Methylphenidate's long-term efficacy in ADHD treatment has been questioned because of a lack of long-term studies. A 2010 study suggested that, "there is increasing evidence...[stimulant drugs such as methylphenidate] do not promote learning and academic achievement".
Some research suggests that methylphenidate treatment need not be indefinite. Weaning off periods to assess symptoms and allay tolerance periodically are sometimes recommended.
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. This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day.
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. This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus.[medical citation needed] An alternate explanation that has been explored is that the methylphenidate affects the action of serotonin in the brain. 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.
Studies confirm that biological and genetic differences of the kinds predicted by low arousal theory are clearly visible in ADHD sufferers, and have been confirmed both genetically and by in vivo scans of ADHD affected brains. 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. 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 increases 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.
Aggression and criminality
Two studies state that methylphenidate is indicated for the treatment of ADHD in adults with a history of aggressive and criminal behavior. A large clinical study conducted in Sweden found a significant reduction of the criminality rate in males (32%) and females (42%) as compared with the rate for the same patients while not receiving medication. Some of these clinical outcomes have been confirmed in similar studies with children and adolescents.
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.
Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial. 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. 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, benefits tend to be only partial with stimulants. Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill.
Therapeutic doses of methylphenidate and amphetamine improve performance on working memory tests both in normal functioning individuals and those with ADHD. Moreover, these stimulants also increase arousal and, within the nucleus accumbens, improve task saliency. Thus, stimulants improve performance on effortful and tedious tasks as well. Based upon studies of self-reported illicit stimulant use among college students, performance-enhancing use, as opposed to abuse as a recreational drug, is the primary reason that students use stimulants. In contrast, at doses much higher than those medically prescribed, methylphenidate 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 cognition enhancement, very high doses of methylphenidate can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia.[medical citation needed]
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 follow-up study whether this occurs in ADHD like animals and whether it occurs in humans. However, long lasting benefits of stimulant drugs have not been found in humans.
Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended. 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. The most common side effects of methylphenidate are nervousness, drowsiness and insomnia.[medical citation needed] Other adverse reactions include:
Recent large-scale studies by the USFDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the medical use of amphetamine, methylphenidate, or other commonly prescribed ADHD stimulants.
Although possible, substance dependence is rare with methylphenidate. Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on methamphetamine. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine dependence in the same way that methadone is used as a replacement for heroin. Its effectiveness in treatment of cocaine or psychostimulant dependence has not been proven and further research is needed.
Early research began in 2007–2008 by Pharmacokinetics and Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, in University of Maryland, Baltimore, Maryland, first published, 19 September 2007 in the United States on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence.
On occasion, treatment emergent psychosis can occur during long-term therapy with methylphenidate. Regular psychiatric monitoring of people who are taking methylphenidate for adverse effects such as psychotic symptomatology has been recommended. In the majority of unremarkable isolated cases methylphenidate overdose is asymptomatic or only incurs minor symptoms even in children under six years of age. Normally any reaction will show within three hours. However, injection (particularly arterial) has sometimes led to toxic necrosis and amputation at the point of injection. Emergency treatment is recommended beyond certain overdose levels, in cases of attempted suicide, and in those using monoamine oxidase inhibitors (MAOIs).
In 2000, by Zito et al. documented "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."
The effects of long-term methylphenidate treatment on the developing brains of children with ADHD is the subject of study and debate. 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. There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks. Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%. 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. The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown. Concerns have been raised that long-term therapy might cause drug dependence, paranoia, schizophrenia and behavioral sensitisation, similar to other stimulants. Psychotic symptoms from methylphenidate can include Auditory hallucination, visual hallucinations, urges to harm oneself, severe anxiety, euphoria, grandiosity, paranoia, confusion, 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.[medical citation needed]
Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects. Juvenile rhesus monkeys chronically administered twice daily methylphenidate doses that cause plasma levels similar to those of higher pharmalogical doses in humans show no apparent lasting effects. Measures tested included D2-like dopamine receptor density, dopamine transporter density, amphetamine-induced dopamine release responsiveness, cognitive performance, and growth.
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%.
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. One of these studies (N = 11) demonstrated no significant increases in malformations. 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. 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.
Overdose and toxicology
In the majority of unremarkable isolated cases MPH overdose is asymptomatic (symptomless) or only incurs minor symptoms even in children under age 6. In cases that manifest symptoms, these can typically include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia. LD50 in mice is 190 mg/kg.
Studies of reported incidents tend to show that most overdoses are unintentional and generally conclude that severe or major toxicity are comparatively rare events (none in the Michigan study of 289 incidents, 0.9% in the 2004 US national analysis with n=8336, and 0.2% in the same analysis for 2010 with n=6503).
Death rates are also comparatively low (none in the Michigan study, 0.36 per 1000 with n=3 for the 2004 US national analysis, 0.15 per 1000 with n=1 for the 2010 analysis; the US national guideline approved 2007 also notes only 2 deaths reported as primarily to MPH overdose from 2000-05).
A 2008 review generally agreed these findings but noted recreation or study use was "fairly common" in US university studies and that the risk could only be said to be low "in the short term" since there was little certainty about long term effects of overdose and abuse. A 2011 Swiss study also agreed the general findings, adding a cautionary note that serious or severe outcomes such as necrosis, abscess and amputation had occurred as a result of severe toxicity at the injection site in 3 cases of abuse via artial injection.
Medical and emergency handling
Key recommendations in US guidelines for overdose handling include:
Well evidenced findings (evidence standard "A"): 0–6 years: <2 mg/kg rarely causes serious toxicity, 0–5 years: up to 40 mg well tolerated, 6–12 years: up to 80 mg well tolerated;
Evidence grade "B" and "C": If <6 years and >2 mg/kg, or <60 kg and >1 mg/kg, or ≥60 kg and >60 mg: refer to emergency help;
Tentative only (D): 4 mg/kg or 120 mg of intact modified (slow) release version: refer to emergency help.
Symptoms (D): "Patients experiencing any changes in behavior other than mild stimulation or agitation should be referred to an emergency department. Examples of moderate to severe symptoms that warrant referral include moderate-to-severe agitation, hallucinations, abnormal muscle movements, headache, chest pain, loss of consciousness, or convulsions".
Other factors: Cases of intent, malicious administration (by another), as well as monoamine oxidase inhibitor (MAOI) users should always be referred to emergency help;
Passage of time/delay: Patients where more than 3 hours have passed without symptoms do not usually need referral to emergency help.
Benzodiazepines may be used as treatment if agitation, dystonia, or convulsions are present.
Poison control center analyses and study findings
A study in 2000 looked in detail at all 289 overdoses of MPH reported to the Children's Hospital of Michigan regional poison control center during 1993 and 1994 (excluded: 105 extended-release formulations or co-ingestants, to ensure MPH overdose effects were not confounded by other effects). The case histories were: Age: 251 aged under 18, 38 adult; Reason: 68 (23%) intentional/unknown/error. In 163 cases (56%) the dose was known and in 41% the patient's own MPH was involved. Variation in overdose ranged from <1 mg/kg (30%) to >3 mg/kg (7.5%) mean 1.7 mg/kg. Findings:
Although no patient developed "severe" symptoms, but "less favourable" symptoms were seen with intentional overdoses. In overdoses below 2 mg/kg the majority (63-75%) suffered no effect and a minority (9-16%) suffered a moderate effect. Above 3 mg/kg around 27% suffered a moderate effect. Overall symptoms occurred in 31% of all overdoses. In paediatric exposures 29% developed symptoms but 66% suffered no clinical effects (mild/moderate effects: 34%). Symptomatic findings were:
"Intentional ingestion of MPH was most commonly associated with isolated symptoms of tachycardia, agitation, lethargy, vomiting, dizziness, mydriasis, and tremor. Of the 8 patients in this group who manifested multiple symptoms, erythema, diaphoresis, hypertension, emesis, chest pain, tremor, fever, and insomnia"
Symptoms were common (33%) in the 0-5 age group: "Isolated lethargy, agitation, headache, and vomiting were most commonly seen. One patient in this group developed dystonia, and two developed agitation in combination with hypertension or tachycardia."
In 2004, the American Association of Poison Control Centers Toxic Exposure Surveillance System annual report showed about 8300 methylphenidate ingestions reported in US poison center data, of which 72% were accidental or unintended, and 19% involved children age 0-6. The most common reasons for intentional exposure were drug abuse and suicide attempts. The 2010 report showed 6500 single reported exposures in the US for the year. 2010 incidents:
By age: 0-5: 24%, 6-12: 38%, 13-19:21%, 20+: 16%, other adult: 1%.
By cause: accident/error: 79%, intended: 18%, other: 3%.
By outcome: moderate: 624, major:13, death:1, others were no outcome, minor, or unknown. (2004 outcomes: moderate: 940, major: 73, death: 3)
A Swiss study in 2011 also concurred, noting similar findings in several studies and national analyses in that country, but noted that these findings were potentially inapplicable to the few cases of abuse via crushed MPH injection, which was the sole situation where "serious" or "severe" local toxicity was observed, leading in their study to pain, necrosis and partial limb or digit amputation in two of 14 adult cases over 8 years (14%) who mistakenly injected arterially, and inguinalabscess and fever in one who injected intravenously.
Legal warning printed on Ritalin packaging
Methylphenidate has some potential for abuse due to its action on dopamine transporters. Methylphenidate, like other stimulants, increases dopamine levels in the brain, but at therapeutic doses this increase is slow, and thus euphoria only rarely occurs even when it is administered intravenously. The abuse and addiction potential of methylphenidate is therefore significantly lower than other dopaminergic stimulants. The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or injected. However, the dose that produces euphoric effects varies among individuals. The primary source of methylphenidate for abuse is diversion from legitimate prescriptions, rather than illicit synthesis. Those who use methylphenidate medicinally generally take it orally, while intranasal and intravenous are the preferred means for recreational use. IV users tend to be adults whose use may cause panlobular pulmonary emphysema.
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. Increased alcohol consumption due to stimulant misuse has additional negative effects on health.
Patients who have been prescribed Ritalin have been known to sell their tablets to others who wish to take the drug recreationally[medical citation needed]. In the USA it is one of the top ten stolen prescription drugs.[medical citation needed] 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[medical citation needed]. 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.
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. 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. 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 want to discuss making students give urine samples to be tested for the drug.
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.
The dosage forms of methylphenidate are tablets, capsules, patches, and liquid.
Ritalin 10 mg tablet
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.
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.
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. 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 controversial idea surrounding ADHD is whether to call it a disorder when patients, in general, have healthy appearing brains with no gross neurological deficits.
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 due to inattention to alternative therapies or measurement of long-term efficacy. Attempts have been made to rebut these charges, primarily by questioning the assumptions of studies conducted long after the treatment period has ended.
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. 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.
Method 1: Methylphenidate preparation according to Jeffrey M. Axten et al. (1998)
Methylphenidate is produced in the United States, Mexico, Spain, Sweden and Pakistan. 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 name Addwize and Inspiral Sr.
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.
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.
While both amphetamine and methylphenidate are dopaminergic, 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 at dopamine-norepinephrine release is still debated, but is fundamentally different from most other phenethylamine derivatives, as methylphenidate is thought to increase general firing rate, whereas amphetamine reverses the flow of the monoamine transporters via TAAR1. Moreover, MPH is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamine.
Methylphenidate taken orally has a bioavailability of 11-52% with a duration of peak action around 2–4 hours for instant release, 3–8 hours for sustained release, and 8–12 hours for extended release (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.
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.
^"Functional Roles of Norepinephrine and Dopamine in ADHD: Dopamine in ADHD". Medscape. 2006. Retrieved 2013-10-08. "Catecholamines not only facilitate attention, they are essential to executive function. The prefrontal cortex directs behaviors, thoughts, and feelings represented in working memory. This representational knowledge is essential to fundamental cognitive abilities that compromise executive functions. These encompass the ability to (1) inhibit inappropriate behaviors and thoughts, (2) regulate our attention, (3) monitor our actions, and (4) plan and organize for the future. Difficulties with these prefrontal cortex functions are evident in neuropsychological and imaging studies of ADHD patients and account for many of the common behavioral symptoms. Measures of prefrontal cortical functioning in animals indicate that these functions are sensitive to small changes in catecholamine modulation of prefrontal cortex cells that can produce profound effects on the ability of the prefrontal cortex to guide behavior. Optimal levels of NE acting at postsynaptic alpha2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine alpha2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of ADHD, including impulsivity and locomotor hyperactivity. Conversely, stimulation of prefrontal cortical alpha2-adrenoceptors strengthens prefrontal cortex regulation of behavior and reduces distractibility. Thus, effective treatments for ADHD facilitate catecholamine transmission and apparently have their therapeutic actions by optimizing catecholamine actions in the prefrontal cortex"
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^Liddle, Elizabeth B.; Hollis, Chris; Batty, Martin J.; Groom, Madeleine J.; Totman, John J.; Liotti, Mario; Scerif, Gaia; Liddle, Peter F. (2011). "Task-related default mode network modulation and inhibitory control in ADHD: Effects of motivation and methylphenidate". Journal of Child Psychology and Psychiatry52 (7): 761–71. doi:10.1111/j.1469-7610.2010.02333.x. PMID21073458.
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^ abcdMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 318. ISBN9780071481274. "Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the dorsolateral 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. Both methylphenidate and amphetamines act by triggering the release of dopamine, norepinephrine, and serotonin, actions mediated via the plasma membrane transporters of these neurotransmitters and via the shared vesicular monoamine transporter (Chapter 6). Based on animal studies with micro-iontophoretic application of selective D1 dopamine receptor agonists (such as the partial agonist SKF38393 or the full agonist SKF81297) and antagonist (such as SCH23390), and clinical evidence in humans with ADHD, it is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control, as will be discussed below. It is important to recognize, however, that 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, probably acting at different sites in the brain through indirect stimulation of dopamine and norepinephrine receptors."
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