In children over age 6 and adolescents, the short-term benefits and cost effectiveness of methylphenidate are well established. A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.
Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms. 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. 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.
The precise magnitude of improvement in ADHD symptoms and quality of life produced by methylphenidate treatment remains uncertain as of March 2023[update]. 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. A 2021 systematic review did not find clear evidence for using IR methylphenidate (immediate-release) for adults.
Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a "study drug" by some populations, which may be harmful. This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD. People in this category can then experience negative side-effects of the drug which worsen their condition.
Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control. Like amphetamine and bupropion, methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system. 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. 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. Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.
Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".
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.
There is some evidence of mild reductions in height with prolonged treatment in children. 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.
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. It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania. There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.Logorrhea is occasionally reported and visual hallucinations are very rarely reported.Priapism is a very rare adverse event that can be potentially serious.
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.
Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.
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.
The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.[d]
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.
When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatictransesterification, 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.
Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.
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. 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. 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.
Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE). Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET). 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. On average, methylphenidate elicits a 3–4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex.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.[f]
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). By contrast, other DAT inhibitors such as bupropion have not been observed to exhibit this effect. 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.
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate. The studied maximized daily dosage of OROS methylphenidate appears to be 144 mg/day.
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. Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.
Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.
The oral bioavailability and speed of absorption for immediate-release methylphenidate is increased when administered with a meal. 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 while liquid-based extended-release formulations showed increased Cmax levels when administered with a high-fat meal, according to some researchers. A 2003 study, however, showed no difference between a high-fat meal administration and a fasting administration of oral methylphenidate.
Methylphenidate is metabolized into ritalinic acid by CES1A1 enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate. 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.
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. 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.
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.
Methylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955. It was synthesized by chemist Leandro Panizzon and sold by Swiss company CIBA (now Novartis). He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure. Methylphenidate was not reported to be a stimulant until 1954. The drug was introduced for medical use in the United States in 1957. Originally, it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo, under the brand name Centedrin. Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer. The erythro isomer was eliminated and now modern formulations of methyphenidate contain only the threo isomer at a 50:50 mixture of d- and l-isomers.
Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression. It was later used to treat memory deficits in the elderly. 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 on the use of psychostimulant drugs, such as Benzedrine, with then called "maladjusted children". 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.
It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012. In 2020, it was the 41st most commonly prescribed medication in the United States, with more than 15million prescriptions. It is available as a generic medication.
Society and culture
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.: 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, Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Equasym, Foquest, Methylin, Penid, Phenida, Prohiper, and Tradea.: 8–9
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.
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.
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. 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.
^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, 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.
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 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.
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.
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. 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.
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%).
A 39 nanograms/mL peak serum concentration of methylphenidate has been found to occur between 7.5–10.5 hours after administration. 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.
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.
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.
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.
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.[need quotation to verify] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources, 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". 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. People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.
Among countries with the highest rates of use of methylphenidate medication is Iceland, where research shows that the drug was the most commonly used substance among people who inject drugs. 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.
Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction. Its effectiveness in treatment of cocaine, psychostimulant addiction or psychological dependence has not been proven.
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.
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.
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.
"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."
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.
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.
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.
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.
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