- central nervous system stimulant (trade name Ritalin) used in the treatment of narcolepsy in adults and attention deficit disorder in children (同)Ritalin
|Systematic (IUPAC) name|
|Trade names||Concerta, Methylin, Ritalin, Medikinet, Equasym XL, Quillivant XR, Metadate|
|Licence data||US FDA:|
|Oral, insufflation, intravenous, transdermal|
|Bioavailability||~30% (range: 11–52%)|
|Biological half-life||2–3 hours|
|CAS Registry Number||Y|
|Molecular mass||233.31 g/mol|
|Melting point||74 °C (165 °F) |
|Boiling point||136 °C (277 °F) |
|Y (what is this?)|
Methylphenidate (trade names Concerta, Methylin, Medikinet, Ritalin, Equasym XL, Quillivant XR, Metadate) is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Methylphenidate has been studied and researched for over 50 years and has a very good efficacy and safety record for the treatment of ADHD. The original patent was owned by CIBA, now Novartis Corporation. It was first licensed by the U.S. Food and Drug Administration (FDA) in 1955 for treating what was then known as hyperactivity.
Prescribed to patients beginning in 1960, the drug has become increasingly prescribed since the 1990s, when the diagnosis of ADHD itself became more widely accepted. Between 2007 and 2012 methylphenidate prescriptions increased by 50% in Britain and in 2013 global methylphenidate consumption increased to 2.4 billion doses, a 66% increase compared to the year before. The US continues to account for more than 80% of global consumption.
ADHD and other similar conditions are believed to be linked to sub-performance of the dopamine and norepinephrine functions in the brain, primarily in the prefrontal cortex, responsible for self-regulatory function (e.g., inhibition, motivation, and memory) and executive function (e.g., reasoning, organizing, problem solving, and planning). Methylphenidate's mechanism of action involves the inhibition of catecholamine reuptake, primarily as a dopamine reuptake inhibitor. Methylphenidate acts by blocking the dopamine transporter and norepinephrine transporter, leading to increased concentrations of dopamine and norepinephrine within the synaptic cleft. This effect in turn leads to increased neurotransmission of dopamine and norepinephrine. Methylphenidate is also a 5HT1A receptor agonist.
- 1 Uses
- 1.1 Medical
- 1.1.1 Attention deficit hyperactivity disorder
- 1.1.2 Narcolepsy
- 1.1.3 Other
- 1.2 Performance-enhancing
- 1.2.1 Ethics of use for performance enhancement
- 1.1 Medical
- 2 Contraindications
- 3 Adverse effects
- 4 Overdose
- 4.1 Addiction and dependence
- 4.1.1 Biomolecular mechanisms
- 4.1 Addiction and dependence
- 5 Interactions
- 6 Pharmacology
- 6.1 Pharmacodynamics
- 6.2 Pharmacokinetics
- 7 Physical and chemical properties
- 7.1 Detection in biological fluids
- 8 History, society, and culture
- 8.1 Legal status
- 8.2 Pharmaceutical products
- 8.2.1 Production and brand-names
- 8.2.2 Available forms
- 126.96.36.199 Immediate-release
- 188.8.131.52 Extended-release
- 8.3 Controversy
- 9 See also
- 10 Notes
- 11 References
- 12 External links
MPH is a commonly prescribed psychostimulant and works by increasing the activity of the central nervous system. It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention. The short-term benefits and cost effectiveness of methylphenidate are well established. Methylphenidate is not approved for children under six years of age. Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder.
Meta-analyses and systematic reviews of magnetic resonance imaging 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. Moreover, reviews of clinical stimulant research have established the safety and effectiveness of the long-term use of ADHD stimulants for individuals with ADHD. In particular, the continuous treatment effectiveness and safety of both amphetamine and methylphenidate have been demonstrated in controlled drug trials with durations of several years.
Attention deficit hyperactivity disorder
Methylphenidate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder. The addition of behavioural modification therapy (e.g. cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome. People with ADHD have an increased risk of substance use disorders, and stimulant medications reduce this risk. A 2010 study on methylphenidate for adult ADHD suggested that methylphenidate doesn't have the previously expected effect of improving long-term academic outcomes in these individuals.
The dosage used can vary quite significantly among individuals with some people responding to quite low doses, whereas others require a higher dose range; consequently, dosage should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects.
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems,[note 1] particularly those involving dopamine and norepinephrine. Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 70% of those who use these stimulants see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, generally perform better in school, are less distractible and impulsive, and have longer attention spans.
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. 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.
The use of stimulants such as methylphenidate in cases of treatment-resistant depression is controversial. Methylphenidate may be used in addition to an antidepressant for refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. Stimulants may have fewer side-effects than tricyclic antidepressants in the elderly and medically ill. 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.
A 2015 meta-analysis of high quality evidence found that therapeutic doses of amphetamine and methylphenidate result in modest improvements in performance on working memory, episodic memory, and inhibitory control tests in normal healthy adults. Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal. Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks, and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than use as a recreational drug, is the primary reason that students use stimulants. 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.
Ethics of use for performance enhancement
Methylphenidate is sometimes used by students to enhance their mental abilities, improving their concentration and helping them to study.
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. 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.
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 want to discuss making students give urine samples to be tested for the drug.
Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine and tranylcypromine), or individuals suffering from agitation, tics, or glaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.
The U.S. FDA gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks. 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.
Methylphenidate is generally well tolerated. The most commonly observed adverse effects with a frequency greater than placebo include 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 resting heart rate). Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis. Other adverse effects may include depression, emotional lability, confusion, and bruxism. Hyperhidrosis (increased sweating) is common. Chest pain is rarely observed.
There is some evidence of mild reductions in growth rate with prolonged treatment in children, but no causal relationship has been established and reductions do not appear to persist long-term. Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported. The Daytrana patch has a much higher rate of dermal reactions than oral methylphenidate.
Methylphenidate can worsen psychosis in psychotic patients, and in very rare cases it has been associated with the emergence of new psychotic symptoms. It should be used with extreme caution in patients with bipolar disorder due to the potential induction of mania or hypomania. There have been very rare reports of suicidal ideation, but evidence does not support a link. Logorrhea is occasionally reported. Libido disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.
USFDA-commissioned studies from 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.
The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, 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) rapid muscle breakdown, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Severe toxic reactions involving abscess and necrosis have been reported following injection of methylphenidate tablets into an artery.
Treatment of a methylphenidate overdose typically involves the application of benzodiazepines, with antipsychotics, α-adrenoceptor agonists, and propofol serving as second-line therapies.
Addiction and dependence
Pharmacological texts describe methylphenidate as a stimulant with effects, addiction liability, and dependence liability similar to the amphetamine, a compound with moderate liability among addictive drugs; accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug. When used above the medical dose range, stimulants are associated with the development of stimulant psychosis. As with all addictive drugs, the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate 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 in the same way that methadone is used as a replacement drug for physical dependence upon heroin. Its effectiveness in treatment of cocaine or psychostimulant addiction or psychological dependence has not been proven and further research is needed.
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, or the reward pathway in particular, to induce persistent ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens; consequently, when used medically and as directed, methylphenidate use has no capacity to cause an addiction. However, when methylphenidate is used at sufficiently high recreational doses through a bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens. Hence, like any other addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated signaling cascades that induce an addiction.
Intake of adrenergic agonist drugs or pemoline with methylphenidate increases the risk of liver toxicity. Methylphenidate may inhibit the metabolism of coumarin 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 metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and alcohol. The reduced potency of ethylyphenidate 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 primarily acts as a dopamine-norepinephrine reuptake inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative which also shares part of its basic structure with catecholamines.
Methylphenidate is most active at modulating levels of dopamine and to a lesser extent norepinephrine. Methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.
While both amphetamine and methylphenidate are dopaminergic drugs, it should be noted that their methods of action are distinct. Specifically, methylphenidate is a dopamine reuptake inhibitor while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. Each of these drugs has a corresponding effect on norepinephrine which is weaker than its effect on dopamine. 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 general firing rate, whereas amphetamine reduces firing rate and reverses the flow of the monoamines via TAAR1 activation.
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 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo- enantiomer binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.
Methylphenidate may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine abuse.
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.
Methylphenidate has been identified as a sigma-1 receptor agonist.
Methylphenidate taken orally has a bioavailability of 11–52% with a duration of peak 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.
d-Methylphenidate is much more bioavailable than l-methylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.
Contrary to the expectation, taking methylphenidate with a meal speeds absorption.
Physical and chemical properties
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 only d-threo-methylphenidate exhibits the pharmacologically usually desired effects. 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 (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 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.
History, society, and culture
Methylphenidate was first synthesized in 1944, and was identified as a stimulant in 1954.
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.
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.
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 or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD) 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 Janssen received U.S. Food and Drug Administration (FDA) approval to market "Concerta", an extended-release form of Ritalin. See the "Extended-release" section of this article, above, for more information about Concerta.
- Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.
- 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 potential for abuse.
- In the United Kingdom, methylphenidate is a controlled 'Class B' substance. Possession without prescription carries with a sentence up to 5 years and/or an unlimited fine, and supplying it is 14 years and/or an unlimited fine.
- In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act (along with LSD, psychedelic mushrooms, and mescaline, among others), and is illegal to possess without a prescription, pursuant to Part G (section G.01.002) of the Food and Drug Regulations under the Food and Drugs Act.
- In New Zealand, methylphenidate 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.
- In Australia, methylphenidate is a 'Schedule 8' controlled substance. Such drugs must be kept in a lockable safe before being handed out and possession without prescription carries hefty fines and even imprisonment.
- In Sweden, methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.
- In France, methylphenidate is covered by the "narcotics" schedule, prescription and distribution conditions are restricted with hospital-only prescription for the initial treatment and yearly consultations.
Production and brand-names
Methylphenidate is produced in the United States, Mexico, Spain, Sweden, Pakistan, and India. Ritalin is also sold in Canada, Australia, the United Kingdom, Spain, Germany and other European countries (although in much lower volumes than in the United States). Other brands include Concerta, Methylin, and Daytrana, and generic forms, including Methylin, Metadate, Phenida and Attenta are produced by numerous pharmaceutical companies throughout the world. In Belgium the product is sold under the name Rilatine and in Brazil, Portugal and Argentina as Ritalina. In Thailand, it is found under the name Hynidate. In India, it is found under the names Addwize and Inspiral SR.
The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade.
Methylphenidate is available in numerous forms, a doctor will prescribe the appropriate method based on patient feedback and product availability. Current available forms are tablet, capsule, adhesive-based matrix transdermal system (patch), and oral suspension (liquid syrup).
A formulation by the Novartis trademark name Ritalin, is an immediate-release racemic mixture, although a variety of formulations and generic brand names exist. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, Tranquilyn and Rubifen. Focalin is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations.
Extended-release methylphenidate products include:
|Brand name||Generic name(s)||Duration||Product format||Comments|
|Concerta||Actavis Methylphenidate ER (US);
Teva-Methylphenidate ER‑C (Canadian);
|Ritalin SR||Metadate ER (US); Methylin ER (US);
methylphenidate SR (Canadian).
|5–8 hours||Pill||Ritalin SR and its generics are less expensive than Concerta. They use a wax-matrix system for drug delivery; this is why the duration of action is so variable.|
|Ritalin LA||8 hours||Pill|
|Quillivant XR||12 hours||Oral suspension|
|Daytrana||Actavis has announced that its generic transdermal methylphenidate patches may become available in September 2015.||11 hours||Transdermal patch|
Some other branded extended-release medications include Equasym XL, Medikinet XL, Biphentin, and Rubifen SR.
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 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. Both Ritalin LA and Equasym XL provide 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% of the beads are immediate release, and the other 70% of the beads are evenly sustained release.
Quillivant XR (brand name) is an extended-release oral suspension (after reconstitution with water): 25 mg per 5 mL (5 mg per mL). It was designed and is patented and made by Pfizer. The medication comes in various sizes from 60ml to 180ml (after reconstitution). Each bottle is shipped with the medication in powder form containing roughly 20% instant-release and 80% extended-release methylphenidate, to which water must be added by the pharmacist in an amount corresponding with the total intended volume of the bottle. The bottle must be shaken vigorously for ten seconds prior to administration via included oral syringe to ensure proper ratio.
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.[clarification needed] 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".
Another controversy concerns the narrow definition of ADHD as the clinical criterion for prescribing methylphenidate. It has shown for instance that the effect of methylphenidate on adults with no ADHD approaches its effect in adults with ADHD. Hence, it may be effective for individuals with acute problems leading to difficulty to concentrate irrespectively of ADHD diagnosis. In Israel, for example, since 2011 general MDs can prescribe methylphenidate with no ADHD diagnosis, for a constrained time period.
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. In the U.S. and the United Kingdom, it is approved for use in children and adolescents. In the U.S., the Food and Drug Administration approved the use of methylphenidate in 2008 for use in treating adult ADHD. In the United Kingdom, while not licensed for use in Adult ADHD, NICE guidelines suggest it be prescribed off-license for the condition. Methylphenidate has been approved for adult use in the treatment of narcolepsy.
The pharmacological effects of methylphenidate resemble those of the class of DNRIs, which is useful in the treatment of ADHD. Shortages of Ritalin in 2011 have been blamed on overmedication.
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.
- This involves impaired dopamine neurotransmission in the mesocortical and mesolimbic pathways and norepinephrine neurotransmission in the prefrontal cortex and locus coeruleus.
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The results of this meta-analysis cannot address the important issues of individual differences in stimulant effects or the role of motivational enhancement in helping perform academic or occupational tasks. However, they do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
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Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [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.
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Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal ... Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that doesn't involve lesions) as well.
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The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB
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Cocaine, [amphetamine], and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects ; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
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Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction. However, meta analysis of available data suggests that treatment of ADHD with stimulant drugs may have a significant protective effect, reducing the risk for addictive substance use (36, 37). Studies with juvenile rats have also indicated that repeated exposure to methylphenidate does not necessarily lead to enhanced drug-seeking behavior in adulthood (38). However, the recent increase of methylphenidate use as a cognitive enhancer by the general public has again raised concerns because of its potential for abuse and addiction (3, 6–10). Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).
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DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.4
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The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. ...
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.
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For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
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ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
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Ritalin‑SR, methylphenidate SR, Methylin ER, and Metadate ER are the same formulation and have the same drug delivery system
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An alternative to Ritalin‑SR from Novartis
- Based on:
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|Wikimedia Commons has media related to Methylphenidate.|
- Methylphenidate at DMOZ
- Department of Energy September 29, 1998 press release on Ritalin at Brookhaven National Laboratory
- U.S. National Library of Medicine: Drug Information Portal – Methylphenidate
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- M e t h y l p h e n i d a t e The Ritalin Kid The Good Drug Guide Methylphenidate (Ritalin) Methylphenidate and drug abuse risk Is methylphenidate (Ritalin, Concerta, etc) like cocaine? e-mail firstname.lastname@example.org
- METHYLPHENIDATE (Ritalin, Concerta) Prescribing Information Physician prescribing information - Epocrates Online Patient information - MedlinePlus. Research Complete research information on methylphenidate. Review Articles - PubMed.
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- 離脱 withdrawal：the development of physical or pschological symptoms after the reduction or cessation of intake of a substance(BBS.73)
- 耐性 tolerance：the need for increased amounts of the substance to achieve the same positive psychological effect(BBS.73)
- 交差耐性 cross-tolerance：the development of tolerance to one substance as the result of using another substance(BBS.73)
- 2. sedatives
- 3. opioids
- 4. hallucinogens and related agents
- 塩酸メチルフェニデート methylphenidate hydrochloride
- リタリン Ritalin, Methylin, Concerta,metadate ER, Flocalin、コンサータ
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