Methylphenidate

Contraindications

Methylphenidate is contraindicated for individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.

Pregnant women are advised to take methylphenidate only 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".

Adverse effects

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), and tachycardia (rapid heart rate). Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis. In some cases, tolerance might be an issue with stimulants like methylphenidate.

Results from a 2024 systematic review showed that methylphenidate significantly improves ADHD symptoms and broadband measures but can cause appetite suppression and other adverse events in children and adolescents. 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.

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.

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. 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 the drug "may be associated with a number of serious adverse events as well as a large number of non‐serious adverse events in children and adolescents". It stated "it is not possible to accurately estimate the actual risk of adverse events" because the quality of evidence in the 260 studies assessed was "very low".

Overdose

The symptoms of a moderate acute overdose of methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.

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

Addiction and dependence

Methylphenidate displays addiction and dependence liability similar to that of amphetamine. It has moderate liability among addictive drugs; addiction and psychological dependence may occur, particularly when methylphenidate is used at high doses or in non-medical contexts. 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. Non-medical routes of administration, such as intranasal insufflation (snorting) or intravenous injection, produce a more rapid increase in brain methylphenidate concentrations than oral administration and are associated with greater subjective euphoria, reinforcing effects, and abuse potential.

Biomolecular mechanisms

Repeated high-dose administration of methylphenidate has been shown to induce the expression of ΔFosB in D1-type medium spiny neurons of the nucleus accumbens, with accumbal ΔFosB levels accumulating over the long-term with chronic exposure due to its unusually long half-life. Overexpression (i.e., a persistently excessive level of gene expression) of ΔFosB in this subset of neurons is a necessary and sufficient biomolecular mechanism for many of the neural adaptations and reward-related behavioral changes associated with drug addiction (e.g., reward sensitization and compulsive drug self-administration).

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. There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.

When methylphenidate is coingested with ethanol, a small amount of ethylphenidate is formed through CES1-mediated transesterification. At therapeutic doses, ethylphenidate is generally a minor metabolite, with most of the metabolite formed being the pharmacologically less active l-isomer. However, ethanol also increases exposure to pharmacologically active d-methylphenidate, and the potential contribution of d-ethylphenidate may become more relevant at high or abusive doses. Therefore, ethylphenidate should not be assumed to be pharmacologically negligible in methylphenidate-ethanol overdose.

Coingestion of alcohol also increases the blood plasma levels of d-methylphenidate by up to 40%.

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.

Pharmacology

Pharmacodynamics

Methylphenidate acts primarily 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 attention deficit hyperactivity disorder (ADHD) suggest, it is associated with functional impairments in some of the brain's neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus. Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the synapse increase and last longer, respectively. Therefore, methylphenidate is called a norepinephrine–dopamine reuptake inhibitor. 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). In vitro binding assays generally indicate greater affinity for DAT than NET; however, human PET studies demonstrate substantial occupancy of both transporters, with inter-study comparison suggesting slightly greater NET than DAT occupancy at clinically relevant doses. Variability exists between the extent of DAT blockade and increases in extracellular dopamine, leading to the hypothesis that methylphenidate amplifies basal dopamine activity as an explanation for nonresponse in individuals with low basal DA activity. In animals and brain tissue, methylphenidate has been shown to dose-dependently increase brain dopamine levels. On average, methylphenidate elicits a 3 to 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.

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, 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.

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.

Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5-HT_1A and 5-HT_2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5-HT_1A receptor, but no significant activity on the 5-HT_2B receptor was found.

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

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

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.

Pharmacokinetics

Methylphenidate taken by mouth has a bioavailability of 11–52% with a duration of action around 2–4 hours for immediate-release (IR) (i.e., Ritalin), 3–8 hours for sustained-release (i.e., Ritalin LA), and 8–12 hours for extended-release (ER) (i.e., Concerta). The half-life of methylphenidate is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours. Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.

d-Methylphenidate is much more bioavailable than l-methylphenidate 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 C_max differ between some extended-release formulations, with combined IR/ER and OROS formulations showing reduced C_max levels while liquid-based extended-release formulations showed increased C_max 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.

Chemistry

Despite the claim made by some urban legends, methylphenidate is not a cocaine derivative nor analogue. However, both compounds contain a methyl piperidinylcarboxylate moiety with 2-carbon distance between nitrogen and ester, methylphenidate containing methyl (piperidin-2-yl)-ethanoate and cocaine containing methyl (piperidin-3-yl)-methanoate. Cocaine is a local anesthetic and ligand channel blocker with SNDRI action, while methylphenidate is an NDRI with 2–3 fold selectivity for the dopamine transporter (DAT) over the norepinephrine transporter (NET). Cocaine is also more potent in serotonin transporters (SERTs) than in NDRI sites.

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro isomers 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.

Detection in biological fluids

The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum, or whole blood to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis of potential poisoning victims or to assist in the forensic investigation in a case of fatal overdose.

History

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 Marguerite, 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 methylphenidate contain only the threo isomer in a 50:50 mixture of d- and l-isomers.

Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression. It was later used to treat memory deficits in the elderly. Beginning in the 1960s, it was used to treat children with attention deficit hyperactivity disorder (ADHD) based on earlier work, starting with the studies by American psychiatrist Charles Bradley 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.

In 2000, Alza Corporation received FDA approval to market Concerta, a modified-release form of methylphenidate that uses the osmotic-controlled release oral delivery system.

It was estimated that the number of methylphenidate doses used globally in 2013 increased by 66% compared to 2012. In 2023, it was the 50th most commonly prescribed medication in the United States, with more than 13 million prescriptions. It is available as a generic medication.

Society and culture

Names

Methylphenidate is sold in most countries worldwide. Brand names for methylphenidate include Ritalin (in honor of Rita, the wife of the molecule discoverer Leandro Panizzon), Rilatine (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta, Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Konsenidat, Equasym, Foquest, Methylin, Penid, Phenida, Prohiper, and Tradea.

Modified-release methylphenidate products include:

Concerta tablets are marked with the letters "ALZA" and followed by "18", "27", "36", or "54", relating to the dosage strength in milligrams. They use osmotic-controlled release oral delivery system. 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 6–7 hours, and subsequent decline in the 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 are an extended-release oral capsule form of methylphenidate. It delivers 50% of the dosage as IR MPH and the remaining 50% in 3–4 hours.

Jornay PM is a delayed-release formulation that is taken at bedtime. An outer polymer coating delays the initial release of the drug until 8 hours after administration, after which an inner coating regulates the rate of drug absorption. Peak plasma concentration occurs 14 hours following administration. This formulation was motivated by the need for a pediatric ADHD medication that is active immediately after morning waking, as most long-acting formulations exhibit a delay between administration and absorption that leads to inadequate therapeutic effect in the early morning.

Cost

Brand-name and generic formulations are available.

Legal status

Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances. Its legal status varies by jurisdiction.

Controversy

Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. The prescription of psychostimulant medication to children to reduce ADHD symptoms has been a major point of criticism. 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 an 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. 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.

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 methylphenidate and described its effects to her husband.

Research

Apathy

Methylphenidate may be effective as a treatment for apathy in Alzheimer's disease and other conditions. It may also be useful in the treatment of more severe disorders of diminished motivation, like abulia and akinetic mutism.

Schizophrenia

Methylphenidate has been shown to reduce rates of hospitalization in patients with schizophrenia, although repeated, elevated doses can provoke psychosis.

Addiction

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 or psychostimulant addiction or psychological dependence has not been proven.

Social anxiety

Methylphenidate has been reported to be effective in the treatment of social anxiety disorder in people who are comorbid for both this condition and attention deficit hyperactivity disorder (ADHD) in small preliminary clinical studies and case reports.