Methylphenidate

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Methylphenidate
Clinical data
Pronunciation/ˌmɛθəlˈfɛnɪdt, -ˈf-/
Trade namesRitalin, Concerta, others
Other namesMPH[1]
AHFS/Drugs.comMonograph
MedlinePlusa682188
License data
Pregnancy
category
  • AU: D
sublingual, transdermal[2]
Drug classCentral nervous system stimulant & norepinephrine–dopamine reuptake inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityInsufflation: approx. 70% Oral: approx. 30% (range: 11–52%)
Protein binding10–33%
MetabolismLiver (80%) mostly CES1A1-mediated
Elimination half-life2–3 hours[12]
Duration of action
  • Instant-release: 3-4 hours
  • Extended-release: 6-12 hours
ExcretionUrine (90%)
Identifiers
  • Methyl phenyl(piperidin-2-yl)acetate
JSmol)
Melting point74 °C (165 °F) [13]
Boiling point136 °C (277 °F) [13]
  • 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 checkY
  • Key:DUGOZIWVEXMGBE-UHFFFAOYSA-N checkY
  (verify)

Methylphenidate, sold under the brand names Ritalin (

UK[14]); 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.[2] For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine[15][16][17][18] but modestly lower than amphetamines.[19][20][21][22]

Common adverse reactions of methylphenidate include:

Methylphenidate is believed to work by blocking the

generic medication.[25] In 2021, it was the 43rd most commonly prescribed medication in the United States, with more than 15.2 million prescriptions.[26][27]

Etymology

The word methylphenidate is a

portmanteau
of the chemical name, Methyl-2-phenyl-2-(piperidin-2-yl) acetate.

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 Ritalin, and described its effects to her husband.[28]

Uses

Methylphenidate is most commonly used to treat ADHD and narcolepsy.[29]

Attention deficit hyperactivity disorder

Methylphenidate is used for the treatment of

titrated to effect, with some guidelines recommending initial treatment with a low dose.[31] Methylphenidate is available in both immediate-release and extended-release (XR) formulations to provide a sustained release of the drug.[32][33] Methylphenidate is not approved for children under six years of age.[34][35]

The precise magnitude of improvement in ADHD symptoms and quality of life produced by methylphenidate treatment remains uncertain as of March 2023[update].

World Health Organization Essential Medicines List, as findings by the World Health Organization indicate evidence of benefit versus harm to be unclear in the treatment of ADHD.[37] A 2021 systematic review did not find clear evidence for using IR methylphenidate (immediate-release) for adults.[38]

Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a "study drug" by some populations, which may be harmful.[39] This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD.[39] People in this category can then experience negative side-effects of the drug, which worsen their condition.[39]

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.[40] 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.[41]

Other medical uses

Methylphenidate may also be prescribed for

HIV-positive patients.[43] There is weak evidence in favor of methylphenidate's effectiveness for depression,[44] including providing additional benefit in combination with antidepressants.[45] 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.[46] 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.[47] 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.[48]

Enhancing performance

Methylphenidate's efficacy as an

euphoriant is supported by research.[49][50][51][52][53][54][55][56][57] 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.[58][59][57]
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;[60][a][61][b] the cognition-enhancing effects of these drugs are known to occur through the
recreational drug, is the primary reason that students use stimulants.[66]

Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and

GPA.[39] Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.[39]

Contraindications

Methylphenidate is

heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[11]

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks.

teratogenic in rats and rabbits, and that it "is not a major human teratogen".[70]

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.[71]

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are

Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.[contradictory][74][75]

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.[76]

There is some evidence of mild reductions in height with prolonged treatment in children.[77] 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.[78][79]

Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.[80]

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.[81] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[82] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[77] Logorrhea is occasionally reported and visual hallucinations are very rarely reported.[74] Priapism is a very rare adverse event that can be potentially serious.[83]

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

sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.[84]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[85]

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.[86]

The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.[86][d]

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from

circulatory collapse.[11][87][88][e]
A methylphenidate overdose is rarely fatal with appropriate care.[88] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[89]

Treatment of a methylphenidate overdose typically involves the administration of

α-adrenoceptor agonists and propofol serving as second-line therapies.[88]

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

addictive drugs;[90][91] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug.[91] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.[92]

Biomolecular mechanisms

Methylphenidate has the potential to induce

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.[91]

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.[10] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[93][94][95][96]

When methylphenidate is coingested with

hepatic transesterification,[97][98] 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.[99][98]

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[100]

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.[101]

Pharmacology

Pharmacodynamics

Binding profile[102][103][104]
Neurotransmitter
transporter
Measure
(units)
dl-MPH d-MPH l-MPH
DAT
nM
Tooltip nanomolar)
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
nM
Tooltip nanomolar)
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

fatigue, and improved attention.[105][106]

Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE).

basal dopamine activity, leading to nonresponse in those with low basal DA activity.[109] On average, methylphenidate elicits a 3–4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex.[1] 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.[110][111][112][f]

Both

VMAT2 function, among other mechanisms.[116][117][g][118][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.
better source needed
]

Methylphenidate has both

receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed.[104] A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.[120]

There exist some paradoxical findings that oppose the notion that methylphenidate acts as silent antagonist of the DAT (DAT inhibitor).[121] 80% occupancy of the DAT is necessary for methylphenidate's euphoriant effect, but re-administration of methylphenidate beyond this level of DAT occupancy has been found to produce similarly potent euphoriant effects (despite DAT occupancy being unchanged with repeated administration).[121] By contrast, other DAT inhibitors such as bupropion have not been observed to exhibit this effect.[122] These observations have prompted the hypothesis that methylphenidate may act as a "DAT inverse agonist" or "negative allosteric modifier of the DAT" by reversing the direction of the dopamine efflux by the DAT at higher dosages.[123]

Methylphenidate may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine use disorder.[124] 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.[124]

The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.[107] The studied maximized daily dosage of OROS methylphenidate appears to be 144 mg/day.[125]

Pharmacokinetics

Methylphenidate taken by mouth has a

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.[12] Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.[9]

Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of

racemic methylphenidate.[12]

The oral

extended-release formulations showed increased Cmax levels when administered with a high-fat meal, according to some researchers.[128] A 2003 study, however, showed no difference between a high-fat meal administration and a fasting administration of oral methylphenidate.[129]

Methylphenidate is

metabolized into ritalinic acid by CES1A1 enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate.[130] 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.[9]

Chemistry