The word methylphenidate is a portmanteau of the chemical name, Methyl-2-phenyl-2-(piperidin-2-yl) acetate.
Uses
Methylphenidate is most commonly used to treat ADHD and narcolepsy.[16]
Attention deficit hyperactivity disorder
Methylphenidate is used for the treatment of attention deficit hyperactivity disorder.[17] The addition of behavioural modification therapy can have additional benefits on treatment outcome.[18][19] The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose.[20] Immediate-release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms.[21][22] Methylphenidate is not approved for children under six years of age.[23][24]
In children over age 6 and adolescents, the short-term benefits and cost effectiveness of methylphenidate are well established.[25][26] A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.[27][28][29]
Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms.[30] 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.[27] 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.[31][32]
The precise magnitude of improvement in ADHD symptoms and quality of life produced by methylphenidate treatment remains uncertain as of March 2023[update].[33] Methylphenidate is not included in the 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.[34] A 2021 systematic review did not find clear evidence for using IR methylphenidate (immediate-release) for adults.[35]
Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a "study drug" by some populations, which may be harmful.[36] This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD.[36] People in this category can then experience negative side-effects of the drug which worsen their condition.[36]
Narcolepsy
Narcolepsy, a chronicsleep disorder characterized by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[37] 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.[38]
Other medical uses
Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder.[39] It can also improve depression in several groups including stroke, cancer, and HIV-positive patients.[40] There is weak evidence in favor of methylphenidate's effectiveness for depression,[41] including providing additional benefit in combination with antidepressants.[42] 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.[43] 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.[44] 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.[45]
Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control.[59][60] Like amphetamine and bupropion, methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system.[64] 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.[10] 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.[36] Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.[36]
Pregnant women are advised to only use the medication if the benefits outweigh the potential risks.[65] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.[66] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".[67]
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.[68]
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.[74]
There is some evidence of mild reductions in height with prolonged treatment in children.[75] 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.[76][77]
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.[78]
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.[79] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[80] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[75]Logorrhea is occasionally reported and visual hallucinations are very rarely reported.[72]Priapism is a very rare adverse event that can be potentially serious.[81]
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.[82]
Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[83]
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.[84]
The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.[84][d]
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;[88][89] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug.[89] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.[90]
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.[89]
When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatictransesterification,[95][96] 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.[97][96]
Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[98]
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.[99]
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.[103] 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.[97] 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.[103][104]
Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE).[105] Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET).[106] 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.[107] 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.[108][109][110][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,[111][112][113] 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.[114][115][g][116][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.[114][better source needed]
There exist some paradoxical findings that oppose the notion that methylphenidate acts as silent antagonist of the DAT (DAT inhibitor). 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).[118] By contrast, other DAT inhibitors such as bupropion have not been observed to exhibit this effect.[119] These observations help corroborate 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.[120]
Methylphenidate may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine use disorder.[121] 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.[121]
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.[105] The studied maximized daily dosage of OROS methylphenidate appears to be 144 mg/day.[122]
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.[11] Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.[8]
Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.[11]
The oral bioavailability and speed of absorption for immediate-release methylphenidate is increased when administered with a meal.[123] 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[124] while liquid-based extended-release formulations showed increased Cmax levels when administered with a high-fat meal, according to some researchers.[125] A 2003 study, however, showed no difference between a high-fat meal administration and a fasting administration of oral methylphenidate.[126]
Methylphenidate is metabolized into ritalinic acid by CES1A1 enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate.[127] 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.[8]
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.[105][130] 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.[131]
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.[134]
History
Methylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955.[135][136][137] It was synthesized by chemist Leandro Panizzon and sold by Swiss company CIBA (now Novartis).[135] He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure.[138] Methylphenidate was not reported to be a stimulant until 1954.[139][140] The drug was introduced for medical use in the United States in 1957.[141] Originally, it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo, under the brand name Centedrin.[139] 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.[139][142][143][144] 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.[139]
Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression.[145] It was later used to treat memory deficits in the elderly.[146] 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[147] on the use of psychostimulant drugs, such as Benzedrine, with then called "maladjusted children".[148] 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.[149]
In 2000, Alza Corporation received US FDA approval to market Concerta, an extended-release form of methylphenidate.[9][150][151]
It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012.[152] In 2020, it was the 41st most commonly prescribed medication in the United States, with more than 15million prescriptions.[153][154] It is available as a generic medication.[2]
Society and culture
Names
Swiss "Ritalin" brand methylphenidate.
Indian "AddWize" branded instant-release and extended-release formulations costing US$1.9 for a strip of instant-release and US$2.9 for a strip of AddWize extended-release.
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), Rilatine (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta,[9] 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. There is some evidence that dexmethylphenidate has better bioavailability and a longer duration of action than methylphenidate.[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.[7]
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.[9] 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]
^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 dosage strength in milligrams. 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[71] 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.[10] 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 has been found to occur between 7.5–10.5 hours after administration.[10] However, the onset to peak effect is 2 hours, and the clinical effects remain up to 2 hours after the patch has been removed. The absorption is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9 hours after application (onto normal, unexposed to heat and uninflamed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug.[10]
"Schedule 8" controlled substance. Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment.
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.
Covered by the "narcotics" schedule, prescription and distribution conditions are restricted with hospital-only prescription for the initial treatment and yearly consultations.
Methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule, 1945. It is dispensed only by physician's prescription. Legally, 2 grams of methylphenidate is classified as a small quantity, and 50 grams as a large or commercial quantity.
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.
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.
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.
Classified as a Schedule IIcontrolled substance, the designation used for substances that have a recognized medical value but present a high potential for misuse.
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.[183][need quotation to verify] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,[184] 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".[185] 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.[186] People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.[187]
Among countries with the highest rates of use of methylphenidate medication is Iceland,[188] where research shows that the drug was the most commonly used substance among people who inject drugs.[189] 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.[190]
Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine.[192] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction.[193][194] Its effectiveness in treatment of cocaine, psychostimulant addiction or psychological dependence has not been proven.[195]
Footnotes
^
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.[57]
^
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.[58]
^
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.[59]
^
"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."[84]
^
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.[86]
^
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.[110]
^
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.[115]
^
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.[116]
^Arnsten AF, Li BM (June 2005). "Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions". Biological Psychiatry. 57 (11): 1377–1384. doi:10.1016/j.biopsych.2004.08.019. PMID15950011. S2CID22992765.
^Stahl SM (11 April 2013). Stahl's Essential Psychopharmacology: Neuroscientific basis and practical applications (4th ed.). Cambridge University Press. ISBN978-1107686465.
^Fone KC, Nutt DJ (February 2005). "Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder". Current Opinion in Pharmacology. 5 (1): 87–93. doi:10.1016/j.coph.2004.10.001. PMID15661631.
^Capp PK, Pearl PL, Conlon C (May 2005). "Methylphenidate HCl: therapy for attention deficit hyperactivity disorder". Expert Review of Neurotherapeutics. 5 (3): 325–331. doi:10.1586/14737175.5.3.325. PMID15938665. S2CID43406596.
^Greenfield B, Hechman L (January 2005). "Treatment of attention deficit hyperactivity disorder in adults". Expert Review of Neurotherapeutics. 5 (1): 107–121. doi:10.1586/14737175.5.1.107. PMID15853481. S2CID38706248.
^Neinstein L (2009). Handbook of Adolescent Health Care. Philadelphia, PA: Wolters Kluwer Health / Lippincott Williams & Wilkins. ISBN978-0-7817-9020-8. OCLC226304727.: 722
^Hermens DF, Rowe DL, Gordon E, Williams LM (May 2006). "Integrative neuroscience approach to predict ADHD stimulant response". Expert Review of Neurotherapeutics. 6 (5): 753–763. doi:10.1586/14737175.6.5.753. PMID16734523. S2CID15971025.
^Gilmore A, Milne R (2001). "Methylphenidate in children with hyperactivity: review and cost-utility analysis". Pharmacoepidemiology and Drug Safety. 10 (2): 85–94. doi:10.1002/pds.564. PMID11499858. S2CID22871134.
^ abMillichap JG (2010). "Chapter 3: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A physician's guide to ADHD (2nd ed.). New York, NY: Springer. pp. 111–113. ISBN9781441913968.
^Millichap JG (2010). "Chapter 3: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A physician's guide to ADHD (2nd ed.). New York, NY: Springer. pp. 121–123. ISBN9781441913968.
^Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, et al. (February 2002). "Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults". Journal of the American Academy of Child and Adolescent Psychiatry. 41 (2 Suppl): 26S–49S. doi:10.1097/00004583-200202001-00003. PMID11833633.((cite journal)): CS1 maint: overridden setting (link)
^Faraone SV, Wilens TE (2007). "Effect of stimulant medications for attention-deficit/hyperactivity disorder on later substance use and the potential for stimulant misuse, abuse, and diversion". The Journal of Clinical Psychiatry. 68 (11): 15–22. doi:10.4088/jcp.1107e28. PMID18307377.
^Wilens TE, Faraone SV, Biederman J, Gunawardene S (January 2003). "Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature". Pediatrics. 111 (1): 179–185. CiteSeerX10.1.1.507.874. doi:10.1542/peds.111.1.179. PMID12509574. S2CID29956425.
^Dell'Osso B, Dobrea C, Cremaschi L, Arici C, Altamura AC (December 2014). "Wake-promoting pharmacotherapy for psychiatric disorders". Current Psychiatry Reports. 16 (12): 524. doi:10.1007/s11920-014-0524-2. PMID25312027. S2CID26314915.
^Leonard BE, McCartan D, White J, King DJ (April 2004). "Methylphenidate: A review of its neuropharmacological, neuropsychological, and adverse clinical effects". Human Psychopharmacology. 19 (3): 151–180. doi:10.1002/hup.579. PMID15079851. S2CID21173346.
^Bahji A, Mesbah-Oskui L (September 2021). "Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis". Journal of Affective Disorders. 292: 416–423. doi:10.1016/j.jad.2021.05.119. PMID34144366.
^Rozans M, Dreisbach A, Lertora JJ, Kahn MJ (January 2002). "Palliative uses of methylphenidate in patients with cancer: a review". Journal of Clinical Oncology. 20 (1): 335–339. doi:10.1200/JCO.20.1.335. PMID11773187.
^Smith KR, Kahlon CH, Brown JN, Britt RB (September 2021). "Methylphenidate use in geriatric depression: A systematic review". International Journal of Geriatric Psychiatry. 36 (9): 1304–1312. doi:10.1002/gps.5536. PMID33829530. S2CID233184870.
^Thoenes MM (1 March 2011). "Heat-related illness risk with methylphenidate use". Journal of Pediatric Health Care. 25 (2): 127–132. doi:10.1016/j.pedhc.2010.07.006. PMID21320685.
^Docherty JR, Alsufyani HA (July 2021). "Cardiovascular and temperature adverse actions of stimulants". British Journal of Pharmacology. 178 (13): 2551–2568. doi:10.1111/bph.15465. PMID33786822. S2CID232431910.
^ abcdMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher cognitive function and behavioral control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A foundation for clinical neuroscience (2nd ed.). New York, NY: McGraw-Hill Medical. p. 318. ISBN9780071481274.
^Agay N, Yechiam E, Carmel Z, Levkovitz Y (July 2010). "Non-specific effects of methylphenidate (Ritalin) on cognitive ability and decision-making of ADHD and healthy adults". Psychopharmacology. 210 (4): 511–519. doi:10.1007/s00213-010-1853-4. PMID20424828. S2CID17083986.
^Ornoy A (February 2018). "Pharmacological Treatment of Attention Deficit Hyperactivity Disorder During Pregnancy and Lactation". Pharmaceutical Research. 35 (3): 46. doi:10.1007/s11095-017-2323-z. PMID29411149. S2CID3663423.
^Nutt D, King LA, Saulsbury W, Blakemore C (March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet. 369 (9566): 1047–1053. doi:10.1016/S0140-6736(07)60464-4. PMID17382831. S2CID5903121.
^Jaanus SD (1992). "Ocular side effects of selected systemic drugs". Optometry Clinics. 2 (4): 73–96. PMID1363080.
^Bron TI, Bijlenga D, Kasander MV, Spuijbroek AT, Beekman AT, Kooij JJ (June 2013). "Long-term relationship between methylphenidate and tobacco consumption and nicotine craving in adults with ADHD in a prospective cohort study". European Neuropsychopharmacology. 23 (6): 542–554. doi:10.1016/j.euroneuro.2012.06.004. PMID22809706. S2CID23148548.
^ abCortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, et al. (March 2013). "Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 54 (3): 227–246. doi:10.1111/jcpp.12036. PMID23294014.((cite journal)): CS1 maint: overridden setting (link)
^Kraemer M, Uekermann J, Wiltfang J, Kis B (July 2010). "Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature". Clinical Neuropharmacology. 33 (4): 204–206. doi:10.1097/WNF.0b013e3181e29174. PMID20571380. S2CID34956456.
^Wingo AP, Ghaemi SN (2008). "Frequency of stimulant treatment and of stimulant-associated mania / hypomania in bipolar disorder patients". Psychopharmacology Bulletin. 41 (4): 37–47. PMID19015628.
^ abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A foundation for clinical neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 368. ISBN9780071481274.
^Ishii M, Tatsuzawa Y, Yoshino A, Nomura S (April 2008). "Serotonin syndrome induced by augmentation of SSRI with methylphenidate". Psychiatry and Clinical Neurosciences. 62 (2): 246. doi:10.1111/j.1440-1819.2008.01767.x. PMID18412855. S2CID5659107.
^Park YM, Jung YK (May 2010). "Manic switch and serotonin syndrome induced by augmentation of paroxetine with methylphenidate in a patient with major depression". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 34 (4): 719–720. doi:10.1016/j.pnpbp.2010.03.016. PMID20298736. S2CID31984813.
^Patrick KS, González MA, Straughn AB, Markowitz JS (January 2005). "New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder". Expert Opinion on Drug Delivery. 2 (1): 121–143. doi:10.1517/17425247.2.1.121. PMID16296740. S2CID25026467.
^ abMarkowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, et al. (June 2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug Metabolism and Disposition. 28 (6): 620–624. PMID10820132.
^ abMarkowitz JS, Logan BK, Diamond F, Patrick KS (August 1999). "Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion". Journal of Clinical Psychopharmacology. 19 (4): 362–366. doi:10.1097/00004714-199908000-00013. PMID10440465.
^Roberts SM, DeMott RP, James RC (1997). "Adrenergic modulation of hepatotoxicity". Drug Metabolism Reviews. 29 (1–2): 329–353. doi:10.3109/03602539709037587. PMID9187524.
^Markowitz JS, Patrick KS (June 2008). "Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: Does chirality matter?". Journal of Clinical Psychopharmacology. 28 (3 Suppl 2): S54–S61. doi:10.1097/JCP.0b013e3181733560. PMID18480678.
^Williard RL, Middaugh LD, Zhu HJ, Patrick KS (February 2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural Pharmacology. 18 (1): 39–51. doi:10.1097/fbp.0b013e3280143226. PMID17218796. S2CID20232871.
^ abMarkowitz JS, DeVane CL, Pestreich LK, Patrick KS, Muniz R (December 2006). "A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study". Journal of Child and Adolescent Psychopharmacology. 16 (6): 687–698. doi:10.1089/cap.2006.16.687. PMID17201613. S2CID22895177.
^ abMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely projecting systems: Monoamines, acetylcholine, and orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A foundation for clinical neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 154–157. ISBN9780071481274.
^ abcHeal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system". CNS Drugs. 20 (9): 713–738. doi:10.2165/00023210-200620090-00002. PMID16953648. S2CID39535277.
^Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ (1 January 2002). "Mechanism of action of methylphenidate: insights from PET imaging studies". Journal of Attention Disorders. 6 (Suppl 1): S31–S43. doi:10.1177/070674370200601s05. PMID12685517. S2CID9132302.
^Markowitz JS, DeVane CL, Ramamoorthy S, Zhu HJ (February 2009). "The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor". Die Pharmazie. 64 (2): 123–125. PMID19322953.
^Lee L, Kepple J, Wang Y, Freestone S, Bakhtiar R, Wang Y, et al. (September 2003). "Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce". Biopharmaceutics & Drug Disposition. 24 (6): 233–243. doi:10.1002/bdd.358. PMID12973820. S2CID29609987.
^Sun Z, Murry DJ, Sanghani SP, Davis WI, Kedishvili NY, Zou Q, et al. (August 2004). "Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1". The Journal of Pharmacology and Experimental Therapeutics. 310 (2): 469–476. doi:10.1124/jpet.104.067116. PMID15082749. S2CID24233422.((cite journal)): CS1 maint: overridden setting (link)
^Preedy VR (2016). Neuropathology of Drug Addictions and Substance Misuse. Vol. 3: General processes and mechanisms, prescription medications, caffeine and areca, polydrug misuse, emerging addictions, and non-drug addictions. Academic Press. p. 651. ISBN9780128006771. Archived from the original on 29 August 2021. Retrieved 19 December 2018.
^Froimowitz M, Patrick KS, Cody V (October 1995). "Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT". Pharmaceutical Research. 12 (10): 1430–1434. doi:10.1023/A:1016262815984. PMID8584475. S2CID26097197.
^Axten JM, Krim L, Kung HF, Winkler JD (1998). "A Stereoselective Synthesis ofdl-threo-Methylphenidate: Preparation and Biological Evaluation of Novel Analogues". The Journal of Organic Chemistry. 63 (26): 9628–9629. doi:10.1021/jo982214t.
^Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID11749256.
^Baselt R, ed. (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 1091–1093.
^Panizzon L (1944). "La preparazione di piridile piperidil-arilacetonitrili e di alcuni prodotti di trasformazione (Parte Ia)". Helvetica Chimica Acta. 27: 1748–1756. doi:10.1002/hlca.194402701222.
^ abcdHeal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system". CNS Drugs. 20 (9): 713–738. doi:10.2165/00023210-200620090-00002. PMID16953648. S2CID39535277.
^Meier R, Gross F, Tripod J (May 1954). "Ritalin, eine neuartige synthetische Verbindung mit spezifischer zentralerregender Wirkungskomponente" [Ritalin, a new synthetic compound with specific analeptic components]. Klinische Wochenschrift (in German). 32 (19–20): 445–450. doi:10.1007/BF01466968. PMID13164273. S2CID24516999.
^US 2507631, Hartmann, M.; Panizzon, L., "Pyridine and piperidine compounds and process of making same", issued 16 May 1950, assigned to CIBA Pharmaceutical Products, Inc
^US 2838519, Rouietscji, R., "Process for the conversion of stereoisomers", issued 10 June 1958, assigned to CIBA Pharmaceutical Products, Inc
^US 2957880, Rouietscji, R., "Process for the conversion of stereoisomers", issued 25 October 1960, assigned to CIBA Pharmaceutical Products, Inc
^"Education / training". Illinois DocAssist. Clinical resources. Chicago, IL: University of Illinois. Archived from the original on 1 January 2013. Retrieved 26 July 2012. Ritalin‑SR, methylphenidate SR, Methylin ER, and Metadate ER are the same formulation and have the same drug delivery system
^Heal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system". CNS Drugs. 20 (9): 713–738. doi:10.2165/00023210-200620090-00002. PMID16953648. S2CID39535277.
Anderson VR, Scott LJ (2006). "Methylphenidate transdermal system: In attention-deficit hyperactivity disorder in children". Drugs. 66 (8): 1117–1126. doi:10.2165/00003495-200666080-00007. PMID16789796. S2CID46975783.
^Controlled Drugs and Substances Act (Report). Laws. Department of Justice, Government of Canada. 25 April 2017. S.C. 1996, c. 19. Archived from the original on 3 April 2011. Retrieved 26 April 2017.
^"Dangerous Drugs Ordinance". Hong Kong e-Legislation. 1438402701417-001. Archived from the original on 28 August 2021. Retrieved 20 March 2019.
^The Drugs and Cosmetics Rules (Report). Ministry of Health & Family Welfare. Government of India. 15 August 2013 [1945]. pp. 729–730. Archived from the original on 8 August 2016. Retrieved 5 December 2016.
^Mehta R (26 February 2014). Drug Law Enforcement Field Officers' Hand Book(PDF) (Report). Narcotics Control Bureau, Ministry of Home Affairs. Government of India. p. 145. Archived from the original(PDF) on 5 March 2017. Retrieved 5 December 2016.
^"Schedule 2: Controlled Drugs". Misuse of Drugs Act (c. 38) (Report). Office of Public Sector Information. 1971. Archived from the original on 28 August 2021. Retrieved 15 June 2009.
^Ouellette EM (1991). "Legal issues in the treatment of children with attention deficit hyperactivity disorder". Journal of Child Neurology. 6 (Suppl): S68–S75. doi:10.1177/0883073891006001S08. PMID2002217. S2CID1773939.
^Theleritis C, Siarkos K, Katirtzoglou E, Politis A (January 2017). "Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities". Journal of Geriatric Psychiatry and Neurology. 30 (1): 26–49. doi:10.1177/0891988716678684. PMID28248559. S2CID24642197.
![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.[7]](/en/File:Structural_formula_for_Concerta.jpg)
