Methylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955. It was originally sold by Swiss company CIBA, now Novartis Corporation. It is estimated that in 2013, 2.4 billion doses of methylphenidate were taken worldwide. In 2018, it was the 45th most commonly prescribed medication in the United States, with more than 17million prescriptions. It is available as a generic medication.
Methylphenidate is most commonly used to treat ADHD and narcolepsy.
The short-term benefits and cost effectiveness of methylphenidate are well established. A number of reviews have established the safety and effectiveness of the stimulants for individuals with ADHD over several years. A 2018 review found tentative evidence that it may cause both serious and non-serious adverse effects in children. The precise magnitude of improvements in ADHD symptoms and quality of life that are produced by methylphenidate treatment remains uncertain as of November 2015. The World Health Organization, however, did not add methylphenidate to the World Health Organization Essential Medicines List as they found the evidence for benefits versus harms to be unclear in ADHD.
Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, 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 without treatment, and stimulant medications reduce this risk. Some studies suggest that since ADHD diagnosis is increasing significantly around the world, using the drug may cause more harm than good in some populations using methylphenidate as a "study drug". This applies to people who potentially may be experiencing a different issue and are misdiagnosed with ADHD. People in this category can then experience negative side-effects of the drug which worsen their condition, and make it harder for them to receive adequate care as providers around them may believe the drugs are sufficient. Methylphenidate is not approved for children under six years of age. Immediate release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms.
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. While literature suggests it might improve cognition, most authors agree that using the drug as a study aid when ADHD diagnosis is not present does not actually improve GPA. Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.
The US Food and Drug Administration (FDA) gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.
There is some evidence of mild reductions in height with prolonged treatment in children. This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.
Packaging of a formulation of methylphenidate advises against crushing the tablets. It is placed under Schedule X of the Indian drug scheduling system. Schedule X medications typically hold abusable medications such as barbiturates or stimulants such as amphetamines.
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.
When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatictransesterification, not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate 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 is a psychostimulant and increases the activity of the central nervous system through inhibition on reuptake of the neurotransmitters norepinephrine and dopamine. As models of ADHD suggest, it is associated with functional impairments in some of the brain's neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus.
Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the synapse increase and last longer, respectively. Therefore, methylphenidate is called a norepinephrine-dopamine reuptake inhibitor. By increasing the effects of norepinephrine and dopamine, methylphenidate increases the activity of the central nervous system and produces effects such as increased alertness, reduced fatigue, and improved attention.
Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE). Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET). 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.Magnetic resonance imaging (MRI) studies suggest that long-term treatment with ADHD stimulants (specifically, amphetamine and methylphenidate) decreases abnormalities in brain structure and function found in subjects with ADHD.
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate. The studied maximized daily dosage of OROS methyphenidate appears to be 144 mg/day.
Methylphenidate taken orally has a bioavailability of 11-52% with a duration of 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. Methylphenidate has a low plasma protein binding of 10-33% and a volume of distribution of 2.65L/kg.
Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.
Contrary to the expectation, taking methylphenidate with a meal speeds absorption. The effects of a high fat meal on the observed Cmax differ between some extended release formulations, with combined IR/ER and OROS formulations showing reduced Cmax levels while liquid-based extended release formulations showed increased Cmax levels when administered with a high fat meal, according to some researchers. A 2003 study, however, showed no difference between a high fat meal administration and a fasting administration of oral methylphenidate.
Methylphenidate is metabolized into ritalinic acid by CES1A1, enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate. 97% of the metabolised drug is excreted in the urine, and between 1 and 3% is excreted in the faeces. A small amount, less than 1%, of the drug is excreted in the urine in its unchanged form.
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 dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2'R)-(+)-threo-methylphenidate hydrochloride has been published.
Method 1: Methylphenidate preparation elucidated by Axten et al. (1998) via Bamford-Stevens reaction.
Method 3: Another synthesis route of methylphenidate which applies Darzens reaction to obtain aldehyde as an intermediate. This route is significant for its selectivity.
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 was first made in 1944, and was identified as a stimulant in 1954.
Methylphenidate was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure.
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 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 FDA approval to market "Concerta", an extended-release form of methylphenidate.
Society and culture
German "Ritalin" brand methylphenidate.
Indian "Add Wize' branded instant release and extended release formulations costing US$1.9 for strip of instant release and US$2.9 for a strip of AddWize extended release.
Methylphenidate is produced in the United States, Switzerland, Canada, Mexico, Spain, Sweden, Pakistan, and India. It is also sold in the majority of countries worldwide (although in much lower volumes than in the United States). Brand names for methylphenidate include Ritalin (in honor to Rita, the wife of the molecule discoverer), Rilatin (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta, Medikinet, Adaphen, Addwize, Artige, Attenta, Cognil, Equasym, Inspiral, Methylin, Penid, Phenida, Prohiper, and Tradea. Generic forms are produced by numerous pharmaceutical companies throughout the world.
Clockwise from top: Concerta 18 mg, Medikinet 5 mg, Methylphenidat TAD 10 mg, Ritalin 10 mg, Medikinet XL 30 mg.
Methylphenidate is available in numerous forms, and a doctor will determine the appropriate formulation of the drug to prescribe based on the patient's history, the doctor's experiences treating other patients with methylphenidate products, and product pricing or availability. Currently available forms include a variety of tablets and capsules, an adhesive-based matrix transdermal system (transdermal patch), and an oral suspension (liquid syrup).
The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade in both an immediate-release and an extended-release form. In some circumstances it may be prescribed instead of methylphenidate, however it has no significant advantages over methylphenidate at equipotent dosages and so it is sometimes considered to be an example of an evergreened drug.
Structural formula for the substance among Ritalin tablet series. (Ritalin, Ritalin LA, Ritalin SR.) The volume of distribution was 2.65±1.11 L/kg for d-methylphenidate and 1.80±0.91 L/kg for l-methylphenidate subsequent to swallow of Ritalin tablet.
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.
Structural formula for the substance inside Concerta tablet. Following administration of Concerta®, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.
^US generics manufactured by County Line Pharmaceuticals and Abhai; CA generic manufactured by Apotex.
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/mL). It was designed and is patented and made by Pfizer. The medication comes in various sizes from 60 mL to 180 mL (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.
A methylphenidate skin patch is sold under the brand name Daytrana in the United States. It was developed and marketed by Noven Pharmaceuticals and approved in the US in 2006. It is also referred to as methylphenidate transdermal system (MTS). It is approved as a once daily treatment in children -- ages 6 to 17 -- with ADHD. It is mainly prescribed as a second-line treatment when oral forms are not well tolerated or if people have difficulty with compliance. Noven's original FDA submission indicated that it should be used for 12 hours. When the FDA rejected the submission they requested evidence that a shorter time period was safe and effective, Noven provided such evidence and it was approved for a 9-hour period.
Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-isomer is extensively metabolized. By circumventing this first-pass metabolism, the relative concentrations of l-threo-methylphenidate are much higher with transdermal administration (50-60% of those of dexmethylphenidate instead of about 14-27%).
A 39 nanograms/mL peak serum concentration of methylphenidate be has been found to occur between 7.5 and 10.5 hours after administration. However the onset to peak effect is 2 hours and the clinical effects remain up to 2 hours after patch has been removed. The absorption is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9 hours after application (onto normal, unexposed to heat and uninflamed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug.
Ritalin 10 mg tablet
The most expensive brand-name extended-release tablets may retail for as much as $12.40 per defined daily dose, per a 2016 source.
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.
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, with unlawful possession punishable by up to three years imprisonment, or (via summary conviction) by up to one year imprisonment and/or fines of up to two thousand dollars. Unlawful possession for the purpose of trafficking is punishable by up to ten years imprisonment, or (via summary conviction) by up to eighteen months imprisonment.
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 Russia, methylphenidate is a List I controlled psychotropic substance without recognized medical value. The Constant Committee for Drug Control of the Russian Ministry of Health has put methylphenidate and its derivatives on the National List of Narcotics, Psychotropic Substances and Their Precursors and the Government banned methylphenidate for any use on 25 October 2014.
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.
In Hong Kong, methylphenidate is controlled under the schedule 1 of the Dangerous Drugs Ordinance (Cap. 134).
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. People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.
Among countries with the highest rates of use of methylphenidate medication is Iceland, where research shows that the drug was the most commonly used substance among people who inject drugs. The study involved 108 people who inject drugs and 88% of them had injected methylphenidate within the last 30 days 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.
^Stevenson RD, Wolraich ML (1989). "Stimulant medication therapy in the treatment of children with attention deficit hyperactivity disorder". Pediatr. Clin. North Am. 36 (5): 1183-97. doi:10.1016/S0031-3955(16)36764-5. PMID2677938.
^Millichap JG (2010). "Chapter 3: Medications for ADHD". In Millichap, JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York: Springer. pp. 121-123. ISBN9781441913968.
^Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, Benson RS, Bukstein O, Kinlan J, McClellan J, Rue D, Shaw JA, Stock S (February 2002). "Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults". J. Am. Acad. Child Adolesc. Psychiatry. 41 (2 Suppl): 26S-49S. doi:10.1097/00004583-200202001-00003. PMID11833633.
^Faraone SV, Wilens TE (2007). "Effect of stimulant medications for attention-deficit/hyperactivity disorder on later substance use and the potential for stimulant misuse, abuse, and diversion". J Clin Psychiatry. 68 Suppl 11 (11): 15-22. doi:10.4088/jcp.1107e28. PMID18307377.
^Leonard BE, McCartan D, White J, King DJ (2004). "Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects". Hum Psychopharmacol. 19 (3): 151-80. doi:10.1002/hup.579. PMID15079851. S2CID21173346.
^ abSpencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biol. Psychiatry. 77 (11): 940-950. doi:10.1016/j.biopsych.2014.09.013. PMC4377121. PMID25499957. 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 ?2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic ?2 versus ?1 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.
^ abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). 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 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.
^Bron TI, Bijlenga D, Kasander MV, Spuijbroek AT, Beekman AT, Kooij JJ (2013). "Long-term relationship between methylphenidate and tobacco consumption and nicotine craving in adults with ADHD in a prospective cohort study". European Neuropsychopharmacology. 23 (6): 542-554. doi:10.1016/j.euroneuro.2012.06.004. PMID22809706. S2CID23148548.
^Jaanus SD (1992). "Ocular side effects of selected systemic drugs". Optometry Clinics. 2 (4): 73-96. PMID1363080.
^ abCortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, et al. (March 2013). "Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 54 (3): 227-46. doi:10.1111/jcpp.12036. PMID23294014.
^Kraemer M, Uekermann J, Wiltfang J, Kis B (July 2010). "Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature". Clinical Neuropharmacology. 33 (4): 204-6. doi:10.1097/WNF.0b013e3181e29174. PMID20571380. S2CID34956456.
^Wingo AP, Ghaemi SN (2008). "Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients". Psychopharmacology Bulletin. 41 (4): 37-47. PMID19015628.
^ abcSpiller HA, Hays HL, Aleguas A (June 2013). "Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management". CNS Drugs. 27 (7): 531-543. doi:10.1007/s40263-013-0084-8. PMID23757186. S2CID40931380. The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. ... However, fatalities are rare with appropriate care
^Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11042-6. Bibcode:2001PNAS...9811042N. doi:10.1073/pnas.191352698. PMC58680. PMID11572966. Although the ?FosB signal is relatively long-lived, it is not permanent. ?FosB degrades gradually and can no longer be detected in brain after 1-2 months of drug withdrawal ... Indeed, ?FosB 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 does not involve lesions) as well.
^Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136-43. doi:10.9758/cpn.2012.10.3.136. PMC3569166. PMID23430970. The 35-37 kD ?FosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ?FosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ?FosB overexpression in nucleus accumbens induces NF?B
^ abcdeMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 368. ISBN9780071481274. 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.
^ abcdefKim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915-20. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC2650365. PMID19202072. 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).
^ abcNestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431-43. doi:10.31887/DCNS.2013.15.4/enestler. PMC3898681. PMID24459410. 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 ?FosB 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 ?FosB target is cFos: as ?FosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ?FosB 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
^Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (?)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428-37. doi:10.3109/00952990.2014.933840. PMID25083822. S2CID19157711. The strong correlation between chronic drug exposure and ?FosB 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 ?FosB induction to investigating its subsequent action (38). It is likely that ?FosB research will now progress into a new era - the use of ?FosB as a biomarker. ... Conclusions ?FosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ?FosB 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 ?FosB 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 ?FosB have been opened by epigenetic studies, and recent advances have illustrated the role of ?FosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ?FosB 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. o Bili?ski P, Wojty?a A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studzi?ski T (2012). "Epigenetic regulation in drug addiction". Annals of Agricultural and Environmental Medicine. 19 (3): 491-6. PMID23020045. For these reasons, ?FosB 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 ?FosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ?FosB. 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 ?FosB transcription o Robison AJ, Nestler EJ (October 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews. Neuroscience. 12 (11): 623-37. doi:10.1038/nrn3111. PMC3272277. PMID21989194. ?FosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ?JunD, a dominant negative mutant of JunD which antagonizes ?FosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22-24. This indicates that ?FosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ?FosB 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 ?FosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
^Park YM, Jung YK (May 2010). "Manic switch and serotonin syndrome induced by augmentation of paroxetine with methylphenidate in a patient with major depression". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 34 (4): 719-20. doi:10.1016/j.pnpbp.2010.03.016. PMID20298736. S2CID31984813.
^ abMarkowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS (2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug Metabolism and Disposition. 28 (6): 620-4. PMID10820132.
^ abMarkowitz JS, Logan BK, Diamond F, Patrick KS (1999). "Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion". Journal of Clinical Psychopharmacology. 19 (4): 362-6. doi:10.1097/00004714-199908000-00013. PMID10440465.
^ abMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 154-157. ISBN9780071481274.
^Sulzer D, Cragg SJ, Rice ME (August 2016). "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia. 6 (3): 123-148. doi:10.1016/j.baga.2016.02.001. PMC4850498. PMID27141430. Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
^Markowitz JS, DeVane CL, Ramamoorthy S, Zhu HJ (February 2009). "The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor". Die Pharmazie. 64 (2): 123-5. PMID19322953.
^"Concerta". Drugs.com. 1 October 2018. Archived from the original on 29 September 2018. Retrieved 2019.
^ ab"FDA"(PDF). Archived(PDF) from the original on 10 February 2017. Retrieved 2019.
^Chan YP, Swanson JM, Soldin SS, Thiessen JJ, Macleod SM, Logan W (1983). "Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid". Pediatrics. 72 (1): 56-59. PMID6866592.
^Sun Z, Murry DJ, Sanghani SP, Davis WI, Kedishvili NY, Zou Q, et al. (August 2004). "Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1". The Journal of Pharmacology and Experimental Therapeutics. 310 (2): 469-76. doi:10.1124/jpet.104.067116. PMID15082749. S2CID24233422.
^Froimowitz M, Patrick KS, Cody V (October 1995). "Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT". Pharmaceutical Research. 12 (10): 1430-4. doi:10.1023/A:1016262815984. PMID8584475. S2CID26097197.
^Axten JM, Krim L, Kung HF, Winkler JD (1998). "A Stereoselective Synthesis ofdl-threo-Methylphenidate: Preparation and Biological Evaluation of Novel Analogues". The Journal of Organic Chemistry. 63 (26): 9628-9629. doi:10.1021/jo982214t.
^Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews. 100 (3): 925-1024. doi:10.1021/cr9700538. PMID11749256.
^R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1091-93.
^Panizzon L (1944). "La preparazione di piridile piperidil-arilacetonitrili e di alcuni prodotti di trasformazione (Parte Ia)". Helvetica Chimica Acta. 27: 1748-56. doi:10.1002/hlca.194402701222.
^"Education/Training » Clinical Resources". Illinois DocAssist website. University of Illinois at Chicago. Archived from the original on 1 January 2013. Retrieved 2012. Ritalin-SR, methylphenidate SR, Methylin ER, and Metadate ER are the same formulation and have the same drug delivery system
^The Ontario Drug Benefit online formulary indicates that, in Ontario, Canada, the local most-expensive methylphenidate product is probably Concerta. Drug prices in the US are often higher than in Canada. The GoodRx website correctly points out that short-term refills (e.g. 30 tablets) often cost more per tablet than longer-term refills (e.g. 90 tablets). For 30 tablets of brand-name Concerta 27 mg, the relevant GoodRx webpageArchived 5 June 2016 at the Wayback Machine offers coupons. However, if a patient ignores the coupons, and if the patient does not shop around, the website indicates that it is possible to pay more than twelve US dollars per defined daily dose. Data retrieved 17 May 2016.
^Theleritis C, Siarkos K, Katirtzoglou E, Politis A (January 2017). "Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities". Journal of Geriatric Psychiatry and Neurology. 30 (1): 26-49. doi:10.1177/0891988716678684. PMID28248559. S2CID24642197.