Methylphenidate


Methylphenidate
Methylphenidate
Systematic (IUPAC) name
methyl phenyl(piperidin-2-yl)acetate
Clinical data
Trade names Concerta, Methylin, Ritalin
AHFS/Drugs.com monograph
MedlinePlus a682188
Licence data US FDA:link
Pregnancy cat. C
Legal status Controlled (S8) (AU) Schedule III (CA) POM (UK) Schedule II (US)
Routes Oral, Transdermal
Pharmacokinetic data
Bioavailability 11–52%
Protein binding 30%
Metabolism Liver (80%)
Half-life 2–4 hours
Excretion Urine
Identifiers
CAS number 113-45-1 YesY
ATC code N06BA04
PubChem CID 4158
DrugBank DB00422
ChemSpider 4015 YesY
UNII 207ZZ9QZ49 YesY
KEGG D04999 YesY
ChEBI CHEBI:6887 N
ChEMBL CHEMBL796 YesY
Chemical data
Formula C14H19NO2 
Mol. mass 233.31 g/mol
SMILES eMolecules & PubChem
Physical data
Melt. point 214 °C (417 °F)
 N(what is this?)  (verify)

Methylphenidate (Ritalin, MPH) is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity. Methylphenidate belongs to the piperidine class of compounds and increases the levels of dopamine and norepinephrine in the brain through reuptake inhibition of the monoamine transporters. Methylphenidate possesses structural similarities to amphetamine and its pharmacological effects are more similar to those of cocaine, though MPH is less potent and longer in duration of action.[1][2][3]

Contents

Medical uses

MPH is the most commonly prescribed psychostimulant and works by increasing the activity of the central nervous system.[4] It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention.[5] The benefits and cost effectiveness of methylphenidate long term are unknown due to a lack of research.[6][7] The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age.[8][9]

Attention deficit hyperactivity disorder

Methylphenidate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention-deficit hyperactivity disorder[10] The addition of behavioural modification therapy (e.g. cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome.[11][12] There is a lack of evidence of the effectiveness in the long term of beneficial effects of methylphenidate with regard to learning and academic performance.[13] A meta analysis of the literature concluded that methylphenidate quickly and effectively reduces the signs and symptoms of ADHD in children under the age of 18 in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature. There have been no placebo controlled trials investigating the long term effectiveness of methylphenidate beyond 4 weeks thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD has also been noted.[14] A diagnosis of ADHD must be confirmed and the benefits and risks and proper use of stimulants as well as alternative treatments should be discussed with the parent before stimulants are prescribed.[15] The dosage used can vary quite significantly from individual child to individual child with some children responding to quite low doses whereas other children require the higher dose range. The dose, therefore, should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects.[16] This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day. Therapy with methylphenidate should not be indefinite. Weaning off periods to assess symptoms are recommended.[17]

Narcolepsy

Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[18] Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test, but performance does not improve to levels comparable to healthy controls.[19]

Adjunctive

Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial.[20] In individuals with cancer, methylphenidate is commonly used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function.[21] Methylphenidate may be used in addition to an antidepressant for treatment-refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients.[22] However, benefits tend to be only partial with stimulants being, in general, less effective than traditional antidepressants and there is some suggestive evidence of a risk of habituation. Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill.[23] A review of the literature found that methylphenidate was ineffective for refractory cases of major depression.[24]

Substance dependence

Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on methamphetamine.[25] Cocaine and methamphetamine interfere with the protein DAT, over time causing DAT upregulation and lower cytoplasmic dopamine levels in their absence. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine dependence[26][27][28][29] in the same way that methadone is used as a replacement for heroin. Its effectiveness in treatment of cocaine or other psychostimulant dependence has not been proven and further research is needed.[30]

Early research began in 2007–2008[citation needed] in some countries[which?] on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence, owing to methylphenidate's longer half life, and reduced vasoconstrictive effects.[31][32] This replacement therapy is used in other classes of drugs such as opiates for maintenance and gradual withdrawal such as methadone, suboxone, etc.

Pervasive developmental disorders

Given the high comorbidity between ADHD and autism, a few studies have examined the efficacy and effectiveness of methylphenidate in the treatment of autism. However, most of these studies examined the effects of methylphenidate on attention and hyperactivity symptoms among children with autism spectrum disorders. Aman and Langworthy (2000) attempted to examine the effects of methylphenidate on social-communication and self-regulation behaviors among children with disorders.[33]

The sample included 33 children with pervasive developmental disorder (29 boys) with a mean age of 6.93 years (range 5–13). This was a 4-week randomized, double-blind, cross-over placebo study, with treatment changing each week between 4 conditions: placebo, low dose, medium dose, and high dose. In this design, neither the experimenters nor the families know which of the 4 treatments the child is receiving at any given time. In addition, the treatment condition changes randomly each week, without anyone knowing the nature of the old or new condition. This allows the experimenters to assume that consistent changes in behaviors that occur during a particular treatment is truly due to the effect of that treatment and not to the expectation of the treatment (placebo effect).

The results indicate that children showed significantly more joint attention behaviors when receiving methylphenidate than when receiving the placebo (although the most effective dosage varied by individual). Furthermore, at a group level, the low dose of methylphenidate resulted in significantly improved joint attention behaviors when compared to the placebo, but no differences were noted between the low, medium, and high doses. Low and medium doses of methylphenidate also resulted in improved self-regulation behavior when compared to placebo.

The study presents compelling preliminary evidence suggesting that methylphenidate is effective in improving some social behaviors among children with autism spectrum disorders.[34]

Investigational

Animal studies using rats with ADHD-like behaviours were used to assess the safety of methylphenidate on the developing brain and found that psychomotor impairments, structural and functional parameters of the dopaminergic system were improved with treatment. This animal data suggests that methylphenidate supports brain development and hyperactivity in children diagnosed with ADHD. However, in normal control animals methylphenidate caused long lasting changes to the dopaminergic system suggesting that if a child is misdiagnosed with ADHD they may be at risk of long lasting adverse effects to brain development. Animal tests found that rats given methylphenidate grew up to be more stressed and emotional. It is unclear due to lack of followup study whether this occurs in ADHD like animals and whether it occurs in humans.[35] However, long lasting benefits of stimulant drugs have not been found in humans.[36]

Pregnancy

The U.S. Food and Drug Administration (FDA) gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks.[37] Not enough animal and human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007, empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical studies.[38] One of these studies (N = 11) demonstrated no significant increases in malformations.[39] A second (N = 13) demonstrated one major malformation in newborns with early exposure to methylphenidate, which was in the expected range of malformations. However, this was a cardiac malformation, which was not within the statistically expected range.[40] Finally, in a retrospective analysis of patients' medical charts (N = 38), researchers examined the relationship between abuse of intravenous methylphenidate and pentazocine in pregnant women. Twenty-one percent of these children were born prematurely, and several had stunted growth and withdrawal symptoms (31% and 28%, respectively). Intravenous methylphenidate abuse was confounded with the concurrent use of other substances (e.g., cigarettes, alcohol) during pregnancy.

Adverse effects

Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended.[41] Some adverse effects of stimulant therapy may emerge during long-term therapy, but there is very little research of the long-term effects of stimulants.[42][43] The most common side effects of methylphenidate are nervousness, drowsiness and insomnia. Other adverse reactions include:[44]

Risks to health

Researchers have also looked into the role of methylphenidate in affecting stature, with some studies finding slight decreases in height acceleration.[46] Other studies indicate height may normalize by adolescence.[47][48] In a 2005 study, only "minimal effects on growth in height and weight were observed" after 2 years of treatment. "No clinically significant effects on vital signs or laboratory test parameters were observed."[49]

A 2003 study tested the effects of dexmethylphenidate (Focalin), levomethylphenidate, and (racemic) dextro-, levomethylphenidate (Ritalin) on mice to search for any carcinogenic effects. The researchers found that all three preparations were non-genotoxic and non-clastogenic; d-MPH, d, l-MPH, and l-MPH did not cause mutations or chromosomal aberrations. They concluded that none of the compounds present a carcinogenic risk to humans.[50] Current scientific evidence supports that long-term methylphenidate treatment does not increase the risk of developing cancer in humans.[51]

It was documented in 2000, by Zito et al.[52] "that at least 1.5% of children between the ages of two and four are medicated with stimulants, anti-depressants and anti-psychotic drugs, despite the paucity of controlled scientific trials confirming safety and long-term effects with preschool children."

On March 22, 2006, the FDA Pediatric Advisory Committee decided that medications using methylphenidate ingredients do not need black box warnings about their risks, noting that "for normal children, these drugs do not appear to pose an obvious cardiovascular risk."[53] Previously, 19 possible cases had been reported of cardiac arrest linked to children taking methylphenidate[54] and the Drug Safety and Risk Management Advisory Committee to the FDA recommend a "black-box" warning in 2006 for stimulant drugs used to treat attention deficit/hyperactivity disorder.[55]

Doses prescribed of stimulants above the recommended dose level is associated with higher levels of psychosis, substance misuse and psychiatric admissions.[56]

Long-term effects

The effects of long-term methylphenidate treatment on the developing brains of children with ADHD is the subject of study and debate.[57][58] Although the safety profile of short-term methylphenidate therapy in clinical trials has been well established, repeated use of psychostimulants such as methylphenidate is less clear. There are no well defined withdrawal schedules for discontinuing long-term use of stimulants.[59] There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks.[60] Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%.[61] A small study of just under 100 children that assessed long-term outcome of stimulant use found that 6% of children became psychotic after months or years of stimulant therapy. Typically, psychosis would abate soon after stopping stimulant therapy. As the study size was small, larger studies have been recommended.[62] The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.[63] Concerns have been raised that long-term therapy might cause drug dependence, paranoia, schizophrenia and behavioral sensitisation, similar to other stimulants.[64] Psychotic symptoms from methylphenidate can include hearing voices, visual hallucinations, urges to harm oneself, severe anxiety, euphoria, grandiosity, paranoid delusions, confusion, increased aggression and irritability. Methylphenidate psychosis is unpredictable in whom it will occur. Family history of mental illness does not predict the incidence of stimulant toxicosis in children with ADHD. High rates of childhood stimulant use is found in patients with a diagnosis of schizophrenia and bipolar disorder independent of ADHD. Individuals with a diagnosis of bipolar or schizophrenia who were prescribed stimulants during childhood typically have a significantly earlier onset of the psychotic disorder and suffer a more severe clinical course of psychotic disorder.[65][66][67] Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects.[68]

Tolerance and behavioural sensitisation may occur with long-term use of methylphenidate.[69] There is also cross tolerance with other stimulants such as amphetamines and cocaine.[70] Stimulant withdrawal or rebound reactions can occur and should be minimised in intensity, e.g. via a gradual tapering off of medication over a period of weeks or months.[71][72][73] A very small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical. Nonetheless, withdrawal reactions may still occur in susceptible individuals.[74] The withdrawal or rebound symptoms of methylphenidate can include psychosis, depression, irritability and a temporary worsening of the original ADHD symptoms. Methylphenidate, due to its very short elimination half life, may be more prone to rebound effects than d-amphetamine.[17][75][76] Up to a third of children with ADHD experience a rebound effect when methylphenidate dose wears off.[77]

Interactions

Intake of adrenergic agonist drugs or pemoline with methylphenidate increases the risk of liver toxicity.[78][79] Antidepressants taken in conjunction with methylphenidate may cause hypertension, hypothermia and convulsions.[17] When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[80][81] not unlike the hepatic formation of cocaethylene from cocaine and alcohol. Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[69] Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[82] but has significantly less activity on the norepinephrine transporter (NET).[83]

Contraindications

Methylphenidate should not be prescribed concomitantly with tricyclic antidepressants, such as desipramine, or monoamine oxidase inhibitors, such as phenelzine or tranylcypromine, as methylphenidate may dangerously increase plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects). Methylphenidate should not be prescribed to patients who suffer from severe arrhythmia, hypertension or liver damage. It should not be prescribed to patients who demonstrate drug-seeking behaviour, pronounced agitation or nervousness.[17] Care should be taken while prescribing methylphenidate to children with a family history of Paroxysmal Supraventricular Tachycardia (PSVT).

Special precautions

Special precaution is recommended in individuals with epilepsy with additional caution in individuals with uncontrolled epilepsy due to the potential for methylphenidate to lower the seizure threshold.[84]

Abuse potential

Legal warning printed on Ritalin packaging

Methylphenidate has high potential for abuse and addiction due to its pharmacological similarity to cocaine and amphetamines.[17][85] Methylphenidate, like other stimulants, increases dopamine levels in the brain, but at therapeutic doses this increase is slow, and thus euphoria does not typically occur except in rare instances. The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or when it is injected, producing effects almost identical to cocaine. Cocaine-like effects can also occur with very large doses taken orally. The dose, however, that produces euphoric effects varies between individuals. Methylphenidate is actually more potent than cocaine in its effect on dopamine transporters. Methylphenidate should not be viewed as a weak stimulant as has previously been hypothesised.[86]

The primary source of methylphenidate for abuse is diversion from legitimate prescriptions, rather than illicit synthesis. Those who use it to stay awake do so by taking it orally, while intranasal and intravenous are the preferred means for inducing euphoria.[87] IV users tend to be adults whose use may cause panlobular pulmonary emphysema.[88]

Abuse of prescription stimulants is higher amongst college students than non-college attending young adults. College students use methylphenidate either as a study aid or to stay awake longer[89]. Increased alcohol consumption due to stimulant misuse has additional negative effects on health.[90] Methylphenidate's pharmacological effect on the central nervous system is almost identical to that of cocaine. Studies have shown that the two drugs are nearly indistinguishable when administered intravenously to cocaine addicts.[91][92]

However, cocaine has a slightly higher affinity for the dopamine receptor in comparison to methylphenidate, which is thought to be the mechanism of the euphoria associated with the relatively short-lived cocaine high.[93] Reports of users experimenting with mixing methylphenidate with caffeine and benzocaine to produce a powder for insufflation (snorting) for an even more cocaine-like effect began to appear in the middle 1970s; this is apparently an incrementation upon a mixture known as Toot containing phenylpropanolamine, caffeine, and benzocaine in the search for legal highs.[citation needed] As moderate doses of cocaine have caffeine-like effects and benzocaine produces a slight stimulant effect of its own perhaps 5% the strength of cocaine with a ceiling in that range, the mixture is reported to have at least some of the sought-after effects.

Patients who have been prescribed Ritalin have been known to sell their tablets to others who wish to take the drug recreationally. In the USA it is one of the top ten stolen prescription drugs and is known as "kiddie coke", "Vitamin R" and "The R Ball". Recreational users may crush the tablets and either snort the powder, or dissolve the powder in water, filter it through cotton wool into a syringe to remove the inactive ingredients and other particles and inject the drug intravenously. Both of these methods increase bioavailability and produce a much more rapid onset of effects than when taken orally (within c.5–10 minutes through insufflation and within just 10–15 seconds through intravenous injection); however the overall duration of action tends to be decreased by any non-oral use of drug preparations made for oral use.[94]

Methylphenidate is sometimes used by students to enhance their mental abilities, improving their concentration and helping them to study. Professor John Harris, an expert in bioethics, has said that it would be unethical to stop healthy people taking the drug. He also argues that it would be "not rational" and against human enhancement to not use the drug to improve people's cognitive abilities.[95] Professor Anjan Chatterjee however has warned that there is a high potential for abuse and may cause serious adverse effects on the heart, meaning that only people with an illness should take the drug. In the British Medical Journal he wrote that it was premature to endorse the use of Ritalin in this way as the effects of the drug on healthy people have not been studied.[96][97] Professor Barbara Sahakian has argued that the use of Ritalin in this way may give students an unfair advantage in examinations and that as a result universities may have to consider making students give urine samples to be tested for the drug.[98]

Overdose

In 2004, over 8000 methylphenidate ingestions were reported in US poison center data.[99] The most common reasons for intentional exposure were drug abuse and suicide attempts.[88] An overdose manifests in agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia.[87] Benzodiazepines may be used as treatment if agitation, dystonia, or convulsions are present.[99]

Detection in biological fluids

The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.[100]

Pharmacology

Methylphenidate is a chain substituted amphetamine derivative that primarily acts as a norepinephrine-dopamine reuptake inhibitor[101] Similar to amphetamines and cocaine, a key target of methylphenidate is the dopamine transporter (DAT).[102] Moreover, it is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamines. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from amphetamines, as methylphenidate is thought to increase general firing rate, whereas amphetamines reverse the flow of the monoamine transporters. [103][104][105][106] Although methylphenidate is an amphetamine derivative, subtle differences exist in its pharmacology; amphetamine works as a dopamine transport substrate whereas methylphenidate works as a dopamine transport blocker.[101] Methylphenidate is most active at modulating levels of dopamine and to a lesser extent noradrenaline.[107]

Methylphenidate has both DAT and NET binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextro- and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed.[108]

The enantiomers and the relative psychoactive effects and CNS stimulation of dextro- and levo-methylphenidate is analogous to what is found in amphetamine, where dextro-amphetamine is considered to have a greater psychoactive and CNS stimulatory effect than levo-amphetamine.

Pharmacodynamics

Methylphenidate exerts its therapeutic effects via blocking the reuptake of dopamine into nerve terminals (as well as stimulating the release of dopamine from dopamine nerve terminals) resulting in increased dopamine levels in the synapse.[103][109] The onset of central nervous system effects occurs rapidly after intake of methylphenidate and persist for about 4 hours.[110] The mechanism of action is comparable with that of cocaine with usual doses of both drugs occupying 50% of dopamine transporters. However, effects such as euphoria that resembles that of cocaine are rare at doses prescribed clinically.[103][111][112]

The means by which methylphenidate affects people diagnosed with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses.[113] This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation that has been explored is that the methylphenidate affects the action of serotonin in the brain.[103][114] However, benefits with other stimulants that have a different mechanism of action indicates that support for a deficit in specific neurotransmitters is unsupported and unproven by the evidence and remains a speculative hypothesis.[115]

Many have asked why a stimulant would be used to treat hyperactivity, as it seems paradoxical. However, MRI scans have revealed that people with ADHD show differences from non-ADHD individuals in brain regions important for attention regulation and control of impulsive behavior.[116] Methylphenidate's cognitive enhancement effects have been investigated using fMRI scans even in non-ADHD brains, which revealed modulation of brain activity in ways that enhance mental focus. Methylphenidate increased activity in the prefrontal cortex and attention-related areas of the parietal cortex during challenging mental tasks; these are the same areas that the above study demonstrated to be shrunken in ADHD brains. Methylphenidate also increased deactivation of default network regions during the task. Thus, by modifying the activity of certain brain regions known to play important roles in the executive functions, methylphenidate stimulates mental focus and self-control.[117]

One study finds that methylphenidate reduces the increases in brain glucose metabolism during performance of a cognitive task by about 50%. This suggests that, similar to increasing dopamine and norepinephrine in the striatum and prefrontal cortex, methylphenidate may focus activation of certain regions and make the brain more efficient. This is consistent with the observation that stimulant drugs can enhance attention and performance in some individuals. If brain resources are not optimally distributed (for example, in individuals with ADHD or sleep deprivation), improved performance could be achieved by reducing task-induced regional activation. Stimulant delivery when brain resources are already optimally distributed may then adversely affect performance.[118]

A paper published in Biological Psychiatry reports that methylphenidate fine-tunes the functioning of neurons in the prefrontal cortex – a brain region involved in attention, decision-making and impulse control – while having few effects outside it. The team studied PFC neurons in rats under a variety of methylphenidate doses, including one that improved the animals' performance in a working memory task of the type that ADHD patients have trouble completing. Using microelectrodes, the scientists observed both the random, spontaneous firings of PFC neurons and their response to stimulation of the hippocampus. When they listened to individual PFC neurons, the scientists found that while cognition-enhancing doses of methylphenidate had little effect on spontaneous activity, the neurons' sensitivity to signals coming from the hippocampus increased dramatically. Under higher, stimulatory doses, on the other hand, PFC neurons stopped responding to incoming information.[119]

Mechanism of action

According to research of U.S. Department of Energy's Brookhaven National Laboratory methylphenidate works in the treatment of attention deficit hyperactivity disorder by increasing levels of dopamine in the brain.[120][121][122] Dopamine, a neurotransmitter, plays a role in feelings of pleasure and is naturally released in rewarding experiences.[123] Neuroimaging studies of medication-free depressed patients have found that depressed subjects have a functional deficiency of synaptic dopamine.[124] Dopamine decreases "background firing" rates and increases the signal to noise ratio in target neurons by increasing dopamine levels in the brain.[121][125] As a result, the drug may improve attention and decrease distractibility in activities that normally do not hold the attention of children with attention deficit hyperactivity disorder.[121] However, sympathomimetic amines do have a dependence liability and a potential for tolerance adaptation because of their dopaminergic effects when taken in doses outside of their therapeutic range or for an extended period of time.[126]

Chemistry

Four isomers of methylphenidate are known to exist. One pair of threo isomers and one pair of erythro are distinguished, from which only d-threo-methylphenidate exhibits the pharmacologically usually desired effects.[107][127] When the drug was first introduced it was sold as a 3:1 mixture of erythro:threo diastereomers. The erythro diastereomers are also pressor amines. "TMP" is referring only to the threo product that does not contain any erythro diastereomers. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotary methylphenidate is called d-TMP. A review on the synthesis of enantiomerically pure ("R,2'R)-(+)-threo-methylphenidate hydrochloride has been published.[128]

Methylphenidate preparation[129]
Methylphenidate production[129]

History

Methylphenidate was first synthesized in 1944,[130] and was identified as a stimulant in 1954.[131]

Methylphenidate was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. His wife, Marguerite, had low blood pressure and would take the drug as a stimulant before playing tennis. He named the substance Ritaline, after his wife's nickname, Rita.[132]

Originally it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo. 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.[133][134][135]

Beginning in the 1960s, it was used to treat children with ADHD or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD). 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.[136]

Most brand-name Ritalin is produced in the United States, and methylphenidate is produced in the United States, Mexico, Spain and Pakistan. Other generic forms, including "Methylin", "Metadate" and "Attenta" are produced by numerous pharmaceutical companies throughout the world. Ritalin is also sold in Canada, Australia, the United Kingdom, Spain, Germany, Israel and other European countries (although in much lower volumes than in the United States). In Belgium the product is sold under the name "Rilatine" and in Brazil, Portugal and Argentina as "Ritalina". Ritalina is not produced in Argentina but in Spain by Novartis Labs.

Sustained-release preparations of methylphenidate are now also available. These include various preparations (e.g. "Ritalin LA", "Equasym XL") that provide two standard doses – half the total dose being released immediately and the other half released four hours later – providing approximately eight hours of continuously sustained effect. In 2000 Janssen received U.S. Food and Drug Administration (FDA) approval to market "Concerta",[137] a controlled-release methylphenidate tablet providing a continuous effect for up to about 12 hours. Although, Concerta has a different time-release profile than Ritalin, with less than half of the dose being immediately released, and the remaining released in a controlled dose over the next 8–12 hours. Metadate CD, another variant of MPH time-release, acts similarly in relation to the profile of Concerta.

Legal status

  • Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[138]
  • In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high likelihood for abuse because of their addictive potential.
  • In the United Kingdom, methylphenidate is a controlled 'Class B' substance, and possession without prescription is illegal, with a sentence up to 14 years and/or an unlimited fine.[139]
  • In New Zealand, it is a 'class B2 controlled substance'. Unlawful possession is punishable by six-month prison sentence and distribution of it is punishable by a 14-year sentence.

Available forms

Ritalin 10 mg tablet
Ritalin 20 mg, 30 mg & 40 mg CR capsules

The dosage forms of methylphenidate are patches, liquid, tablets, and capsules. A formulation by the Novartis trademark name Ritalin, is an instant-release racemic mixture, although a variety of formulations and generic brand names exist. Generic brand names include Ritalina, Rilatine, Attenta, Methylin, Penid, and Rubifen; and the sustained release tablets Concerta, Metadate CD, Methylin ER, Ritalin LA, and Ritalin-SR. Focalin is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations. A newer way of taking methylphenidate is by using a transdermal patch (under the brand name Daytrana), similar to those used for nicotine replacement therapy. Brand names include Concerta, MediKinet, Equasym XL, Metadate, Methylin, and MPH

Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the mg dosage strength. Approximately 22% of the Concerta dose is immediate release,[140] and the remaining 78% of the dose is evenly released over 10–12 hours post ingestion.[141]

Ritalin LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. The capsules contain two types of beads; 50% of the beads are immediate release, and the other 50% of the beads are enteric-coated, designed to give a second delayed release approximately 5 hours post ingestion.[142]

Metadate CD capsules contain two types of beads; 30% of the beads are immediate release, and the other 70% of the beads are evenly sustained release over approximately 8 hours.[143]

Controversy

Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. One such criticism is prescribing psychostimulants medication to children to reduce ADHD symptoms.[144] Calls have been made that methylphenidate be severely restricted in its use.[17] The pharmacological effects of methylphenidate resemble closely those of cocaine and amphetamines,[145] which is the desired effect in the treatment of ADHD,[146] and how methylphenidate works.[147]

The abuse pattern of methylphenidate is very similar to heroin and amphetamines.[17] A 2002 study showed that rats treated with methylphenidate are more receptive to the reinforcing effects of cocaine.[93] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,[148][149][150] 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".[151]

Another controversial idea surrounding ADHD is that a group of ADHD children have, in general, healthy brains with no gross neurological deficits.[152] This concept, however, is seen as outdated by a few scientists in current medical research, who claim they can identify an ADHD child's brain using CT brain scans,[153] and how methylphenidate interacts with it.[147] The problem herein is that no control was used in the cited research that would differentiate an ADHD child's brain from one that had been treated with stimulants beforehand.

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.[154] In the U.S. and the United Kingdom, it is approved for use in children and adolescents. The FDA recently approved the use of methylphenidate for use in treating adult ADHD.[155] Methylphenidate has been approved for adult use in the treatment of narcolepsy.[156][157]

Anti-Ritalin political campaign

In 2002, Neil Bush told the New York Post that he "endured his own Ritalin hell seven years ago when educators in a Houston private school diagnosed his son, Pierce, (then) 16, with Attention Deficit Disorder (ADD) and pushed medication."

In a September 26, 2002, episode of CNN Interview,[158] Bush told Connie Chung:

You know, we have a knee-jerk reaction in this education system where, if the kid doesn't perform well, then the reaction is to try to assign a label. The label is followed by a drug. The drug allows the kid to sit cooperatively, to pay attention, to focus in school.

Neil Bush spent years researching the issue and found that "the educators were wrong" about his son. "There is a systemic problem in this country, where schools are often forcing parents to turn to Ritalin," he said. "It's obvious to me that we have a crisis." Also that year, Bush testified before a hearing of the United States Congress to speak out against over-medicating children for learning disorders.

He has suggested that many parents believe the ADD and ADHD diagnoses and subsequent medicating of their children because it explains why they aren't doing well in school, saying "it's the system that is failing to engage children in the classroom. My heart goes out to any parents who are being led to believe their kids have a disorder or are disabled."[159]

Neil Bush (along with filmmaker Michael Moore) is credited in the cast of a 2005 documentary called The Drugging of Our Children[160] directed by Gary Null. In the film's trailer[161] Bush says: "Just because it is easy to drug a kid and get them to be compliant doesn't make it right to do it".

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