphoric stimulant high that non-users experience at equivalent intake levels.
Regulatory Status and Public Health Debates
Nearly all national jurisdictions classify methylphenidate as a scheduled controlled substance, due to well-documented risks of misuse, physical dependence, and severe adverse events including cardiac arrhythmia and stimulant-induced psychosis when taken at doses far above recommended clinical limits. Long-running public discourse over potential overprescription persists, particularly for pediatric populations, with critics noting that a notable share of child prescriptions are issued without full formal diagnostic assessment for ADHD.
Non-Medical Misuse Trends
Diversion of legitimate methylphenidate prescriptions to non-patients, most commonly high school and university students, is a widespread global trend. These non-users typically take diverted doses as an unregulated "study drug" intended to boost exam cram performance, but research confirms they do not gain sustained cognitive improvements, and face significantly elevated risks of severe anxiety, chronic insomnia, and unexpected cardiovascular complications.
Methylphenidate, sold under the brand name Ritalin and Concerta, among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.It may be taken by mouth or applied to the skin, and different formulations have varying durations of effect.[12] For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine[13][14][15][16] but modestly lower than amphetamine.[17][18][19][20] However, methylphenidate is preferred as a first-line treatment in children, while amphetamine is preferred in adults.[21] Methylphenidate reduces core ADHD symptoms and may do so in part by enhancing executive functions, such as working memory, sustained attention, and inhibitory control.[22][23][24]
At therapeutic doses, methylphenidate increases alertness and concentration and reduces hyperactivity and impulsive behavior in individuals with ADHD.Common side effects include loss of appetite, weight loss, trouble sleeping, and small increases in heart rate and blood pressure.[25] Long-term treatment in children has been associated with slightly slower growth.[12] Methylphenidate can be misused; dependence and withdrawal are mainly reported with high-dose or non-medical use and are uncommon at therapeutic doses.[26]
Methylphenidate is believed to work by blocking the reuptake of dopamine and norepinephrine by neurons.[27][28] It is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes.It is available as a generic medication.[29] In 2023, it was the 50th most commonly prescribed medication in the United States, with more than 13million prescriptions.[30][31]
Uses
Medical
Methylphenidate is most commonly used to treat ADHD and narcolepsy.[32]
Attention deficit hyperactivity disorder
Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD).[33] The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose.[34] Methylphenidate is available in both immediate-release and modified-release formulations.[35][36]
Contraindications
Methylphenidate is contraindicated for individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[88]
Pregnant women are advised to only use the medication if the benefits outweigh the potential risks.[89] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.[90] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".[91]
Adverse effects
The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia.[93]Gastrointestinal adverse effects may include abdominal pain[94] and weight loss.Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), lethargy (drowsiness/fatigue), and dizziness.Cardiac adverse effects may include palpitations, changes in blood pressure, and heart rate (typically mild), and tachycardia (rapid heart rate).[95]Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis.[96]
Interactions
Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors).Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations.[88] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[121][122][123][124]
When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatictransesterification,
Pharmacology
Pharmacodynamics
Methylphenidate acts primarily as a norepinephrine–dopamine reuptake inhibitor (NDRI).It is a benzylpiperidine and phenethylaminederivative which also shares part of its basic structure with catecholamines.
Methylphenidate is a psychostimulant and increases the activity of the central nervous system through inhibition on reuptake of the neurotransmitters norepinephrine and dopamine.[133] As models of attention deficit hyperactivity disorder (ADHD) suggest, it is associated with functional impairments in some of the brain's neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus. 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 synapse increase and last longer, respectively.Therefore, methylphenidate is called a norepinephrine–dopamine reuptake inhibitor.[127]
Chemistry
Despite the claim made by some urban legends, methylphenidate is not a cocaine derivative nor analog.However, both compounds contain a methyl piperidinylcarboxylate moiety with 2-carbon distance between nitrogen and ester, methylphenidate containing methyl (piperidin-2-yl)-ethanoate and cocaine containing methyl (piperidin-3-yl)-methanoate.Cocaine is a local anesthetic and ligand channel blocker with SNDRI action, while methylphenidate is an NDRI with 2–3 fold selectivity for the dopamine transporter (DAT) over the norepinephrine transporter (NET).Cocaine is also more potent in serotonin transporters (SERTs) than NDRI sites.[166][167]
Four isomers 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.[136][168]
History
Methylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955.[173][174][175] It was synthesized by chemist Leandro Panizzon and sold by Swiss company CIBA (now Novartis).[173] He named the drug after his wife Marguerite, nicknamed Rita, who used Ritalin to compensate for low blood pressure.[176][177] Methylphenidate was not reported to be a stimulant until 1954.[178]
Society and culture
Names
Methylphenidate is sold in the majority of countries worldwide.[192] Brand names for methylphenidate include Ritalin (in honor of Rita, the wife of the molecule discoverer Leandro Panizzon), Rilatine (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta,[88] Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Konsenidat, Equasym, Foquest,[193] Methylin, Penid, Phenida, Prohiper, and Tradea.[192]
Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the dosage strength in milligrams. They use osmotic-controlled release oral delivery system.
Etymology
The word methylphenidate is a portmanteau of the chemical name, Methyl -2- phen yl-2-(p i peri d in-2-yl) acet ate.
The name "Ritalin" derives from Marguerite "Rita" Panizzon, the wife of Leandro Panizzon, who first synthesized the drug in 1944. Rita was the first person to take methylphenidate and described its effects to her husband.[176][177]
Research
Apathy
Methylphenidate may be effective as a treatment for apathy in Alzheimer's disease and other conditions.[63][232][233][234] It may also be useful in the treatment of more severe disorders of diminished motivation, like abulia and akinetic mutism.[234][235]
External links
References
1.Prescriber's Guide: Stahl's Essential Psychopharmacology Cambridge University Press, April 2024^
The International Consensus Statement on ADHD shows that the results from systematic reviews, meta-analyses and large scale studies are clear: methylphenidate is safe and among the most efficacious drugs in all of medicine; treatment in the long-term substantially reduces accidental injuries, traumatic brain injury, substance abuse, cigarette smoking, educational underachievement, bone fractures, sexually transmitted infections, depression, suicide, criminal activity, teenage pregnancy, vehicle crashes, burn injuries and overall-cause mortality, and eliminates the increased risk for obesity.[39]
One committee from the World Health Organization (WHO) responsible for the World Health Organization Essential Medicines List rejected an application in 2019, and a second application endorsed by 51 professional medical groups in 2021, for methylphenidate's inclusion due to uncertainty about its efficacy and safety.[40][41] However, in November 2023, the WHO Mental Health Gap Action Programme Guidelines for mental, neurological, and substance use disorders recommended that methylphenidate should be considered for children aged 6 years and older who have ADHD, noting specifically that, "methylphenidate treatment shows substantial effects on symptom reduction",[42] in addition to other WHO publications.[43] In 2024, the European Society for Child and Adolescent Psychiatry (ESCAP) and the American Academy of Paediatrics (AAP) endorsed the inclusion of methylphenidate in the WHO EML.[44][45] A new application for methylphenidate's inclusion is currently pending review,[46] having sparked debate in the comment process among researchers engaged in the evaluation of the evidence-base.[47][48][49]
Safety and efficacy data have been reviewed extensively by medical regulators (e.g., the US Food and Drug Administration and the European Medicines Agency), the developers of evidence-based national guidelines (e.g., the UK National Institute for Health and Care Excellence and the American Academy of Pediatrics), and government agencies who have endorsed these guidelines (e.g., the Australian National Health and Medical Research Council).These professional groups unanimously conclude, based on the scientific evidence, that methylphenidate is safe and effective and should be considered as a first-line treatment for ADHD.[39]
Since the diagnosis of ADHD has increased around the world, methylphenidate may be misused as a "study drug" by students, which may be harmful.[50] This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD.[50] People in this category are prone to experience the adverse effects of the drug, which can worsen their condition.[50]
Long-term meta-analyses and systematic reviews show that the medications used to treat ADHD are not associated with observed deficits in brain structure, but with improved brain development and functioning, most prominently in inferior frontal and striatal regions.[39] The most comprehensive meta-analysis available (19 studies with over 3.9 million participants) found "no statistically significant association between ADHD medications [including methylphenidate] and the risk of cardiovascular event among children and adolescents, young and middle-aged adults, or older adults";[51] as do other systematic reviews and meta-analyses.[52][53][54]
Narcolepsy
Narcolepsy, a chronicsleep disorder characterized by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants.Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[55] Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test (MSLT), but performance does not improve to levels comparable to healthy people.[56]
Other medical uses
Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder.[57] It can also improve depression in several groups, including stroke, cancer, and HIV-positive patients.[58] There is weak evidence in favor of methylphenidate's effectiveness for depression,[59] including providing additional benefit in combination with antidepressants.[60] In individuals with terminal cancer, methylphenidate can be used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function.[61] 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 citalopram.[62] A 2018 review found low-quality evidence supporting its use to treat apathy as seen in Alzheimer's disease, in addition to slight benefits for cognition and cognitive performance.[63]
Attention deficit hyperactivity disorder
Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD).[33] The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose.[34] Methylphenidate is available in both immediate-release and modified-release formulations.[35][36] Methylphenidate is not approved for children under six years of age.[37][38]
The International Consensus Statement on ADHD shows that the results from systematic reviews, meta-analyses and large scale studies are clear: methylphenidate is safe and among the most efficacious drugs in all of medicine; treatment in the long-term substantially reduces accidental injuries, traumatic brain injury, substance abuse, cigarette smoking, educational underachievement, bone fractures, sexually transmitted infections, depression, suicide, criminal activity, teenage pregnancy, vehicle crashes, burn injuries and overall-cause mortality, and eliminates the increased risk for obesity.[39]
One committee from the World Health Organization (WHO) responsible for the World Health Organization Essential Medicines List rejected an application in 2019, and a second application endorsed by 51 professional medical groups in 2021, for methylphenidate's inclusion due to uncertainty about its efficacy and safety.[40][41] However, in November 2023, the WHO Mental Health Gap Action Programme Guidelines for mental, neurological, and substance use disorders recommended that methylphenidate should be considered for children aged 6 years and older who have ADHD, noting specifically that, "methylphenidate treatment shows substantial effects on symptom reduction",[42] in addition to other WHO publications.[43] In 2024, the European Society for Child and Adolescent Psychiatry (ESCAP) and the American Academy of Paediatrics (AAP) endorsed the inclusion of methylphenidate in the WHO EML.[44][45] A new application for methylphenidate's inclusion is currently pending review,[46]
Safety and efficacy data have been reviewed extensively by medical regulators (e.g., the US Food and Drug Administration and the European Medicines Agency), the developers of evidence-based national guidelines (e.g., the UK National Institute for Health and Care Excellence and the American Academy of Pediatrics), and government agencies who have endorsed these guidelines (e.g., the Australian National Health and Medical Research Council).These professional groups unanimously conclude, based on the scientific evidence, that methylphenidate is safe and effective and should be considered as a first-line treatment for ADHD.[39]
Since the diagnosis of ADHD has increased around the world, methylphenidate may be misused as a "study drug" by students, which may be harmful.[50] This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD.[50] People in this category are prone to experience the adverse effects of the drug, which can worsen their condition.[50]
Long-term meta-analyses and systematic reviews show that the medications used to treat ADHD are not associated with observed deficits in brain structure, but with improved brain development and functioning, most prominently in inferior frontal and striatal regions.[39] The most comprehensive meta-analysis available (19 studies with over 3.9 million participants) found "no statistically significant association between ADHD medications [including methylphenidate] and the risk of cardiovascular event among children and adolescents, young and middle-aged adults, or older adults";[51] as do other systematic reviews and meta-analyses.[52][53][54]
Narcolepsy
Narcolepsy, a chronicsleep disorder characterized by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants.Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[55] Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test (MSLT), but performance does not improve to levels comparable to healthy people.[56]
Other medical uses
Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder.[57] It can also improve depression in several groups, including stroke, cancer, and HIV-positive patients.[58] There is weak evidence in favor of methylphenidate's effectiveness for depression,[59] including providing additional benefit in combination with antidepressants.[60] In individuals with terminal cancer, methylphenidate can be used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function.[61] 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 citalopram.[62] A 2018 review found low-quality evidence supporting its use to treat apathy as seen in Alzheimer's disease, in addition to slight benefits for cognition and cognitive performance.[63]
Enhancing performance
Methylphenidate's efficacy as an athletic performance enhancer, cognitive enhancer, aphrodisiac, and euphoriant is supported by research.[64][65][66][67][68][69][70][71][72] 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.[73][74][72]
A 2015 review found that therapeutic doses of amphetamine and methylphenidate result in modest improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults;[75][76] the cognition-enhancing effects of these drugs are known to occur through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[75] Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal.[77][78] Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks,[77][78]
Excessive doses of methylphenidate, above the therapeutic range, could interfere with working memory and cognitive control.[77][78] Methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system.[82] Similar to the loss of cognitive enhancement when using large amounts, large doses of methylphenidate could induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia.[83] While literature suggests it might improve cognition, there isn't evidence that its use as a study aid without an ADHD diagnosis improves one's GPA.[50]
Available forms
The most common formulations of methylphenidate are based on its hydrochloride salt and are available as both immediate-release and extended-release oral dosage forms, as well as transdermal patches.Methylphenidate is a chiral compound with two stereocenters; clinical use overwhelmingly utilizes the racematethreo diastereomer, with the pharmacologically active component being the d-threo-methylphenidate enantiomer. Additionally, dexmethylphenidate (Focalin) is the single d-threo enantiomer formulation approved for medicinal use. There is some evidence that dexmethylphenidate has better bioavailability and a longer duration of action than methylphenidate.
Immediate-release
In the Ritalin tablets 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 swallowing. Following administration of Concerta, plasma concentrations of the l-isomer were approximately 1⁄40 the plasma concentrations of the d-isomer.
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.
Modified-release
Modified-release methylphenidate products are formulations designed to deliver methylphenidate in two distinct phases, a rapid initial release followed by a slower, extended release—to maintain therapeutic concentrations over several hours, reducing the need for multiple daily dosing.These products include a range of brand names such as Concerta XL, Medikinet XL, Equasym XL, and Ritalin LA, each with different ratios of immediate-release to modified-release components and varying duration of action from 8 to 12 hours.[84]
Skin patch
A methylphenidate 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.[83] It is also referred to as methylphenidate transdermal system (MTS). It is approved as a once-daily treatment in children with ADHD aged 6–17 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 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.[85]
Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-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 dexmethylphenidate instead of about 14–27%).[86]
A 39 nanograms/mL peak serum concentration of methylphenidate has been found to occur between 7.5–10.5 hours after administration.[83]
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 mg methylphenidate HCl and 100 mg lactose in lyophilized (freeze-dried) form. It was also available as single-dose ampoules containing 20 mg methylphenidate HCl. Instructions were to reconstitute with 10mL sterile solvent (water). The indication was 10 to 20 mg (1.0mL from MDV's, up to one full single-use ampoule) to produce a focused, talkative state that could help certain patients break down 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.[87]
Immediate-release
In the Ritalin tablets 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 swallowing. Following administration of Concerta, plasma concentrations of the l-isomer were approximately 1⁄40 the plasma concentrations of the d-isomer.
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.
Modified-release
Modified-release methylphenidate products are formulations designed to deliver methylphenidate in two distinct phases, a rapid initial release followed by a slower, extended release—to maintain therapeutic concentrations over several hours, reducing the need for multiple daily dosing.These products include a range of brand names such as Concerta XL, Medikinet XL, Equasym XL, and Ritalin LA, each with different ratios of immediate-release to modified-release components and varying duration of action from 8 to 12 hours.[84]
Skin patch
A methylphenidate 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.[83] It is also referred to as methylphenidate transdermal system (MTS). It is approved as a once-daily treatment in children with ADHD aged 6–17 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 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.[85]
Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-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 dexmethylphenidate instead of about 14–27%).[86]
A 39 nanograms/mL peak serum concentration of methylphenidate has been found to occur between 7.5–10.5 hours after administration.[83] However, the onset to peak effect is 2 hours, and the clinical effects remain up to 2 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 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.[83]
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 mg methylphenidate HCl and 100 mg lactose in lyophilized (freeze-dried) form. It was also available as single-dose ampoules containing 20 mg methylphenidate HCl. Instructions were to reconstitute with 10mL sterile solvent (water). The indication was 10 to 20 mg (1.0mL from MDV's, up to one full single-use ampoule) to produce a focused, talkative state that could help certain patients break down 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.[87]
In some cases,
tolerance
might be an issue with stimulants like methylphenidate.
Results from a 2024 systematic review showed that methylphenidate significantly improves ADHD symptoms and broadband measures but can cause appetite suppression and other adverse events in children and adolescents.[98] Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.[99]
There is some evidence of mild reductions in height with prolonged treatment in children.[100] This has been estimated at 1 cm or less per year during the first three years with a total decrease of 3 cm over 10 years.[101][102]
Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate.The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.[103]
Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms.[104] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[105] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[100]Logorrhea is occasionally reported and visual hallucinations are very rarely reported.[106]Priapism is a very rare adverse event that can be potentially serious.[107]
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 cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.[108]
Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[109]
A 2018 Cochrane review found the drug "may be associated with a number of serious adverse events as well as a large number of non‐serious adverse events in children and adolescents".It stated "it is not possible to accurately estimate the actual risk of adverse events" because the quality of evidence in the 260 studies assessed was "very low".[110]
Overdose
The symptoms of a moderate acute overdose of methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.[83] A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse.[83][111][112]A methylphenidate overdose is rarely fatal with appropriate care.[112] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[113]
Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies.[112]
Addiction and dependence
Methylphenidate displays addiction and dependence liability similar to that of amphetamine.It has moderate liability among addictive drugs;[114][115] addiction and psychological dependence may occur, particularly when methylphenidate is used at high doses or in non-medical contexts.[115] Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain's 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 addiction.[115]
Biomolecular mechanisms
Biomolecular mechanisms
Repeated high-dose administration of methylphenidate has been shown to induce the expression of ΔFosB in D1-type medium spiny neurons of the nucleus accumbens, with accumbal ΔFosB levels accumulating over the long-term with chronic exposure due to its unusually long half-life.[116][117]Overexpression (i.e., a persistently excessive level of gene expression) of ΔFosB in this subset of neurons is a necessary and sufficient biomolecular mechanism for many of the neural adaptations and reward-related behavioral changes associated with drug addiction (e.g., reward sensitization and compulsive drug self-administration).[118][119][120]
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.[127][126]
Coingestion of alcohol also increases the blood plasma levels of d-methylphenidate by up to 40%.[128]
Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.[129]
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
Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE).[136] Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET).[137] Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that methylphenidate amplifies basal dopamine activity, leading to nonresponse in those with low basal DA activity.[138] In animals and brain tissue, methylphenidate has been shown to dose-dependently increase brain dopamine levels.[139][140][141] On average, methylphenidate elicits a 3 to 4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex.[142]Magnetic resonance imaging (MRI) studies suggest that long-term treatment with ADHD stimulants (specifically, amphetamine and methylphenidate) decreases abnormalities in brain structure and function found in subjects with ADHD.[143][144][145]
Both amphetamine and methylphenidate are predominantly dopaminergic drugs, yet their mechanisms of action are distinct.[133] Methylphenidate acts as a norepinephrine–dopamine reuptake inhibitor, while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine.[133] Methylphenidate's mechanism of action in the release of dopamine and norepinephrine is fundamentally different from most other phenethylamine derivatives, as methylphenidate is thought to increase neuronal firing rate,[146][147][148] whereas amphetamine reduces firing rate, but causes monoamine release by reversing the flow of the monoamines through monoamine transporters via a diverse set of mechanisms, including TAAR1 activation and modulation of VMAT2 function, among other mechanisms.[133][149][150]
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.[151]
Methylphenidate has both dopamine transporter and norepinephrine transporterbinding affinity, with the dextromethylphenidateenantiomers displaying a prominent affinity for the norepinephrine transporter.[152] Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic5-HT1A and 5-HT2B subtypes, though direct binding to the serotonin transporter was not observed.[132] A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5-HT1A receptor, but no significant activity on the 5-HT2B receptor was found.[153]
There exist some paradoxical findings that oppose the notion that methylphenidate acts as silent antagonist of the DAT (DAT inhibitor). DAT occupancy of 80% 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).[154] By contrast, other DAT inhibitors such as bupropion have not been observed to exhibit this effect.[155] These observations, among others, 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 flux through the DAT at higher concentrations, rather than by acting solely as a reuptake inhibitor.[156]
Methylphenidate may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine use disorder.[157] The hypothesized mechanism of neuroprotection is through inhibition of methamphetamine–DAT interactions, and through reducing cytosolic dopamine, leading to decreased production of dopamine-related reactive oxygen species.[157]
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.[136] The studied maximized daily dosage of OROS methylphenidate appears to be 144 mg/day.[158]
Pharmacokinetics
Methylphenidate taken by mouth has a bioavailability of 11–52% with a duration of action around 2–4 hours for immediate-release (IR) (i.e., Ritalin), 3–8 hours for sustained-release (i.e., Ritalin LA), and 8–12 hours for extended-release (ER) (i.e., Concerta).The half-life of methylphenidate is 2–3 hours, depending on the individual.The peak plasma time is achieved at about 2 hours.[159] Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.[160]
d-Methylphenidate is much more bioavailable than l-methylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.[159]
The oral bioavailability and speed of absorption for immediate-release methylphenidate is increased when administered with a meal.[161] The effects of a high fat meal on the observed Cmax differ between some extended-release formulations, with combined IR/ER and OROS formulations showing reduced Cmax levels[162] while liquid-based extended-release formulations showed increased Cmax levels when administered with a high-fat meal, according to some researchers.[163] A 2003 study, however, showed no difference between a high-fat meal administration and a fasting administration of oral methylphenidate.[164]
Methylphenidate is metabolized into ritalinic acid by CES1A1 enzymes in the liver.Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate.[165] 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.[160]
The erythro
diastereomers
are
pressor
amines, a property not shared with the threo diastereomers.
When the drug was first introduced it was sold as a 4:1 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 dexmethylphenidate, d-MPH, or d-threo-methylphenidate.
A review on the synthesis of enantiomerically pure (2R,2 ' R)-(+)-threo-methylphenidate hydrochloride has been published.[169]
Detection in biological fluids
The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum, or whole blood to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis of potential poisoning victims or to assist in the forensic investigation in a case of fatal overdose.[172]
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.
The erythro isomer was eliminated, and now modern formulations of methylphenidate contain only the threo isomer in a 50:50 mixture of d- and l-isomers.
Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression.[184] It was later used to treat memory deficits in the elderly.[185] Beginning in the 1960s, it was used to treat children with attention deficit hyperactivity disorder (ADHD) based on earlier work, starting with the studies by American psychiatrist Charles Bradley[186] on the use of psychostimulant drugs, such as Benzedrine, with then-called "maladjusted children".[187] 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.[188]
In 2000, Alza Corporation received FDA approval to market Concerta, a modified-release form of methylphenidate that uses the osmotic-controlled release oral delivery system.[88][189][190]
It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012.[191] In 2023, it was the 50th most commonly prescribed medication in the United States, with more than 13million prescriptions.[31] It is available as a generic medication.[12]
Approximately 22% of the dose is immediate-release,[205] and the remaining 78% of the dose is released over 10–12 hours post-ingestion, with an initial increase over the first 6–7 hours, and subsequent decline in the released drug.[206]
Ritalin LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. Ritalin LA[95] 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 CD capsules contain two types of beads: 30% are immediate-release, and the other 70% are evenly sustained release.[207]
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.[208][209]
Jornay PM is a delayed release formulation that is taken at bedtime. An outer polymer coating delays the initial release of the drug until 8 hours after administration, after which an inner coating regulates the rate of drug absorption. Peak plasma concentration occurs 14 hours following administration.[203] This formulation was motivated by the need for a pediatric ADHD medication that is active immediately after morning waking, as most long-acting formulations exhibit a delay between administration and absorption that leads to inadequate therapeutic effect in the early morning.[210]
Cost
Brand-name and generic formulations are available.[12]
Legal status
Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[211] Its legal status varies by jurisdiction.
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.[224] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,[225] 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".[226] 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.[227] People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.[228]
Among countries with the highest rates of use of methylphenidate medication is Iceland,[229] where research shows that the drug was the most commonly used substance among people who inject drugs.[230] 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 informed consent, inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems.[231]
Schizophrenia
Methylphenidate has been shown to reduce rates of hospitalization in patients with schizophrenia, although repeated, elevated doses can provoke psychosis.[236]
Addiction
Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine.[237] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction.[238][239] Its effectiveness in treatment of cocaine or psychostimulant addiction or psychological dependence has not been proven.[240]
Social anxiety
Methylphenidate has been reported to be effective in the treatment of social anxiety disorder in people who are comorbid for both this condition and attention deficit hyperactivity disorder (ADHD) in small preliminary clinical studies and case reports.[241][242]<r[243]<r[244]<r[245]<r[246]
13.A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients Journal of Psychopharmacology, May 2016^
14.Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis Journal of Attention Disorders, November 2011^
15.Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis BMC Psychiatry, November 2011^
16.Comparative efficacy of methylphenidate and atomoxetine in the treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review and meta-analysis Medical Journal of the Islamic Republic of Iran, 10 February 2016^
17.Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis The Annals of Pharmacotherapy, February 2019^
18.Efficacy of Adderall and methylphenidate in attention deficit hyperactivity disorder: a reanalysis using drug-placebo and drug-drug response curve methodology Journal of Child and Adolescent Psychopharmacology, June 2001^
19.Comparative efficacy of Adderall and methylphenidate in attention-deficit/hyperactivity disorder: a meta-analysis Journal of Clinical Psychopharmacology, October 2002^
20.Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis European Child & Adolescent Psychiatry, April 2010^
21.Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis The Lancet. Psychiatry, September 2018^
23.The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder Neuroscience and Biobehavioral Reviews, September 2021^
24.Executive function assessment and adult attention-deficit/Hyperactivity disorder: Tasks versus ratings on the Barkley Deficits in Executive Functioning Scale Psychological Assessment, 2014^
25.Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD) Cochrane Database of Systematic Reviews, 2023-03-27^
26.Medical management of ADHD in adults: part 2 Drug and Therapeutics Bulletin, 2025-06-03^
27.Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions Biological Psychiatry, June 2005^
28.Stahl's Essential Psychopharmacology: Neuroscientific basis and practical applications Cambridge University Press, 11 April 2013^
33.Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder Current Opinion in Pharmacology, February 2005^
34.Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity Neuropsychiatric Disease and Treatment, 2 June 2021^
35.ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit / hyperactivity disorder in children and adolescents Pediatrics, November 2011^
36.Handbook of Adolescent Health Care Wolters Kluwer Health / Lippincott Williams & Wilkins, 2009^
37.Psychopharmacology for young children: clinical needs and research opportunities Pediatrics, October 2001^
38.Integrative neuroscience approach to predict ADHD stimulant response Expert Review of Neurotherapeutics, May 2006^
39.The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder Neuroscience and Biobehavioral Reviews, September 2021^
44.ESCAP endorses the inclusion of methylphenidate in the WHO model lists of essential medicines and in the Union list of critical medicines European Child & Adolescent Psychiatry, May 2024^
50.Mitigating risks of students use of study drugs through understanding motivations for use and applying harm reduction theory: a literature review Harm Reduction Journal, October 2017^
51.Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis JAMA Network Open, November 2022^
52.The Effect of Methylphenidate and Atomoxetine on Heart Rate and Systolic Blood Pressure in Young People and Adults with Attention-Deficit Hyperactivity Disorder (ADHD): Systematic Review, Meta-Analysis, and Meta-Regression International Journal of Environmental Research and Public Health, August 2018^
53.Association of ADHD medications with the risk of cardiovascular diseases: a meta-analysis European Child & Adolescent Psychiatry, October 2019^
54.ADHD medications and risk of serious cardiovascular events in young and middle-aged adults JAMA, December 2011^
55.Treatment modalities for narcolepsy Neurology, February 1998^
56.Evaluation of treatment with stimulants in narcolepsy Sleep, December 1994^
57.Wake-promoting pharmacotherapy for psychiatric disorders Current Psychiatry Reports, December 2014^
58.Methylphenidate: A review of its neuropharmacological, neuropsychological, and adverse clinical effects Human Psychopharmacology, April 2004^
59.Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis Journal of Affective Disorders, September 2021^
60.A Review of Psychostimulants for Adults With Depression Federal Practitioner, April 2015^
61.Palliative uses of methylphenidate in patients with cancer: a review Journal of Clinical Oncology, January 2002^
62.Methylphenidate use in geriatric depression: A systematic review International Journal of Geriatric Psychiatry, September 2021^
63.Pharmacological interventions for apathy in Alzheimer's disease The Cochrane Database of Systematic Reviews, May 2018^
64.Treatment nhs.uk, 1 June 2018, retrieved 24 October 2022^
65.Chronic oral methylphenidate treatment reversibly increases striatal dopamine transporter and dopamine type 1 receptor binding in rats Journal of Neural Transmission, May 2017^
66.The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex Biological Psychiatry, June 2015^
68.From Clinical Application to Cognitive Enhancement: The Example of Methylphenidate Current Neuropharmacology, 2016^
69.Use of cognitive enhancers: methylphenidate and analogs European Review for Medical and Pharmacological Sciences, January 2019^
70.Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine Psychopharmacology, February 2021^
77.Molecular Neuropharmacology: A foundation for clinical neuroscience McGraw-Hill Medical, 2009^
78.Psychostimulants and cognition: a continuum of behavioral and cognitive activation Pharmacological Reviews, January 2014^
79.Non-specific effects of methylphenidate (Ritalin) on cognitive ability and decision-making of ADHD and healthy adults Psychopharmacology, July 2010^
81.Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration Pharmacotherapy, October 2006^
82.Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing Sports Medicine, May 2013^
86.Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system CNS Drugs, 2006Methylphenidate transdermal system: In attention-deficit hyperactivity disorder in children Drugs, 2006^
90.Exposure to attention deficit hyperactivity disorder medications during pregnancy Canadian Family Physician, July 2007^
91.Pharmacological Treatment of Attention Deficit Hyperactivity Disorder During Pregnancy and Lactation Pharmaceutical Research, February 2018^
92.Development of a rational scale to assess the harm of drugs of potential misuse Lancet, March 2007^
93.Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies BMC Psychiatry, Springer Science and Business Media LLC, September 2013^
96.Ocular side effects of selected systemic drugs Optometry Clinics, 1992^
97.Treatment of ADHD when tolerance to methylphenidate develops Psychiatric Services, January 2002^
98.Treatments for ADHD in Children and Adolescents: A Systematic Review Pediatrics, April 2024^
99.Long-term relationship between methylphenidate and tobacco consumption and nicotine craving in adults with ADHD in a prospective cohort study European Neuropsychopharmacology, June 2013^
100.Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents Journal of Child Psychology and Psychiatry, and Allied Disciplines, March 2013^
101.Growth on stimulant medication; clarifying the confusion: a review Archives of Disease in Childhood, August 2005^
102.ADHD, Multimodal Treatment, and Longitudinal outcome: Evidence, paradox, and challenge Wiley Interdisciplinary Reviews. Cognitive Science, January 2015^
103.Transdermal therapy for attention-deficit hyperactivity disorder with the methylphenidate patch (MTS) CNS Drugs, March 2014^
104.Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature Clinical Neuropharmacology, July 2010^
105.Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients Psychopharmacology Bulletin, 2025^
106.Drug therapy of attention deficit hyperactivity disorder: current trends Mens Sana Monographs, January 2012^
109.Attention deficit hyperactivity disorder: Possible causes and treatment International Journal of Clinical Practice, 1999^
110.Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies The Cochrane Database of Systematic Reviews, May 2018^
112.Overdose of drugs for attention-deficit hyperactivity disorder: Clinical presentation, mechanisms of toxicity, and management CNS Drugs, July 2013^
113.Severe toxicity due to injected but not oral or nasal abuse of methylphenidate tablets Swiss Medical Weekly, 2011^
114.Methylphenidate Abuse and Psychiatric Side Effects Primary Care Companion to the Journal of Clinical Psychiatry, October 2000^
115.Molecular Neuropharmacology: A foundation for clinical neuroscience McGraw-Hill Medical, 2009^
116.DeltaFosB: a sustained molecular switch for addiction Proc. Natl. Acad. Sci. U.S.A., September 2001^
117.Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens Proceedings of the National Academy of Sciences of the United States of America, February 2009^
118.DeltaFosB: a sustained molecular switch for addiction Proceedings of the National Academy of Sciences of the United States of America, September 2001^
119.Ruffle JK. Molecular neurobiology of addiction: what's all the (Δ)FosB about? The American Journal of Drug and Alcohol Abuse, November 2014^
120.Transcriptional and epigenetic mechanisms of addiction Nature Reviews Neuroscience, November 2011^
121.Serotonin syndrome induced by augmentation of SSRI with methylphenidate Psychiatry and Clinical Neurosciences, April 2008^
122.Serotonin syndrome with sertraline and methylphenidate in an adolescent Clinical Neuropharmacology, 2015^
123.Manic switch and serotonin syndrome induced by augmentation of paroxetine with methylphenidate in a patient with major depression Progress in Neuro-Psychopharmacology & Biological Psychiatry, May 2010^
125.New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder Expert Opinion on Drug Delivery, January 2005^
126.Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol Drug Metabolism and Disposition, June 2000^
127.Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion Journal of Clinical Psychopharmacology, August 1999^
128.Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics Clinical Pharmacology and Therapeutics, March 2007^
129.Adrenergic modulation of hepatotoxicity Drug Metabolism Reviews, 1997^
130.Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: Does chirality matter? Journal of Clinical Psychopharmacology, June 2008^
131.Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity Behavioural Pharmacology, February 2007^
132.A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study Journal of Child and Adolescent Psychopharmacology, December 2006^
133.Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review Neurology and Therapy, 2022-08-11^
134.Molecular Neuropharmacology: A foundation for clinical neuroscience McGraw-Hill Medical, 2009^
136.Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system CNS Drugs, 2006^
137.Neurotransmitter transporters and their impact on the development of psychopharmacology British Journal of Pharmacology, January 2006^
138.Mechanism of action of methylphenidate: insights from PET imaging studies Journal of Attention Disorders, 1 January 2002^
139.Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment 2012^
140.Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology J Psychopharmacol, June 2022^
141.In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis Synapse, 1990^
142.Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options European Child & Adolescent Psychiatry, September 2012^
143.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 JAMA Psychiatry, February 2013^
144.Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies The Journal of Clinical Psychiatry, September 2013^
145.Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects Acta Psychiatrica Scandinavica, February 2012^
146.Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling Neural Plasticity, 2004^
149.VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse Annals of the New York Academy of Sciences, January 2011^
150.Striatal dopamine neurotransmission: regulation of release and uptake Basal Ganglia, August 2016^
151.The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity Journal of Neurochemistry, January 2011^
152.Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder Neuropsychiatric Disease and Treatment, December 2006^
153.The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor Die Pharmazie, February 2009^
154.Relationship between psychostimulant-induced "high" and dopamine transporter occupancy Proceedings of the National Academy of Sciences of the United States of America, September 1996^
155.Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence Drug and Alcohol Dependence, August 2008^
156.Dopamine reuptake transporter (DAT) "inverse agonism" – a novel hypothesis to explain the enigmatic pharmacology of cocaine Neuropharmacology, December 2014^
157.Neuropharmacological mechanisms underlying the neuroprotective effects of methylphenidate Current Neuropharmacology, December 2008^
158.Concerta Drugs.com, 1 October 2018, retrieved 11 March 2019^
159.Pharmacokinetics and clinical effectiveness of methylphenidate Clinical Pharmacokinetics, December 1999^
164.Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce Biopharmaceutics & Drug Disposition, September 2003^
165.Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1 The Journal of Pharmacology and Experimental Therapeutics, August 2004^
167.Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: A systematic review Addiction, April 2014^
168.Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT Pharmaceutical Research, October 1995^
169.Approaches to the Preparation of Enantiomerically Pure (2R,2R)-(+)-threo-Methylphenidate Hydrochloride Adv. Synth. Catal., 2001^
170.A Stereoselective Synthesis of dl-threo-Methylphenidate: Preparation and Biological Evaluation of Novel Analogues The Journal of Organic Chemistry, 1998^
171.Chemistry, design, and structure-activity relationship of cocaine antagonists Chemical Reviews, March 2000^
172.Disposition of Toxic Drugs and Chemicals in Man Biomedical Publications, 2011^
173.The history of attention deficit hyperactivity disorder Attention Deficit and Hyperactivity Disorders, December 2010^
174.Classics in chemical neuroscience: Methylphenidate ACS Chem Neurosci, August 2016^
175.Panizzon L. La preparazione di piridile piperidil-arilacetonitrili e di alcuni prodotti di trasformazione (Parte Ia) Helvetica Chimica Acta, 1944^
178.Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system CNS Drugs, 2006^
179.Ritalin, eine neuartige synthetische Verbindung mit spezifischer zentralerregender Wirkungskomponente Klinische Wochenschrift, May 1954^
180.Psychostimulants and cognition: A continuum of behavioral and cognitive activation Pharmacol Rev, 2014^
181.Pyridine and piperidine compounds and process of making same^
207.Metadate CD eMedTV: Health Information Brought To Life^
208.Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies BMC Psychiatry, September 2013^
227.Stimulant treatment of ADHD and cigarette smoking: A meta-analysis Pediatrics, June 2014^
228.Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature Pediatrics, January 2003^
229.Use of drugs for ADHD among adults-a multinational study among 15.8 million adults in the Nordic countries European Journal of Clinical Pharmacology, December 2016^
230.Prevalent intravenous abuse of methylphenidate among treatment-seeking patients with substance abuse disorders: a descriptive population-based study Journal of Addiction Medicine, 29 November 2016^
231.Legal issues in the treatment of children with attention deficit hyperactivity disorder Journal of Child Neurology, 1991^
232.Efficacy of methylphenidate for the treatment of apathy in patients with Alzheimer's disease: a systematic review and meta-analysis of randomized controlled studies Psychopharmacology (Berl), December 2022^
233.Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities Journal of Geriatric Psychiatry and Neurology, January 2017^
235.On the pathophysiology and treatment of akinetic mutism Neurosci Biobehav Rev, May 2020^
236.Effectiveness of Prescription-Based CNS Stimulants on Hospitalization in Patients With Schizophrenia: A Nation-Wide Register Study Schizophrenia Bulletin, January 2018^
237.Pharmacotherapy of methamphetamine addiction: an update Substance Abuse, 2008^
238.Replacement medication for cocaine dependence: methylphenidate Journal of Clinical Psychopharmacology, December 1997^
240.The principles of agonist pharmacotherapy for psychostimulant dependence Drug and Alcohol Review, May 2008^
241.Pharmacological treatment of attention-deficit hyperactivity disorder comorbid with an anxiety disorder: a systematic review Int Clin Psychopharmacol, March 2019^
242.Comorbidity in social anxiety disorder: diagnostic and therapeutic challenges Drugs Context, 2019^
243.Therapeutic strategies for social anxiety disorder: where are we now? Expert Rev Neurother, December 2019^
244.Methylphenidate treatment in children with attention deficit hyperactivity disorder and comorbid social phobia Int Clin Psychopharmacol, July 2014^
245.Extended-release Methylphenidate Treatment and Outcomes in Comorbid Social Anxiety Disorder and Attention-deficit/Hyperactivity Disorder: 2 Case Reports J Psychiatr Pract, May 2015^
246.Extended-release methylphenidate monotherapy in patients with comorbid social anxiety disorder and adult attention-deficit/hyperactivity disorder: retrospective case series Ther Adv Psychopharmacol, November 2017^
having sparked debate in the comment process among researchers engaged in the evaluation of the evidence-base.
However, the onset to peak effect is 2 hours, and the clinical effects remain up to 2 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 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.[83]
Repeated high-dose administration of methylphenidate has been shown to induce the expression of ΔFosB in D1-type medium spiny neurons of the nucleus accumbens, with accumbal ΔFosB levels accumulating over the long-term with chronic exposure due to its unusually long half-life.[116][117]Overexpression (i.e., a persistently excessive level of gene expression) of ΔFosB in this subset of neurons is a necessary and sufficient biomolecular mechanism for many of the neural adaptations and reward-related behavioral changes associated with drug addiction (e.g., reward sensitization and compulsive drug self-administration).[118][119][120]
