|Trade names||Ritalin, Concerta, Aptensio, Biphentin, Daytrana, Equasym, Medikinet, Metadate, Methylin, QuilliChew, Quillivant|
|Oral, insufflation, intravenous, transdermal|
|Bioavailability||~30% (range: 11–52%)|
|Metabolism||Liver (80%) mostly CES1A1-mediated|
|Biological half-life||2–3 hours|
|Chemical and physical data|
|Molar mass||233.31 g/mol|
|3D model (Jmol)|
|Melting point||74 °C (165 °F) |
|Boiling point||136 °C (277 °F) |
Methylphenidate, sold under various trade names, Ritalin being one of the most commonly known, 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. The original patent was owned by CIBA, now Novartis Corporation. It was first licensed by the US Food and Drug Administration (FDA) in 1955 for treating what was then known as hyperactivity.
Medical use began in 1960; the drug has become increasingly prescribed since the 1990s, when the diagnosis of ADHD became more widely accepted. Between 2007 and 2012 methylphenidate prescriptions increased by 50% in the United Kingdom and in 2013 global methylphenidate consumption increased to 2.4 billion doses, a 66% increase from the year before. The United States 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 executive function (e.g., reasoning, inhibiting behaviors, organizing, problem solving, planning, etc.). 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 weak 5HT1A receptor agonist.
- 1 Uses
- 2 Contraindications
- 3 Adverse effects
- 4 Overdose
- 5 Interactions
- 6 Pharmacology
- 7 Chemistry
- 8 Pharmaceutical products
- 9 History, society, and culture
- 10 See also
- 11 Notes
- 12 References
- 13 External links
Methylphenidate 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; however, the precise magnitude of improvements in ADHD symptoms and quality of life that are produced by methylphenidate treatment remains uncertain as of November 2015.
Attention deficit hyperactivity disorder
Methylphenidate is approved by the US 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)) can have additional benefits on treatment outcome. The dosage used can vary quite significantly among individuals; consequently, dosage must be titrated precisely.
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. People with ADHD have an increased risk of substance use disorders, and stimulant medications reduce this risk.
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.
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. However, the use of stimulants such as methylphenidate in cases of treatment-resistant depression is controversial. 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.
In 2015, a systematic review and a meta-analysis of high quality clinical trials found that therapeutic doses of amphetamine and methylphenidate result in modest yet unambiguous improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults; the cognition-enhancing effects of these drugs are known to occur through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex. 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 pointed out the logical non sequitur which would result if people were to draw a parallel between the claims of a university that they could "set out deliberately to improve the mental capacities of its students; suppose its stated aims were to ensure that students left the university more intelligent and learned than when they arrived. Suppose they further claimed that not only could they achieve this but that their students would be more intelligent and mentally alert than any students in history." He then asked the rhetorical question of whether, "if the claims could be sustained, should we be pleased?" He argues that it would be "not rational" and against human enhancement to not use the drug to improve people's cognitive abilities.
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 with agitation, tics, or glaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.
The US 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.
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 the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens; 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. 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.
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 norepinephrine–dopamine 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. Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that methylphenidate amplifies basal dopamine activity, leading to nonresponse in those with low basal DA activity. On average, methylphenidate elicits a 3-4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex.
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 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 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.
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.
Contrary to the expectation, taking methylphenidate with a meal speeds absorption.
Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects. The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotary 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 in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.
Methylphenidate is produced in the United States, Mexico, Spain, Sweden, Pakistan, and India. It is also sold in Canada, Australia, the United Kingdom, Spain, Germany, Belgium, Brazil, Portugal, Argentina, Thailand, and several other European countries (although in much lower volumes than in the United States). Brand names for methylphenidate include Ritalin, Concerta, Aptensio, Biphentin, Daytrana, Equasym, Medikinet, Metadate, Methylin, and Quillivant. Generic forms 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.
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).
Methylphenidate was originally available as an immediate-release racemic mixture formulation under the Novartis trademark name Ritalin, although a variety of generics are now available, some under other brand names. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, Tranquilyn, and Rubifen.
Extended-release methylphenidate products include:
|Brand name(s)||Generic name(s)||Duration||Product format|
|Aptensio XR (US);
|12 hours||Pill (capsule)|
Concerta XL (UK)
|Actavis Methylphenidate ER (US);
Teva-Methylphenidate ER‑C (CA);
pms-Methylphenidate ER (CA)
|12 hours||Pill (OROS tablet)|
|Quillivant XR||12 hours||Oral suspension|
|Daytrana||11 hours||Transdermal patch|
|Metadate CD (US);
Equasym XL (UK)
|Corepharma methylphenidate ER (US);
Mallinckrodt methylphenidate ER (US);
Teva methylphenidate ER (US)
|8–10 hours||Pill (capsule)|
|QuilliChew ER (US)||8 hours||Tablet (chewable)|
|Ritalin LA (US);
Medikinet XL (UK)
|Barr methylphenidate ER (US);
Mayne methylphenidate ER (US)
|8 hours||Pill (capsule)|
|Ritalin SR (US/CA/UK);
Rubifen SR (NZ)
|Metadate ER (US);
Methylin ER (US);
methylphenidate SR (US/CA)
|5–8 hours||Pill (CR tablet)|
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. 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.
Quillivant XR 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.
Generic immediate-release methylphenidate is relatively inexpensive. The average wholesale cost is about US$0.15 per defined daily dose (retail pharmacies normally charge more). However, the most expensive brand-name extended-release tablets may retail for as much as $12.40 per defined daily dose.
There are two main reasons for this price difference:
- Generic formulations are less expensive than brand-name formulations.
- Immediate-release tablets are less expensive than 8-hour extended-release tablets, which are much less expensive than 12-hour extended-release tablets.
History, society, and culture
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 ALZA Corporation received US Food and Drug Administration (FDA) approval to market "Concerta", an extended-release form of methylphenidate. 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 a sentence up to 5 years or an unlimited fine, or both; supplying methylphenidate is 14 years or an unlimited fine, or both.
- In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act 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 by a 14-year sentence.
- In Australia, methylphenidate is a 'Schedule 8' controlled substance. Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment.
- 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.
- In India, methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule, 1945. It is dispensed only by physician's prescription. Legally, 2 grams of methylphenidate are classified as a small quantity, and 50 grams as a large or commercial quantity.
Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. The prescription of psychostimulant medication to children to reduce ADHD symptoms has been a major point of criticism.[need quotation to verify] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources, according to which abuse is statistically very low and "stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life". A study found that ADHD medication was not associated with increased risk of cigarette use, and in fact stimulant treatments such as Ritalin seemed to lower this risk.  and research shows that the drug was the most commonly abused substance among intravenous substance abusers in Iceland. The study involved 108 IV substance abusers and 88% of them had injected methylphenidate within the last 30 days and for 63% of them, methylphenidate was the most preferred substance.
Treatment of ADHD by way of methylphenidate has led to legal actions, including malpractice suits regarding informed consent, inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems. In the US and the UK, it is approved for use in children and adolescents. In the US, the Food and Drug Administration approved the use of methylphenidate in 2008 for use in treating adult ADHD. In the UK, 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.
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Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
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The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
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Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
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Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. 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 spatial 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
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