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Wikipedia

Methylphenidate

March 06, 2023

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD (e.g. in UK[11]); it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect, commonly ranging from 2–4 hours.[1] Methylphenidate's efficacy as a athletic performance enhancer, cognitive enhancer, aphrodisiac, and euphoriant is somewhat supported by research.[12][13][14][15][16][17][18][19][20] However, the manner in which methylphenidate is used for these purposes (high doses and temperatures, alternate routes of administration, etc.) can result in severe unintended side effects.[21][22][20]

Methylphenidate
Clinical data
Pronunciation/ˌmɛθəlˈfɛnɪdeɪt, -ˈfiː-/
Trade namesRitalin, Concerta, others
AHFS/Drugs.comMonograph
MedlinePlusa682188
License data
  • US DailyMed: Methylphenidate
  • US FDA: Methylphenidate
Pregnancy
category
  • AU: D
Dependence
liability		High[1]
Addiction
liability		High[2]
Routes of
administration		By mouth, transdermal[1]
Drug classCNS stimulant & NDRI
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityApprox. 30% (range: 11–52%)
Protein binding10–33%
MetabolismLiver (80%) mostly CES1A1-mediated
Elimination half-life2–3 hours[9]
Duration of actionInstant-release:
  • • Ritalin: 3–4 hours
Extended-release:
  • • Adhansia XR: 16 hours
  • • Concerta: 9–11 hours
  • • Ritalin LA: 6–7 hours
ExcretionUrine (90%)
Identifiers
  • Methyl phenyl(piperidin-2-yl)acetate
CAS Number
  • 20748-11-2 Y
PubChem CID
  • 4158
IUPHAR/BPS
  • 7236
DrugBank
  • DB00422 Y
ChemSpider
  • 4015 Y
UNII
  • 207ZZ9QZ49
KEGG
  • D04999 Y
ChEBI
  • CHEBI:6887 Y
ChEMBL
  • ChEMBL796 Y
CompTox Dashboard (EPA)
  • DTXSID5023299
ECHA InfoCard100.003.662
Chemical and physical data
FormulaC14H19NO2
Molar mass233.311 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point74 °C (165 °F) [10]
Boiling point136 °C (277 °F) [10]
  • COC(=O)C(c1ccccc1)C1CCCCN1
  • InChI=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 Y
  • Key:DUGOZIWVEXMGBE-UHFFFAOYSA-N Y
  (verify)

Common adverse reactions of methylphenidate include: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain.[5] Withdrawal symptoms may include: chills, depression, drowsiness, dysphoria, exhaustion, headache, irritability, lethargy, nightmares, restlessness, suicidal thoughts, and weakness.[1]

Methylphenidate is believed to work by blocking the reuptake of dopamine and norepinephrine by neurons.[23][24] It is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes. Despite the claim made by some urban legends, it is not a cocaine derivative nor analog; 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.[25][26]

Etymology

The word methylphenidate is a portmanteau of the chemical name, Methyl-2-phenyl-2-(piperidin-2-yl) acetate.

History

Methylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955.[27] It was originally sold by Swiss company CIBA (now Novartis).[27] It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012.[28] In 2020, it was the 41st most commonly prescribed medication in the United States, with more than 15 million prescriptions.[29][30] It is available as a generic medication.[1]

Uses

Methylphenidate is most commonly used to treat ADHD and narcolepsy.[31]

Attention deficit hyperactivity disorder

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder.[32] The addition of behavioural modification therapy can have additional benefits on treatment outcome.[33][34] The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose.[35] Immediate release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms.[36][37] Methylphenidate is not approved for children under six years of age.[38][39]

In children over age 6 and adolescents, the short-term benefits and cost effectiveness of methylphenidate are well established.[40][41] A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.[42][43][44]

Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms.[45] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[42] There is evidence to suggest that children diagnosed with ADHD who do not receive treatment will have an increased risk of substance use disorders as adults.[46][47]

The precise magnitude of improvement in ADHD symptoms and quality of life that are produced by methylphenidate treatment remains uncertain as of November 2015.[48] Methylphenidate is not included in the World Health Organization Essential Medicines List, as findings by the World Health Organization indicate that evidence of benefit versus harm to be unclear in the treatment of ADHD.[49] A 2021 systematic review did not find clear evidence for using IR Methylphenidate (immediate-release) for adults.[50]

Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a "study drug" by some populations, which may be harmful.[51] This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD.[51] People in this category can then experience negative side-effects of the drug which worsen their condition.[51]

Narcolepsy

Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[52] 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.[53]

Other medical uses

Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder.[54] It can also improve depression in several groups including stroke, cancer, and HIV-positive patients.[55] There is weak evidence in favor of methylphenidate's effectiveness for depression,[56] including providing additional benefit in combination with antidepressants.[57] 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.[58] 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.[59] 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.[60]

Enhancing performance

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;[61][a][62][b] 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.[61] Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal.[63][64] Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks,[63][c][64][65] and are used by some students as a study and test-taking aid.[51][66] 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.[67]

Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control.[63][64] Like amphetamine and bupropion, methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system.[68] Similar to the loss of cognitive enhancement when using large amounts, large doses of methylphenidate can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia.[8] While literature suggests it might improve cognition, most authors agree that using the drug as a study aid when ADHD diagnosis is not present does not actually improve GPA.[51] Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.[51]

Contraindications

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[8]

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks.[69] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.[70] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".[71]

Adverse effects

 
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.[72]

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia.[73] Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), oromandibular dystonia,[74] 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).[75] Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.[76][77]

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.[78]

There is some evidence of mild reductions in height with prolonged treatment in children.[79] This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.[80][81]

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.[82]

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.[83] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[84] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[79] Logorrhea is occasionally reported. Libido disorders, disorientation, and visual hallucinations are very rarely reported.[76] Priapism is a very rare adverse event that can be potentially serious.[85]

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.[86]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[87]

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.[88]

A 2018 review found tentative evidence that it may cause both serious and non-serious adverse effects in children.[89][d]

Overdose

The symptoms of a moderate acute overdose on 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.[8][90] A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse.[8][90][91][e] A methylphenidate overdose is rarely fatal with appropriate care.[91] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[92]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies.[91]

 
Packaging of a formulation of methylphenidate advises against crushing the tablets. It is placed under Schedule X of the Indian drug scheduling system. Schedule 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 amphetamine. It has moderate liability among addictive drugs;[93][94] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug.[94] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.[95]

Biomolecular mechanisms

Further information: Addiction § Biomolecular mechanisms

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.[94]

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.[7] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[96][97][98][99]

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[100][101] not unlike the hepatic formation of cocaethylene from 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.[102][101]

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[103]

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.[104]

Pharmacology

Pharmacodynamics

Binding profile[105][106][107]
Neurotransmitter
transporter 		Measure
(units) 		dl-MPH d-MPH l-MPH
DAT Ki (nM) 121 161 2250
IC50 (nM) 20 23 1600
NET Ki (nM) 788 206 >10000
IC50 (nM) 51 39 980
SERT Ki (nM) >10000 >10000 >6700
IC50 (nM) — >10000 >10000
GPCR Measure
(units) 		dl-MPH d-MPH l-MPH
5-HT1A Ki (nM) 5000 3400 >10000
IC50 (nM) 10000 6800 >10000
5-HT2B Ki (nM) >10000 4700 >10000
IC50 (nM) >10000 4900 >10000

Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative 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. 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 mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus.[108] 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.[102] 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.[108][109]

Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE).[110] Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET).[111] 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.[112] On average, methylphenidate elicits a 3–4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex.[113] 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.[114][115][116][f]

Both amphetamine and methylphenidate are predominantly dopaminergic drugs, yet their mechanisms of action are distinct. Methylphenidate acts as a norepinephrine–dopamine reuptake inhibitor, while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. 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,[117][118][119] 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.[120][121][g][122][h] 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.[120][better source needed]

Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter.[citation needed] Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed.[107] A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.[123]

There exist some paradoxical findings that oppose the notion that methylphenidate acts primarily through DAT inhibition. 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 still produce euphoriant effects.[124] By contrast, other DAT inhibitors such as bupropion have not been observed to exhibit this effect.[125] These observations help corroborate the hypothesis that methylphenidate may act as a "DAT inverse agonist" by reversing the direction of the dopamine efflux by the DAT at higher dosages.[126]

Methylphenidate may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine use disorder.[127] 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.[127]

The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.[110] The studied maximized daily dosage of OROS methylphenidate appears to be 144 mg/day.[128]

Pharmacokinetics

Further information: § Available forms

Methylphenidate taken by mouth has a bioavailability of 11–52% with a duration of action around 2–4 hours for instant release (i.e. Ritalin), 3–8 hours for sustained release (i.e. Ritalin SR), and 8–12 hours for extended release (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.[9] Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.[6]

Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.[9]

The oral bioavailability and speed of absorption for immediate-release methylphenidate is increased when administered with a meal.[129] 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[130] while liquid-based extended release formulations showed increased Cmax levels when administered with a high fat meal, according to some researchers.[131] A 2003 study, however, showed no difference between a high fat meal administration and a fasting administration of oral methylphenidate.[132]

Methylphenidate is metabolized into ritalinic acid by CES1A1 enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate.[133] 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.[6]

Chemistry

See also: List of methylphenidate analogues

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.[110][134] 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.[135]

Methylphenidate synthesis
 
Method 1: Methylphenidate preparation elucidated by Axten et al. (1998)[136] via Bamford-Stevens reaction.
 
Method 2: Classic methylphenidate synthesis[137]

Detection in biological fluids

The concentration of methylphenidate or ritalinic acid, its major 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.[138]

History

Methylphenidate was first synthesized in 1944.[139][140] It was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure.[141] Methylphenidate was not reported to be a stimulant until 1954.[142][143] The drug was introduced for medical use in the United States in 1957.[144] Originally, it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo, under the brand name Centedrin.[142] 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.[142][145][146][147] The erythro isomer was eliminated and now modern formulations of methyphenidate contain only the threo isomer at a 50:50 mixture of d- and l-isomers.[142]

Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression.[148] It was later used to treat memory deficits in the elderly.[149] 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[150] on the use of psychostimulant drugs, such as Benzedrine, with then called "maladjusted children".[151] 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.[152]

In 2000, Alza Corporation received US FDA approval to market Concerta, an extended-release form of methylphenidate.[7][153][154]

Society and culture

Names

  •  

    Swiss "Ritalin" brand methylphenidate.

  •  

    Indian "AddWize" branded instant release and extended release formulations costing US$1.9 for strip of instant release and US$2.9 for a strip of AddWize extended release.

  •  

    Clockwise from top: Concerta 18 mg, Medikinet 5 mg, Methylphenidat TAD 10 mg, Ritalin 10 mg, Medikinet XL 30 mg.

Methylphenidate is sold in the majority of countries worldwide.[155]: 8–9  Brand names for methylphenidate include Ritalin (in honor to Rita, the wife of the molecule discoverer), Rilatin (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta,[7] Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Equasym, Foquest,[156] Methylin, Penid, Phenida, Prohiper, and Tradea.[155]: 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. In some circumstances it may be prescribed instead of methylphenidate, however it has no significant advantages over methylphenidate at equally potent doses, and so it is sometimes considered to be an example of an "evergreened" drug.[157]

Immediate-release

  •  

    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.[5]

  •  

    Structural formula for the substance inside Concerta tablet. Following administration of Concerta, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.[7] Note that the substance is the same as for Concerta - the differences lies in other aspects of the individual pills.

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]

Extended-release

Extended-release methylphenidate products include:

Brand name(s) Generic name(s)[158][159][160][161] Duration Dosage
form
Aptensio XR (US);
Biphentin (CA) 		Currently unavailable 12 hours[162][163] XR
capsule
Concerta (US/CA);
Concerta XL (UK) 		methylphenidate ER (US/CA);[i]
methylphenidate ER‑C (CA)[ii]		 12 hours[164] OROS
tablet
Quillivant XR (US) Currently unavailable 12 hours[164] oral
suspension
Daytrana (US) methylphenidate film, extended release;transdermal (US)[iii] 11 hours[165] transdermal
patch
Metadate CD (US);
Equasym XL (UK) 		methylphenidate ER (US)[iv] 8–10 hours[164] CD/XL
capsule
QuilliChew ER (US) Currently unavailable 8 hours[166] chewable
tablet
Ritalin LA (US);
Medikinet XL (UK) 		methylphenidate ER (US)[v] 8 hours[164] ER
capsule
Ritalin SR (US/CA/UK);
Rubifen SR (NZ) 		Metadate ER (US);[vi]
Methylin ER (US);[vii]
methylphenidate SR (US/CA)[viii]		 5–8 hours[164] CR
tablet
  1. ^ US generic manufactured by Actavis; CA generics manufactured by Pharmascience and Apotex.
  2. ^ Manufactured by Teva.
  3. ^ Manufactured by Mylan Tech Viatris
  4. ^ Manufactured by Impax, Mallinckrodt, and Teva.
  5. ^ Manufactured by Barr and Mayne.
  6. ^ Manufactured by UCB.
  7. ^ Manufactured by Mallinckrodt.
  8. ^ US generics manufactured by County Line Pharmaceuticals and Abhai; CA generic manufactured by Apotex.

Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the mg dosage strength. Approximately 22% of the dose is immediate release,[167] and the remaining 78% of the dose is released over 10–12 hours post-ingestion, with an initial increase over the first 6 to 7 hours, and subsequent decline in released drug.[168]

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[75] 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.[169]

Medikinet Retard/CR/Adult/Modified Release tablets is an extended-release oral capsule form of Methylphenidate. It delivers 50% of dosage as IR MPH and the remaining 50% in 3–4 hours.[citation needed]

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.[8] 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.[170]

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%).[171]

A 39 nanograms/mL peak serum concentration of methylphenidate be has been found to occur between 7.5–10.5 hours after administration.[8] However the onset to peak effect is 2 hours and the clinical effects remain up to 2 hours after 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.[8]

Cost

 
Ritalin 10 mg tablet

Brand-name and generic formulations are available.[1]

Legal status

 
Legal warning printed on Ritalin packaging
  • Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[172]
  • In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for misuse.
  • In the United Kingdom, methylphenidate is a controlled 'Class B' substance. Possession without prescription carries a sentence up to 5 years or an unlimited fine, or both; supplying methylphenidate is 14 years or an unlimited fine, or both.[173]
  • In Canada, methylphenidate is listed in 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.[174]
  • 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.
  • In Australia, methylphenidate is a 'Schedule 8' controlled substance.[175] Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment.
  • In Russia, methylphenidate is a List 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.[176]
  • In Sweden, methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.[177]
  • In France, methylphenidate is covered by the "narcotics" schedule, prescription and distribution conditions are restricted with hospital-only prescription for the initial treatment and yearly consultations.[178]
  • In India, methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule, 1945. It is dispensed only by physician's prescription.[179] Legally, 2 grams of methylphenidate are classified as a small quantity, and 50 grams as a large or commercial quantity.[180]
  • In Hong Kong, methylphenidate is controlled under the schedule 1 of the Dangerous Drugs Ordinance (cap. 134).[181]

Controversy

Further information: Attention deficit hyperactivity disorder controversies § Concerns about medication

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.[182][need quotation to verify] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,[183] 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".[184] A study found that ADHD medication was not associated with increased risk of cigarette use, and in fact stimulant treatments such as Ritalin seemed to lower this risk.[185] People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.[186]

Among countries with the highest rates of use of methylphenidate medication is Iceland,[187] where research shows that the drug was the most commonly used substance among people who inject drugs.[188] 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.[189]

Research

Methylphenidate may be effective as a treatment for apathy in Alzheimer's disease.[190]

Replacement therapy

Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine.[191] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction.[192][193] Its effectiveness in treatment of cocaine, psychostimulant addiction or psychological dependence has not been proven.[194]

Footnotes

  1. ^ 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.[61]
  2. ^ 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.[62]
  3. ^ 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.[63]
  4. ^ 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.[89]
  5. ^ 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.[91]
  6. ^ 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.[116]
  7. ^ 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.[121]
  8. ^ 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.[122]

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  • "Methylphenidate". Drug Information Portal. U.S. National Library of Medicine.

March 06, 2023
methylphenidate, sold, under, brand, names, ritalin, concerta, among, others, central, nervous, system, stimulant, used, medically, treat, attention, deficit, hyperactivity, disorder, adhd, lesser, extent, narcolepsy, primary, medication, adhd, taken, mouth, a. Methylphenidate sold under the brand names Ritalin and Concerta among others is a central nervous system CNS stimulant used medically to treat attention deficit hyperactivity disorder ADHD and to a lesser extent narcolepsy It is a primary medication for ADHD e g in UK 11 it may be taken by mouth or applied to the skin and different formulations have varying durations of effect commonly ranging from 2 4 hours 1 Methylphenidate s efficacy as a athletic performance enhancer cognitive enhancer aphrodisiac and euphoriant is somewhat supported by research 12 13 14 15 16 17 18 19 20 However the manner in which methylphenidate is used for these purposes high doses and temperatures alternate routes of administration etc can result in severe unintended side effects 21 22 20 MethylphenidateClinical dataPronunciation ˌ m ɛ 8 el ˈ f ɛ n ɪ d eɪ t ˈ f iː Trade namesRitalin Concerta othersAHFS Drugs comMonographMedlinePlusa682188License dataUS DailyMed Methylphenidate US FDA MethylphenidatePregnancycategoryAU DDependenceliabilityHigh 1 AddictionliabilityHigh 2 Routes ofadministrationBy mouth transdermal 1 Drug classCNS stimulant amp NDRIATC codeN06BA04 WHO Legal statusLegal statusAU S8 Controlled drug CA Schedule III 3 4 DE Anlage III Special prescription form required UK Class B US Schedule II 5 6 7 8 UN Psychotropic Schedule IIPharmacokinetic dataBioavailabilityApprox 30 range 11 52 Protein binding10 33 MetabolismLiver 80 mostly CES1A1 mediatedElimination half life2 3 hours 9 Duration of actionInstant release Ritalin 3 4 hours Extended release Adhansia XR 16 hours Concerta 9 11 hours Ritalin LA 6 7 hoursExcretionUrine 90 IdentifiersIUPAC name Methyl phenyl piperidin 2 yl acetateCAS Number20748 11 2 YPubChem CID4158IUPHAR BPS7236DrugBankDB00422 YChemSpider4015 YUNII207ZZ9QZ49KEGGD04999 YChEBICHEBI 6887 YChEMBLChEMBL796 YCompTox Dashboard EPA DTXSID5023299ECHA InfoCard100 003 662Chemical and physical dataFormulaC 14H 19N O 2Molar mass233 311 g mol 13D model JSmol Interactive imageMelting point74 C 165 F 10 Boiling point136 C 277 F 10 SMILES COC O C c1ccccc1 C1CCCCN1InChI InChI 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 YKey DUGOZIWVEXMGBE UHFFFAOYSA N Y verify Common adverse reactions of methylphenidate include tachycardia palpitations headache insomnia anxiety hyperhidrosis weight loss decreased appetite dry mouth nausea and abdominal pain 5 Withdrawal symptoms may include chills depression drowsiness dysphoria exhaustion headache irritability lethargy nightmares restlessness suicidal thoughts and weakness 1 Methylphenidate is believed to work by blocking the reuptake of dopamine and norepinephrine by neurons 23 24 It is a central nervous system CNS stimulant of the phenethylamine and piperidine classes Despite the claim made by some urban legends it is not a cocaine derivative nor analog 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 25 26 Contents 1 Etymology 2 History 3 Uses 3 1 Attention deficit hyperactivity disorder 3 2 Narcolepsy 3 3 Other medical uses 3 4 Enhancing performance 4 Contraindications 5 Adverse effects 5 1 Overdose 5 2 Addiction and dependence 5 2 1 Biomolecular mechanisms 6 Interactions 7 Pharmacology 7 1 Pharmacodynamics 7 2 Pharmacokinetics 8 Chemistry 8 1 Detection in biological fluids 9 History 10 Society and culture 10 1 Names 10 2 Available forms 10 2 1 Immediate release 10 2 2 Extended release 10 2 3 Skin patch 10 3 Cost 10 4 Legal status 10 5 Controversy 11 Research 11 1 Replacement therapy 12 Footnotes 13 References 14 External linksEtymology EditThe word methylphenidate is a portmanteau of the chemical name Methyl 2 phenyl 2 piperidin 2 yl acetate History EditMethylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955 27 It was originally sold by Swiss company CIBA now Novartis 27 It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66 compared to 2012 28 In 2020 it was the 41st most commonly prescribed medication in the United States with more than 15 million prescriptions 29 30 It is available as a generic medication 1 Uses EditMethylphenidate is most commonly used to treat ADHD and narcolepsy 31 Attention deficit hyperactivity disorder Edit Methylphenidate is used for the treatment of attention deficit hyperactivity disorder 32 The addition of behavioural modification therapy can have additional benefits on treatment outcome 33 34 The dosage may vary and is titrated to effect with some guidelines recommending initial treatment with a low dose 35 Immediate release methylphenidate is used daily along with the longer acting form to achieve full day control of symptoms 36 37 Methylphenidate is not approved for children under six years of age 38 39 In children over age 6 and adolescents the short term benefits and cost effectiveness of methylphenidate are well established 40 41 A number of reviews have established the safety and effectiveness for individuals with ADHD over several years 42 43 44 Approximately 70 of those who use methylphenidate see improvements in ADHD symptoms 45 Children with ADHD who use stimulant medications generally have better relationships with peers and family members perform better in school are less distractible and impulsive and have longer attention spans 42 There is evidence to suggest that children diagnosed with ADHD who do not receive treatment will have an increased risk of substance use disorders as adults 46 47 The precise magnitude of improvement in ADHD symptoms and quality of life that are produced by methylphenidate treatment remains uncertain as of November 2015 48 Methylphenidate is not included in the World Health Organization Essential Medicines List as findings by the World Health Organization indicate that evidence of benefit versus harm to be unclear in the treatment of ADHD 49 A 2021 systematic review did not find clear evidence for using IR Methylphenidate immediate release for adults 50 Since ADHD diagnosis has increased around the world methylphenidate may be misused as a study drug by some populations which may be harmful 51 This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD 51 People in this category can then experience negative side effects of the drug which worsen their condition 51 Narcolepsy Edit Narcolepsy a chronic sleep disorder characterized by overwhelming daytime drowsiness and uncontrollable sleep is treated primarily with stimulants Methylphenidate is considered effective in increasing wakefulness vigilance and performance 52 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 53 Other medical uses Edit Methylphenidate may also be prescribed for off label use in treatment resistant cases of bipolar disorder and major depressive disorder 54 It can also improve depression in several groups including stroke cancer and HIV positive patients 55 There is weak evidence in favor of methylphenidate s effectiveness for depression 56 including providing additional benefit in combination with antidepressants 57 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 58 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 59 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 60 Enhancing performance Edit 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 61 a 62 b the cognition enhancing effects of these drugs are known to occur through the indirect activation of both dopamine receptor D1 and adrenoceptor a2 in the prefrontal cortex 61 Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal 63 64 Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks 63 c 64 65 and are used by some students as a study and test taking aid 51 66 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 67 Excessive doses of methylphenidate above the therapeutic range can interfere with working memory and cognitive control 63 64 Like amphetamine and bupropion methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system 68 Similar to the loss of cognitive enhancement when using large amounts large doses of methylphenidate can induce side effects that impair athletic performance such as rhabdomyolysis and hyperthermia 8 While literature suggests it might improve cognition most authors agree that using the drug as a study aid when ADHD diagnosis is not present does not actually improve GPA 51 Moreover it has been suggested that students who use the drug for studying may be self medicating for potentially deeper underlying issues 51 Contraindications EditMethylphenidate is contraindicated for individuals using monoamine oxidase inhibitors e g phenelzine and tranylcypromine or individuals with agitation tics glaucoma heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals 8 Pregnant women are advised to only use the medication if the benefits outweigh the potential risks 69 Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development 70 In 2018 a review concluded that it has not been teratogenic in rats and rabbits and that it is not a major human teratogen 71 Adverse effects Edit Addiction experts in psychiatry chemistry pharmacology forensic science epidemiology and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs Methylphenidate was ranked 13th in dependence 12th in physical harm and 18th in social harm 72 The most common side effects associated with methylphenidate in standard and extended release formulations are appetite loss dry mouth anxiety nervousness nausea and insomnia 73 Gastrointestinal adverse effects may include abdominal pain and weight loss Nervous system adverse effects may include akathisia agitation restlessness irritability dyskinesia tics oromandibular dystonia 74 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 75 Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes with less frequent reports of diplopia and mydriasis 76 77 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 78 There is some evidence of mild reductions in height with prolonged treatment in children 79 This has been estimated at 1 centimetre 0 4 in or less per year during the first three years with a total decrease of 3 centimetres 1 2 in over 10 years 80 81 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 82 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 83 It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania 84 There have been very rare reports of suicidal ideation but some authors claim that evidence does not support a link 79 Logorrhea is occasionally reported Libido disorders disorientation and visual hallucinations are very rarely reported 76 Priapism is a very rare adverse event that can be potentially serious 85 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 86 Because some adverse effects may only emerge during chronic use of methylphenidate a constant watch for adverse effects is recommended 87 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 88 A 2018 review found tentative evidence that it may cause both serious and non serious adverse effects in children 89 d Overdose Edit The symptoms of a moderate acute overdose on 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 8 90 A severe overdose may involve symptoms such as hyperpyrexia sympathomimetic toxidrome convulsions paranoia stereotypy a repetitive movement disorder rhabdomyolysis coma and circulatory collapse 8 90 91 e A methylphenidate overdose is rarely fatal with appropriate care 91 Following injection of methylphenidate tablets into an artery severe toxic reactions involving abscess formation and necrosis have been reported 92 Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines with antipsychotics a adrenoceptor agonists and propofol serving as second line therapies 91 Packaging of a formulation of methylphenidate advises against crushing the tablets It is placed under Schedule X of the Indian drug scheduling system Schedule X medications typically hold abusable medications such as barbiturates or stimulants such as amphetamines Addiction and dependence Edit Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine It has moderate liability among addictive drugs 93 94 accordingly addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug 94 When used above the medical dose range stimulants are associated with the development of stimulant psychosis 95 Biomolecular mechanisms Edit Further information Addiction Biomolecular mechanisms 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 94 Interactions EditMethylphenidate 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 7 There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants 96 97 98 99 When methylphenidate is coingested with ethanol a metabolite called ethylphenidate is formed via hepatic transesterification 100 101 not unlike the hepatic formation of cocaethylene from 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 102 101 Coingestion of alcohol ethanol also increases the blood plasma levels of d methylphenidate by up to 40 103 Liver toxicity from methylphenidate is extremely rare but limited evidence suggests that intake of b adrenergic agonists with methylphenidate may increase the risk of liver toxicity 104 Pharmacology EditPharmacodynamics Edit Binding profile 105 106 107 Neurotransmittertransporter Measure units dl MPH d MPH l MPHDAT Ki nM 121 161 2250IC50 nM 20 23 1600NET Ki nM 788 206 gt 10000IC50 nM 51 39 980SERT Ki nM gt 10000 gt 10000 gt 6700IC50 nM gt 10000 gt 10000GPCR Measure units dl MPH d MPH l MPH5 HT1A Ki nM 5000 3400 gt 10000IC50 nM 10000 6800 gt 100005 HT2B Ki nM gt 10000 4700 gt 10000IC50 nM gt 10000 4900 gt 10000Methylphenidate primarily acts as a norepinephrine dopamine reuptake inhibitor NDRI It is a benzylpiperidine and phenethylamine derivative 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 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 mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus 108 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 102 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 108 109 Methylphenidate is most active at modulating levels of dopamine DA and to a lesser extent norepinephrine NE 110 Methylphenidate binds to and blocks dopamine transporters DAT and norepinephrine transporters NET 111 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 112 On average methylphenidate elicits a 3 4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex 113 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 114 115 116 f Both amphetamine and methylphenidate are predominantly dopaminergic drugs yet their mechanisms of action are distinct Methylphenidate acts as a norepinephrine dopamine reuptake inhibitor while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine 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 117 118 119 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 120 121 g 122 h 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 120 better source needed Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter citation needed Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes though direct binding to the serotonin transporter was not observed 107 A later study confirmed the d threo methylphenidate dexmethylphenidate binding to the 5HT1A receptor but no significant activity on the 5HT2B receptor was found 123 There exist some paradoxical findings that oppose the notion that methylphenidate acts primarily through DAT inhibition 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 still produce euphoriant effects 124 By contrast other DAT inhibitors such as bupropion have not been observed to exhibit this effect 125 These observations help corroborate the hypothesis that methylphenidate may act as a DAT inverse agonist by reversing the direction of the dopamine efflux by the DAT at higher dosages 126 Methylphenidate may protect neurons from the neurotoxic effects of Parkinson s disease and methamphetamine use disorder 127 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 127 The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers and some medications therefore only contain dexmethylphenidate 110 The studied maximized daily dosage of OROS methylphenidate appears to be 144 mg day 128 Pharmacokinetics Edit Further information Available forms Methylphenidate taken by mouth has a bioavailability of 11 52 with a duration of action around 2 4 hours for instant release i e Ritalin 3 8 hours for sustained release i e Ritalin SR and 8 12 hours for extended release 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 9 Methylphenidate has a low plasma protein binding of 10 33 and a volume of distribution of 2 65 L kg 6 Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally and is primarily responsible for the psychoactivity of racemic methylphenidate 9 The oral bioavailability and speed of absorption for immediate release methylphenidate is increased when administered with a meal 129 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 130 while liquid based extended release formulations showed increased Cmax levels when administered with a high fat meal according to some researchers 131 A 2003 study however showed no difference between a high fat meal administration and a fasting administration of oral methylphenidate 132 Methylphenidate is metabolized into ritalinic acid by CES1A1 enzymes in the liver Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate 133 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 6 Chemistry EditSee also List of methylphenidate analogues 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 110 134 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 135 Methylphenidate synthesis Method 1 Methylphenidate preparation elucidated by Axten et al 1998 136 via Bamford Stevens reaction Method 2 Classic methylphenidate synthesis 137 Detection in biological fluids Edit The concentration of methylphenidate or ritalinic acid its major 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 138 History EditMethylphenidate was first synthesized in 1944 139 140 It was synthesized by Ciba now Novartis chemist Leandro Panizzon He named the drug after his wife Margarita nicknamed Rita who used Ritalin to compensate for low blood pressure 141 Methylphenidate was not reported to be a stimulant until 1954 142 143 The drug was introduced for medical use in the United States in 1957 144 Originally it was marketed as a mixture of two racemates 80 erythro and 20 threo under the brand name Centedrin 142 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 142 145 146 147 The erythro isomer was eliminated and now modern formulations of methyphenidate contain only the threo isomer at a 50 50 mixture of d and l isomers 142 Methylphenidate was first used to allay barbiturate induced coma narcolepsy and depression 148 It was later used to treat memory deficits in the elderly 149 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 150 on the use of psychostimulant drugs such as Benzedrine with then called maladjusted children 151 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 152 In 2000 Alza Corporation received US FDA approval to market Concerta an extended release form of methylphenidate 7 153 154 Society and culture EditNames Edit Swiss Ritalin brand methylphenidate Indian AddWize branded instant release and extended release formulations costing US 1 9 for strip of instant release and US 2 9 for a strip of AddWize extended release Clockwise from top Concerta 18 mg Medikinet 5 mg Methylphenidat TAD 10 mg Ritalin 10 mg Medikinet XL 30 mg Methylphenidate is sold in the majority of countries worldwide 155 8 9 Brand names for methylphenidate include Ritalin in honor to Rita the wife of the molecule discoverer Rilatin in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company Concerta 7 Medikinet Adaphen Addwize Inspiral Methmild Artige Attenta Cognil Equasym Foquest 156 Methylin Penid Phenida Prohiper and Tradea 155 8 9 Available forms Edit 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 In some circumstances it may be prescribed instead of methylphenidate however it has no significant advantages over methylphenidate at equally potent doses and so it is sometimes considered to be an example of an evergreened drug 157 Immediate release Edit 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 5 Structural formula for the substance inside Concerta tablet Following administration of Concerta plasma concentrations of the l isomer were approximately 1 40 the plasma concentrations of the d isomer 7 Note that the substance is the same as for Concerta the differences lies in other aspects of the individual pills 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 Extended release Edit Extended release methylphenidate products include Brand name s Generic name s 158 159 160 161 Duration DosageformAptensio XR US Biphentin CA Currently unavailable 12 hours 162 163 XRcapsuleConcerta US CA Concerta XL UK methylphenidate ER US CA i methylphenidate ER C CA ii 12 hours 164 OROStabletQuillivant XR US Currently unavailable 12 hours 164 oralsuspensionDaytrana US methylphenidate film extended release transdermal US iii 11 hours 165 transdermalpatchMetadate CD US Equasym XL UK methylphenidate ER US iv 8 10 hours 164 CD XLcapsuleQuilliChew ER US Currently unavailable 8 hours 166 chewabletabletRitalin LA US Medikinet XL UK methylphenidate ER US v 8 hours 164 ERcapsuleRitalin SR US CA UK Rubifen SR NZ Metadate ER US vi Methylin ER US vii methylphenidate SR US CA viii 5 8 hours 164 CRtablet US generic manufactured by Actavis CA generics manufactured by Pharmascience and Apotex Manufactured by Teva Manufactured by Mylan Tech Viatris Manufactured by Impax Mallinckrodt and Teva Manufactured by Barr and Mayne Manufactured by UCB Manufactured by Mallinckrodt US generics manufactured by County Line Pharmaceuticals and Abhai CA generic manufactured by Apotex Concerta tablets are marked with the letters ALZA and followed by 18 27 36 or 54 relating to the mg dosage strength Approximately 22 of the dose is immediate release 167 and the remaining 78 of the dose is released over 10 12 hours post ingestion with an initial increase over the first 6 to 7 hours and subsequent decline in released drug 168 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 75 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 169 Medikinet Retard CR Adult Modified Release tablets is an extended release oral capsule form of Methylphenidate It delivers 50 of dosage as IR MPH and the remaining 50 in 3 4 hours citation needed Skin patch Edit 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 8 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 170 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 27 171 A 39 nanograms mL peak serum concentration of methylphenidate be has been found to occur between 7 5 10 5 hours after administration 8 However the onset to peak effect is 2 hours and the clinical effects remain up to 2 hours after 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 8 Cost Edit Ritalin 10 mg tablet Brand name and generic formulations are available 1 Legal status Edit Legal warning printed on Ritalin packaging Internationally methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances 172 In the United States methylphenidate is classified as a Schedule II controlled substance the designation used for substances that have a recognized medical value but present a high potential for misuse In the United Kingdom methylphenidate is a controlled Class B substance Possession without prescription carries a sentence up to 5 years or an unlimited fine or both supplying methylphenidate is 14 years or an unlimited fine or both 173 In Canada methylphenidate is listed in 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 174 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 In Australia methylphenidate is a Schedule 8 controlled substance 175 Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment In Russia methylphenidate is a List 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 176 In Sweden methylphenidate is a List II controlled substance with recognized medical value Possession without a prescription is punishable by up to three years in prison 177 In France methylphenidate is covered by the narcotics schedule prescription and distribution conditions are restricted with hospital only prescription for the initial treatment and yearly consultations 178 In India methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule 1945 It is dispensed only by physician s prescription 179 Legally 2 grams of methylphenidate are classified as a small quantity and 50 grams as a large or commercial quantity 180 In Hong Kong methylphenidate is controlled under the schedule 1 of the Dangerous Drugs Ordinance cap 134 181 Controversy Edit Further information Attention deficit hyperactivity disorder controversies Concerns about medication 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 182 need quotation to verify The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources 183 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 184 A study found that ADHD medication was not associated with increased risk of cigarette use and in fact stimulant treatments such as Ritalin seemed to lower this risk 185 People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood 186 Among countries with the highest rates of use of methylphenidate medication is Iceland 187 where research shows that the drug was the most commonly used substance among people who inject drugs 188 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 189 Research EditMethylphenidate may be effective as a treatment for apathy in Alzheimer s disease 190 Replacement therapy Edit Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine 191 Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction 192 193 Its effectiveness in treatment of cocaine psychostimulant addiction or psychological dependence has not been proven 194 Footnotes Edit 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 a2 and dopamine D1 receptors This differential modulation of PFC dependent processes across dose appears to be associated with the differential involvement of noradrenergic a2 versus a1 receptors 61 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 62 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 63 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 89 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 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