Methylphenidate chemical structure Methylphenidate methyl 2-phenyl-2-(piperidin-2-yl)acetate IUPAC name CAS number 113-45-1 ATC code N06BA04 PubChem 4158 DrugBank APRD00657 Chemical formula {{{chemical_formula}}} Molecular weight 233.31 g/mol Bioavailability 11–52% Metabolism Liver Elimination half-life 2–4 hours Excretion Urine Pregnancy category C Legal status Routes of administration Oral, Transdermal, IV, Nasal Indicated for: ADD ADHD narcolepsy Other uses: treatment-resistant depression appetite suppressant antidepressant augmentation Contraindications: Use of tricyclic antidepressants (e.g. desipramine), as methylphenidate may dangerously increase their plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects). Use of MAO Inhibitors, such as phenelzine (Nardil) or tranylcypromine (Parnate), and certain other drugs. methylphenidate should not be given to patients who suffer from the following conditions: Severe Arrhythmia, Hypertension or Liver damage. Drug-seeking behaviour Pronounced agitation or nervousness. Other side effects include drowsiness, and mood swings Side effects:[1][2] Atypical sensations: Cardiovascular: Arrhythmia or increase in blood pressure Ear, nose, and throat: Endocrinal: Appetite loss Eye: Blurred vision Gastrointestinal: Nausea/vomiting, abdominal pain Hematological: Musculoskeletal: Muscle twitches Neurological: Insomnia, drowsiness, dizziness, headache Psychological: Psychosis (abnormal thoughts or hallucinations) Nervousness Euphoria Respiratory: Increased respiration rate Skin: Urogenital and reproductive: Miscellaneous: Fever Methylphenidate[3] (MPH) is a prescription stimulant commonly used to treat Attention-deficit hyperactivity disorder, or ADHD. It is also one of the primary drugs used to treat the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. The drug is seeing early use to treat cancer-related fatigue.[4] Contents 1 Production and brand-names 2 History 3 Indications 4 Pharmacology 4.1 ADHD and stimulant dynamics in general 5 Pharmacokinetics 5.1 Detection in biological fluids 6 Medical uses 6.1 Attention deficit hyperactivity disorder 6.1.1 Mechanisms of ADHD 6.2 Narcolepsy 6.3 Aggression and criminality in Adult ADHD 6.4 Adjunctive 6.5 Substance dependence 6.6 Investigational 6.7 Side effects 7 Side effects 7.1 Treatment emergent psychosis 7.2 Long-term effects 8 Cognitive effects 9 Precautions 9.1 Interactions 9.2 Contraindications 9.3 Special precautions 9.4 Pregnancy 10 Overdose and toxicology 10.1 Medical and emergency handling 10.2 Poison control centre analyses and study findings 11 Tolerance 12 Legal status 13 Available forms 13.1 Immediate-release 13.2 Extended-release 14 Delivery formulations 14.1 Tablet 14.2 Capsules 14.3 Patches 15 Criticism 16 Chemistry 17 See also 18 References 19 External links Production and brand-names Brand names of drugs that contain methylphenidate include Ritalin (Ritalina, Rilatine, Attenta, Methylin, Penid, Rubifen); and the sustained release tablets Concerta, Metadate CD, Methylin ER, Ritalin LA, and Ritalin-SR. Focalin is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations. A newer way of taking methylphenidate is by using a transdermal patch (under the brand name Daytrana), similar to those used for hormone replacement therapy (HRT), nicotine release and pain relief (Fentanyl).  Methylphenidate is produced in the United States, Mexico, Spain 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 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.  The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade.  History Methylphenidate was patented in 1954 by the CIBA pharmaceutical company (now Novartis) as a potential cure for Mohr's disease.[How to reference and link to summary or text] 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). Today methylphenidate is the most commonly prescribed medication to treat ADHD around the world.[How to reference and link to summary or text] 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.[5] Most brand-name Ritalin is produced in the United States, and methylphenidate is produced in the United States, Mexico, Argentina and Pakistan. Other generic forms, such as "methylin", are produced by several U.S. pharmaceutical companies. Ritalin is also sold in the United Kingdom, Germany and other European countries (although in much lower volumes than in the United States). These generic versions of methylphenidate tend to outsell brand-name Ritalin four to one.[How to reference and link to summary or text] In Belgium the product is sold under the name "Rilatine".  Another medicine is Concerta, a once-daily extended-release form of methylphenidate, which was approved in April 2000. Studies have demonstrated that long-acting methylphenidate preparations such as Concerta are just as effective, if not more effective, than IR (instant release) formulas.[6][7][8][9] Time-release medications are also less prone to misuse.  In April 2006, the FDA approved a transdermal patch for the treatment of ADHD called Daytrana.[10] Indications File:Methylin2.jpg Methylphenidate 10 mg Tablet (Mallinckrodt) Methylphenidate is a central nervous system (CNS) stimulant,[11][12][13]. Adults who have ADD often report that methylphenidate increases their ability to focus on tasks and organize their lives[How to reference and link to summary or text].  Methylphenidate has been found to have a lower incidence of side effects than dextroamphetamine, a less commonly prescribed medication.[14] When prescribed at the correct dosage, methylphenidate is usually well tolerated by patients.[6] A 2006 review assessing the safety of methylphenidate on the developing brain found that in animals with psychomotor impairments, structural and functional parameters of the dopamine system were improved with treatment.[15] This indicates that in subjects with ADD, methylphenidate treatment may positively support brain development[How to reference and link to summary or text].  Pharmacology File:Methylphenidate2.png 3D space-filling model methylphenidate molecule Methylphenidate primarily acts as a dopamine-norepinephrine reuptake inhibitor. It is a benzylpiperidine derivative which also shares part of its basic structure with catecholamines and phenethylamines.  Methylphenidate is most active at modulating levels of dopamine and to a lesser extent norepinephrine.[16] Methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.[17] 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 a dopamine releasing agent. 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 phenethylamine derivatives, as methylphenidate is thought to increase general firing rate, whereas amphetamine reverses the flow of the monoamine transporters.[18][19][20][21] 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.[22] 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.[23] Methylphenidate may also exert a neuroprotective action against the neurotoxic effects of Parkinson's disease and methamphetamine abuse.[24] The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.[citation needed] ADHD and stimulant dynamics in general Main article: Attention deficit hyperactivity disorder#Pathophysiology 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.[25] 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.[26] 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.[27] This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation which has been explored is that the methylphenidate affects the action of serotonin in the brain.[28] It has been established that Ritalin only works in ADHD when levels of an important neurotransmitter called Phenylethylamine is increased. [How to reference and link to summary or text] It is commonly asked why a stimulant should be used to treat hyperactivity, which seems paradoxical. However, CTs of ADHD brains show decreased activity in the brain centers critical to concentration and goal-directed activities.[How to reference and link to summary or text] Treatment with methylphenidate (etc.) results in increased activity in those regions, in ADHD patients, and in healthy controls as well. Thus the model explanation is that hyperactive children (and adults) have underactive concentration centers, and stimulating them reduces hyperactivity. Thus the stimulants do not work paradoxically. They stimulate portions of the brain that are underactive by increasing dopamine and norepinephrine in the striatum and prefontal cortex.  One study finds that methylphenidate reduces the increases in brain glucose metabolism during performance of a cognitive task by about 50%. This suggests that, similar to increasing dopamine and norepinephrine in the striatum and prefontal cortex, methylphenidate may focus activation of certain regions and make the brain more efficient. This is consistent with the observation that stimulant drugs can enhance attention and performance in some individuals. If brain resources are not optimally distributed (for example, in individuals with ADHD or sleep deprivation), improved performance could be achieved by reducing task-induced regional activation. Stimulant delivery when brain resources are already optimally distributed may then adversely affect performance.[29] Pharmacokinetics 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.[30] Contrary to the expectation, taking methylphenidate with a meal speeds absorption.[31] 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.[32] Medical uses MPH is the most commonly prescribed psychostimulant and works by increasing the activity of the central nervous system.[33] It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention.[6] The short-term benefits and cost effectiveness of methylphenidate are well established, although long-term effects are unknown.[34][35] The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age.[36][37] Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of lethargy, Bipolar depression, Major Depressive Disorder, and obesity.  Attention deficit hyperactivity disorder Methylphenidate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder.[38] The addition of behavioural modification therapy (e.g. cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome.[39][40] While stimulants such as methylphenidate increase attention and concentration, they do not improve learning and academic performance.[41] People with ADHD have an increased risk of substance abuse, and stimulant medications reduce this risk.[42][43] A meta analysis of the literature concluded that methylphenidate quickly and effectively reduces the signs and symptoms of ADHD in children under the age of 18 in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature.  There have been no placebo controlled trials investigating the long term effectiveness of methylphenidate beyond 4 weeks thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD have also been noted.[44] A diagnosis of ADHD must be confirmed and the benefits and risks and proper use of stimulants as well as alternative treatments should be discussed with the parent before stimulants are prescribed.[45] The dosage used can vary quite significantly from individual child to individual child with some children responding to quite low doses whereas other children require the higher dose range. The dose, therefore, should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects.[46] This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day. Therapy with methylphenidate should not be indefinite. Weaning off periods to assess symptoms are recommended.[47] Mechanisms of ADHD 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.[48] This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation that has been explored is that the methylphenidate affects the action of serotonin in the brain.[18][49] 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.[50] Narcolepsy Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[51] 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.[52] Aggression and criminality in Adult ADHD While side-effects and misuse of methylphenidate have been associated with an increased risk of aggression and psychosis, newer studies indicate that it could be useful in 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.[53] Some of these clinical outcomes have been confirmed in similar studies with children and adolescents.[54] Adjunctive Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial.[55] 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.[56] 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.[57] However, benefits tend to be only partial with stimulants being, in general, less effective than traditional antidepressants and there is some suggestive evidence of a risk of habituation. Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill.[58] Substance dependence Although possible, substance dependence is rare with Methylphenidate.[59] Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on methamphetamine.[60] Cocaine and methamphetamine block the protein DAT, over time causing DAT upregulation and lower cytoplasmic dopamine levels in their absence. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine dependence[61][62][63][64] in the same way that methadone is used as a replacement for heroin. Its effectiveness in treatment of cocaine or other psychostimulant dependence has not been proven and further research is needed.[65] 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[66] on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence, owing to methylphenidate's longer half life, and reduced vasoconstrictive effects.[67][68] This replacement therapy is used in other classes of drugs such as opiates for maintenance and gradual withdrawal such as methadone, suboxone, etc. A second generation of N-substituted 3α-[bis(4′-fluorophenyl)methoxy]-tropanes (GA 1–69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague–Dawley rats. The BZT analogs displayed a higher distribution (Vd = 8.69–34.3 vs. 0.9 L/kg) along with longer elimination (t1/2: 4.1–5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3–2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain dopamine levels ranged from minimal effects (GA 1–69) to several fold elevation (∼850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure–response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit dopamine reuptake (0.1–0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 1993–2007, 2008[69] Investigational Animal studies using rats with ADHD-like behaviours were used to assess the safety of methylphenidate on the developing brain and found that psychomotor impairments, structural and functional parameters of the dopaminergic system were improved with treatment. This animal data suggests that methylphenidate supports brain development and hyperactivity in children diagnosed with ADHD. However, in normal control animals methylphenidate caused long lasting changes to the dopaminergic system suggesting that if a child is misdiagnosed with ADHD they may be at risk of long lasting adverse effects to brain development. Animal tests found that rats given methylphenidate grew up to be more stressed and emotional. It is unclear due to lack of follow-up study whether this occurs in ADHD like animals and whether it occurs in humans.[70] However, long lasting benefits of stimulant drugs have not been found in humans.[71] Side effects Side effects Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended.[72] 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.[73][74] The most common side effects of methylphenidate are nervousness, drowsiness and insomnia. Other adverse reactions include:[75] Abdominal pain Akathisia (restlessness) Alopecia (loss of hair) Angina (chest pain) Appetite loss Anxiety/Nervousness Blood pressure and pulse changes (both up and down) Cardiac arrhythmia Depression Diaphoresis (sweating) Dizziness Dyskinesia (uncontrollable tics) Euphoria or dysphoria Headache Hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme, necrotizing vasculitis, and thrombocytopenic purpura) Irritability Lethargy Libido increased or decreased Mania or hypomania Nausea Palpitations Pupil dilation[76] Psychosis and psychiatric disorders - stimulants above the recommended dose level are associated with higher levels of psychosis, substance misuse and psychiatric admissions.[77] Short-term weight loss Somnolence Stunted growth Suicidal ideation Tachycardia (rapid resting heart rate) Xerostomia (dry mouth) On March 22, 2006, the FDA Pediatric Advisory Committee decided that medications using methylphenidate ingredients do not need black box warnings about their risks, noting that "for normal children, these drugs do not appear to pose an obvious cardiovascular risk."[78] Previously, 19 possible cases had been reported of cardiac arrest linked to children taking methylphenidate[79] and the Drug Safety and Risk Management Advisory Committee to the FDA recommend a "black-box" warning in 2006 for stimulant drugs used to treat attention deficit/hyperactivity disorder.[80] Historical concerns related to child growth and cancer risk have existed, and these are still monitored and studied, however current scientific consensus is that the evidence of studies suggests these are either dubious or low-significance risks. (See : Previous health concerns now considered doubtful or largely minor) Treatment emergent psychosis Main article: Methylphenidate psychosis 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.[81] In the majority of unremarkable isolated cases methylphenidate overdose is asymptomatic or only incurs minor symptoms even in children under six years of age.[82][83][84] Normally any reaction will show within three hours.[84] However, injection (particularly arterial) has sometimes led to toxic necrosis and amputation at the point of injection.[85] Emergency treatment is recommended beyond certain overdose levels, in cases of attempted suicide, and in those using monoamine oxidase inhibitors (MAOIs).[84] Long-term effects It was documented in 2000, by Zito et al.[86] "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.[87][88] 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.[89] There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks.[90] Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%.[91] 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.[92] The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.[93] Concerns have been raised that long-term therapy might cause drug dependence, paranoia, schizophrenia and behavioral sensitisation, similar to other stimulants.[94] Psychotic symptoms from methylphenidate can include hearing voices, visual hallucinations, urges to harm oneself, severe anxiety, euphoria, grandiosity, paranoid delusions, confusion, increased aggression and irritability. Methylphenidate psychosis is unpredictable in whom it will occur. Family history of mental illness does not predict the incidence of stimulant toxicosis in children with ADHD. High rates of childhood stimulant use is found in patients with a diagnosis of schizophrenia and bipolar disorder independent of ADHD. Individuals with a diagnosis of bipolar or schizophrenia who were prescribed stimulants during childhood typically have a significantly earlier onset of the psychotic disorder and suffer a more severe clinical course of psychotic disorder.[95][96][97] Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects.[98] 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.[99] Measures tested included D2-like dopamine receptor density, dopamine transporter density, amphetamine-induced dopamine release responsiveness, cognitive performance, and growth.[99] Cognitive effects According to a small study conducted by the Society of Nuclear Medicine, the use of methylphenidate in certain individuals for reasons outside of its intended clinical applications may adversely affect cognitive performance. Specifically, methylphenidate positively affected brain glucose metabolism in subjects who performed well at baseline on an accuracy-controlled cognitive task, but caused further deterioration of mental processing in subjects who performed poorly at baseline. In other words, certain individuals without ADHD who take the drug to enhance concentration and focus may inadvertently make things worse.[100] However, in a paper published in Biological Psychiatry (June 24, 2008 online), researchers report that methylphenidate fine-tunes the functioning of neurons in the prefrontal cortex - a brain region involved in attention, decision-making and impulse control - while having few effects outside it. The team studied PFC neurons in rats under a variety of methylphenidate doses, including one that improved the animals' performance in a working memory task of the type that ADHD patients have trouble completing. Using microelectrodes, the scientists observed both the random, spontaneous firings of PFC neurons and their response to stimulation of the hippocampus. When they listened to individual PFC neurons, the scientists found that while cognition-enhancing doses of methylphenidate had little effect on spontaneous activity, the neurons' sensitivity to signals coming from the hippocampus increased dramatically. Under higher, stimulatory doses, on the other hand, PFC neurons stopped responding to incoming information.[101] Another study suggests that methylphenidate improves spatial orientation and working memory in rats on the radial arm maze.  Precautions Interactions Intake of adrenergic agonist drugs or pemoline with methylphenidate increases the risk of liver toxicity.[102][103] When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[104][105] 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.[33][106] Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[107] Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[108] but has significantly less activity on the norepinephrine transporter (NET).[109] Contraindications Methylphenidate should not be prescribed concomitantly with tricyclic antidepressants, such as desipramine, or monoamine oxidase inhibitors, such as phenelzine or tranylcypromine, as methylphenidate may dangerously increase plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects).[citation needed][vague] Methylphenidate should not be prescribed to patients who suffer from severe arrhythmia, hypertension or liver damage. It should not be prescribed to patients who demonstrate drug-seeking behaviour, pronounced agitation or nervousness.[47] Care should be taken while prescribing methylphenidate to children with a family history of Paroxysmal Supraventricular Tachycardia (PSVT).  Special precautions Special precaution is recommended in individuals with epilepsy with additional caution in individuals with uncontrolled epilepsy due to the potential for methylphenidate to lower the seizure threshold.[110] There is no published evidence to suggest that either the short or long term treatment with methylphenidate increases the risk of developing seizures in children with ADHD.[110] A number of small trials suggest that it is safe for use in children with epilepsy. Further randomised control trials are needed.  Pregnancy 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.[111] 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.[112] One of these studies (N = 11) demonstrated no significant increases in malformations.[113] 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.[114] 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.[82][83][84] In cases that manifest symptoms, these can typically include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia.[115] LD50 in mice is 190 mg/kg.[116] 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,[82] 0.9% in the 2004 US national analysis with n=8336,[117] and 0.2% in the same analysis for 2010 with n=6503[83]).  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[84]).  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.[118] 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 injection, especially when arterial.[85] Medical and emergency handling Key recommendations in US guidelines for overdose handling include:[84] Well evidenced findings (evidence standard "A"): 0–6 years: 2 mg/kg, or 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 centre 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).[82] 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 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:[82] "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,[84][117] 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.[119] The 2010 report[83] 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)[117] 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 inguinal abscess and fever in one who injected intravenously.[85] Tolerance Tolerance and behavioural sensitisation may occur with long-term use of methylphenidate.[107] There is also cross tolerance with other stimulants such as amphetamine and cocaine.[120] Stimulant withdrawal or rebound reactions can occur and should be minimised in intensity, e.g. via a gradual tapering off of medication over a period of weeks or months.[121][122][123] A very small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical. Nonetheless, withdrawal reactions may still occur in susceptible individuals.[124] The withdrawal or rebound symptoms of methylphenidate can include psychosis, depression, irritability and a temporary worsening of the original ADHD symptoms. Methylphenidate, due to its very short elimination half life, may be more prone to rebound effects than d-amphetamine.[47][125][126] Up to a third of children with ADHD experience a rebound effect when methylphenidate dose wears off.[127] However, there have also been studies that show that chronic administration of methylphenidate increases sensitivity.[128] This phenomenon, known as sensitization, is known to occur with chronic administration of amphetamine.[129] File:Ritalin.jpg Legal warning printed on Ritalin packaging Methylphenidate has some potential for abuse due to its action on dopamine transporters, although individuals with ADHD are unable to get any recreational use.[47][130] 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.[131] The abuse and addiction potential of methylphenidate is therefore significantly lower than that of cocaine.[131] The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or when it is injected, producing effects somewhat similar to cocaine.[132] Cocaine-like effects can also occur with very large doses taken orally.[citation needed] However, the dose that produces euphoric effects varies among individuals. Methylphenidate has less abuse potential than cocaine and amphetamine.[133] 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.[115] IV users tend to be adults whose use may cause panlobular pulmonary emphysema.[119] 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.[134] Patients who have been prescribed Ritalin have been known to sell their tablets to others who wish to take the drug recreationally. In the USA it is one of the top ten stolen prescription drugs.[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. 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.[135] 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.[136] 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.[137][138] 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.[139] Legal status Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[140] In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for abuse. In the United Kingdom, methylphenidate is a controlled 'Class B' substance. Possession without prescription carries with a sentence up to 5 years and/or an unlimited fine, and supplying it is 14 years and/or an unlimited fine.[141] 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 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. Available forms File:Methylphenidate Formulations.jpg Clockwise from top: Concerta 18 mg (OROS), Medikinet 10 mg, Methylphenidat TAD 10 mg, Ritalin 10 mg (immediate release tablets), Medikinet XL 30 mg (CR capsule).  The dosage forms of methylphenidate are tablets, capsules, patches, and liquid.  Immediate-release File:Ritalin Pill.jpg 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, and Rubifen. Focalin is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations.  Extended-release Extended-release tablets or capsules include: Concerta (brand-name); Watson methylphenidate ER (US generic); Teva-Methylphenidate ER‑C (Canadian generic). Each pill is effective for 12 hours.[142] Equasym XL; Medikinet XL; Metadate CD; Ritalin LA; Rubifen SR. Some of these work identically to each other; some do not. Ritalin‑SR (brand-name); Methylin ER (US generic); Metadate ER (US generic); methylphenidate SR (Canadian generic).[143][144][145] Each pill is effective for 5–8 hours.[142] A newer way of taking methylphenidate is by using a transdermal patch (under the brand name Daytrana), similar to those used for nicotine replacement therapy.  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,[146] 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.[147] 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[148] 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.[149] Delivery formulations File:Ritalin Pill.jpg Ritalin 10mg Pill (Ciba/Novartis) All media are in milligrams.  Tablet Ritalin: 5, 10 or 20mg tablets. Ritalin SR: 20mg controlled-release tablets. Attenta: 10mg tablets. Methylin: 5, 10 or 20mg tablets. Methylin ER: 10 and 20mg controlled-release tablets. Metadate ER: 10 and 20mg controlled-release tablets. Concerta: 18, 27, 36 and 54mg controlled-release tablets. [150] (goes off patent in 2018)[151] Equasym: 5, 10, 20 or 30mg tablets. Rubifen: 5, 10 or 20mg tablets. Capsules Ritalin LA: 10, 20, 30 or 40mg controlled-release capsules. Metadate CD: 10, 20, 30, 40 or 60mg controlled-release capsules. Patches Daytrana 10, 15, 20 or 30mg controlled-release patches (1.1, 1.6, 2.2 or 3.3 mg/hour for 9 hours). Criticism Main article: Attention deficit hyperactivity disorder controversies 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.[152] The pharmacological effects of methylphenidate resemble closely those of cocaine and amphetamine,[153] which is the desired effect in the treatment of ADHD,[154] and how methylphenidate works. However, while Methylphenidate may resemble closely those of cocaine individuals with ADHD have no recreational use of Methylphenidate.[155] Shortages of Ritalin in 2011[156] have been blamed on overmedication, itself ironically due to inattention to alternative therapies or measurement of long-term efficacy.[157] Attempts have been made to rebut these charges, primarily by questioning the assumptions of studies conducted long after the treatment period has ended.[158] A 2002 study showed that rats treated with methylphenidate are more receptive to the reinforcing effects of cocaine.[159] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,[160][161][162] 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".[163] 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.[164] 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.[165] 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.[166] Methylphenidate has been approved for adult use in the treatment of narcolepsy.[167][168] Chemistry Four isomers of methylphenidate are known to exist. One pair of threo isomers and one pair of erythro are distinguished, from which only d-threo-methylphenidate exhibits the pharmacologically usually desired effects.[16][169] 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.[170] File:Methylphenidate preparation.svg Methylphenidate preparation according to Jeffrey M. Axten et al. (1998)[171] File:Classical Ritalin Production .svg Methylphenidate production[172] See also Amphetamine Analeptic drugs Benzedrine Controversy about ADHD Ethylphenidate Methamphetamine Pethadine Pemoline Psychoactive drug Steroid References ↑ Methylphenidate - Oral (Ritalin) side effects, medical uses and drug interactions. URL accessed on 2007-11-02. ↑ Ritalin (methylphenidate) Side Effects and Abuse. URL accessed on 2007-11-02. ↑ Pronounciation ↑ includeonly>"An Old Drug May Give Cancer Patients a Lift", ACS News Center, American Cancer Society, 2002-01-24. Retrieved on 2008-02-24. ↑ News from DEA, Congressional Testimony, 05/16/00. URL accessed on 2007-11-02. ↑ Jump up to: 6.0 6.1 6.2 Steele, M., et al. (2006). "A randomized, controlled effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in Attention Deficit-Hyperactivity DisorderPDF (293 KB)". Can J Clin Pharmacol. 2006 Winter;13(1):e50-62. Cite error: Invalid tag; name "steele" defined multiple times with different content ↑ Pelham, W.E., et al. (2001). "Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings". Pediatrics. 2001 Jun;107(6):E105. ↑ Keating, G.M., McClellan, K., Jarvis, B. (2001). "Methylphenidate (OROS formulation)". CNS Drugs. 2001;15(6):495-500; discussion 501-3. ↑ Hoare, P., et al. (2005). "12-month efficacy and safety of OROS methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder switched from MPHPDF". Eur Child Adolesc Psychiatry. 2005 Sep;14(6):305-9. ↑ Peck, P. (2006, 7 April). FDA Approves Daytrana Transdermal Patch for ADHD. MedPage today. Retrieved April 7, 2006, from ↑ Fone KC, Nutt DJ. (February 2005). Stimulants: use and abuse in the treatment of attention deficit disorder.. Current opinion in pharmacology. 5 (1): 87-93. ↑ Sharma RP, Javaid JI, Pandey GN, Easton M, Davis JM. (April 1990). Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone.. Psychiatry research. 32 (1): 9-17. ↑ Shults T, Kownacki AA, Woods WE, Valentine R, Dougherty J, Tobin T. (May 1981). Pharmacokinetics and behavioral effects of methylphenidate in Thoroughbred horses.. American journal of veterinary research. 42 (5): 722-6. ↑ Barbaresi, W.J., et al. (2006). "Long-Term Stimulant Medication Treatment of Attention-Deficit/Hyperactivity Disorder: Results from a Population-Based Study". J Dev Behav Pediatr. 2006 Feb;27(1):1-10. ↑ Grund T., et al. 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"Dopamine Transporter Occupancies in the Human Brain Induced by Therapeutic Doses of Oral Methylphenidate". Am J Psychiatry 155:1325-1331, October 1998. ↑ Gainetdinov, Raul R., Caron, Marc G. (March 2001). Genetics of Childhood Disorders: XXIV. ADHD, Part 8: Hyperdopaminergic Mice as an Animal Model of ADHD. Journal of the American Academy of Child & Adolescent Psychiatry 40 (3): 380-382. ↑ Volkow, ND, Fowler JS, Wang GJ, Telang F, Logan J, Wong C, Ma J, Pradhan K, Benveniste H, Swanson JM (April 2008). Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task. PLoS ONE 3 (4): e2017. PMID 18414677. ↑ Kimko HC, Cross JT, Abernethy DR. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet 1999 Dec; 37 (6): 457-70 ↑ PMID 6866592 (PMID 6866592) Citation will be completed automatically in a few minutes. Jump the queue or expand by hand ↑ R. 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ADHD & Women's Health – Attention-deficit hyperactivity disorder National Women's Health Report. ↑ Edmund J. S. Sonuga-Barke, Margaret Thompson, Howard Abikoff, Rachel Klein, Laurie Miller Brotman. Nonpharmacological Interventions for Preschoolers With ADHD: The Case for Specialized Parent Training. Infants & Young Children 19 (2): 142–153. ↑ Ashton H, Gallagher P, Moore B (2006). The adult psychiatrist's dilemma: psychostimulant use in attention deficit/hyperactivity disorder. J. Psychopharmacol. (Oxford) 20 (5): 602–10. ↑ Kociancic T, Reed MD, Findling RL (2004). Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children. Expert Opin Drug Saf 3 (2): 93–100. ↑ (2007). Ritalin & Ritalin-SR Prescribing Information. (PDF) Novartis. ↑ Cherland E, Fitzpatrick R (1999). Psychotic side effects of psychostimulants: a 5-year review. Can J Psychiatry 44 (8): 811–3. ↑ Kimko HC, Cross JT, Abernethy DR (1999). Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet 37 (6): 457–70. ↑ Dafny N, Yang PB (2006). The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects. Brain Research Bulletin 68 (6): 393–405. ↑ Ross RG (2006). Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry 163 (7): 1149–52. ↑ DelBello MP, Soutullo CA, Hendricks W, Niemeier RT, McElroy SL, Strakowski SM (2001). Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset. Bipolar Disord 3 (2): 53–7. ↑ Soutullo CA, DelBello MP, Ochsner JE, et al. (2002). Severity of bipolarity in hospitalized manic adolescents with history of stimulant or antidepressant treatment. J Affect Disord 70 (3): 323–7. ↑ Kuczenski R, Segal DS (2005). Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse. Biol. Psychiatry 57 (11): 1391–6. ↑ Jump up to: 99.0 99.1 Soto, Paul L., Kristin M Wilcox, Yun Zhou, Nancy A Ator, Mark A Riddle, Dean F Wong, Michael R Weed (18). Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology, Behavior, and Dopamine System Development. Neuropsychopharmacology 37: 2566–2579. ↑ Popular Stimulant's Role In Brain Function Deterioration Is Cause For Concern, According To Researchers ↑ Study Uncovers How Ritalin Works in Brain to Boost Cognition, Focus Attention Newswise, Retrieved on June 24, 2008. ↑ Roberts SM, DeMott RP, James RC (1997). Adrenergic modulation of hepatotoxicity. Drug Metab. Rev. 29 (1–2): 329–53. ↑ Marotta PJ, Roberts EA (1998). Pemoline hepatotoxicity in children. The Journal of Pediatrics 132 (5): 894–7. ↑ Patrick KS, González MA, Straughn AB, Markowitz JS (2005). New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder. Expert Opinion on Drug Delivery 2 (1): 121–43. ↑ Markowitz JS, DeVane CL, Boulton DW, et al. (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. ↑ PMID 10820132 (PMID 10820132) Citation will be completed automatically in a few minutes. Jump the queue or expand by hand ↑ Jump up to: 107.0 107.1 Patrick KS, Straughn AB, Perkins JS, González MA (2009). Evolution of stimulants to treat ADHD: transdermal methylphenidate. Human Psychopharmacology 24 (1): 1–17. ↑ Patrick KS, Williard RL, VanWert AL, Dowd JJ, Oatis JE, Middaugh LD (2005). Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol. Journal of Medicinal Chemistry 48 (8): 2876–81. ↑ Williard RL, Middaugh LD, Zhu HJ, Patrick KS (2007). Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity. Behavioural Pharmacology 18 (1): 39–51. ↑ Jump up to: 110.0 110.1 Tan M, Appleton R (2005). Attention deficit and hyperactivity disorder, methylphenidate, and epilepsy. Archives of Disease in Childhood 90 (1): 57–9. ↑ Methylphenidate Use During Pregnancy and Breastfeeding. Retrieved on 2011-04-30. ↑ Humphreys C, Garcia-Bournissen F, Ito S, Koren G (2007). Exposure to attention deficit hyperactivity disorder medications during pregnancy. Canadian Family Physician 53 (7): 1153–5. ↑ Kaufman, David Myland; Heinonen, Olli P.; Slone, Dennis; Shapiro, Samuel (1977). Birth defects and drugs in pregnancy, Littleton, Mass: Publishing Sciences Group.Template:Page needed ↑ Yaffe, Sumner J.; Briggs, Gerald G.; Freeman, Roger Anthony (2005). Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk, Hagerstwon, MD: Lippincott Williams & Wilkins.Template:Page needed ↑ Jump up to: 115.0 115.1 Klein-Schwartz W (2002). Abuse and toxicity of methylphenidate. Current Opinion in Pediatrics 14 (2): 219–23. ↑ ↑ Jump up to: 117.0 117.1 117.2 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System - Table 22B p.652 ↑ Safety of therapeutic methylphenidate in adults: a systematic review of the evidence - 2008, Godfrey ↑ Jump up to: 119.0 119.1 Stern EJ, Frank MS, Schmutz JF, Glenny RW, Schmidt RA, Godwin JD (1994). Panlobular pulmonary emphysema caused by i.v. injection of methylphenidate (Ritalin): findings on chest radiographs and CT scans. American Journal of Roentgenology 162 (3): 555–60. ↑ Leith NJ, Barrett RJ (1981). Self-stimulation and amphetamine: tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate. Psychopharmacology (Berl.) 74 (1): 23–8. ↑ Cohen D, Leo J, Stanton T, et al. (2002). A boy who stops taking stimulants for "ADHD": commentaries on a Pediatrics case study. Ethical Hum Sci Serv 4 (3): 189–209. ↑ Schwartz RH, Rushton HG (2004). Stuttering priapism associated with withdrawal from sustained-release methylphenidate. J. Pediatr. 144 (5): 675–6. ↑ Garland EJ (1998). Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats. J. Psychopharmacol. (Oxford) 12 (4): 385–95. ↑ Nolan EE, Gadow KD, Sprafkin J (1999). Stimulant medication withdrawal during long-term therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Pediatrics 103 (4 Pt 1): 730–7. ↑ Smucker WD, Hedayat M (2001). Evaluation and treatment of ADHD. Am Fam Physician 64 (5): 817–29. ↑ Rosenfeld AA (1979). Depression and psychotic regression following prolonged methylphenidate use and withdrawal: case report. Am J Psychiatry 136 (2): 226–8. ↑ Riccio CA, Waldrop JJ, Reynolds CR, Lowe P (2001). Effects of stimulants on the continuous performance test (CPT): implications for CPT use and interpretation. J Neuropsychiatry Clin Neurosci 13 (3): 326–35. ↑ Yang Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization. URL accessed on 2 April 2013. ↑ DOI:10.1016/j.pnpbp.2007.08.025 This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand ↑ Zhu J, Reith ME (2008). Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse. CNS & Neurological Disorders Drug Targets 7 (5): 393–409. ↑ Jump up to: 131.0 131.1 PMID 9862747 (PMID 9862747) Citation will be completed automatically in a few minutes. Jump the queue or expand by hand ↑ Morton WA, Stockton GG (2000). Methylphenidate Abuse and Psychiatric Side Effects. Primary Care Companion Journal of Clinical Psychiatry 2 (5): 159–64. ↑ Volkow ND, Swanson JM (2003). Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. The American Journal of Psychiatry 160 (11): 1909–18. ↑ Arria AM, Wish ED (2006). Nonmedical use of prescription stimulants among students. Pediatric Annals 35 (8): 565–71. ↑ includeonly>Midgely, Carol. "Kiddie coke: A new peril in the playground", The Times, February 21, 2003. Retrieved on 21 February 2010.Template:Unreliable medical source ↑ Harris J (2009). Is it acceptable for people to take methylphenidate to enhance performance? Yes. BMJ 338: b1955. ↑ Chatterjee A (2009). Is it acceptable for people to take methylphenidate to enhance performance? No. BMJ 338: b1956. ↑ Ritalin backed as brain-booster. BBC News. URL accessed on 21 February 2010. ↑ includeonly>Davies, Caroline. "Universities told to consider dope tests as student use of 'smart drugs' soars", The Observer, 21 February 2010. Retrieved on 21 February 2010. ↑ Green List: Annex to the annual statistical report on psychotropic substances (form P)PDF (1.63 MB) 23rd edition. August 2003. International Narcotics Board, Vienna International Centre. Retrieved 2 March 2006. ↑ ↑ Jump up to: 142.0 142.1 Moses, Scott Methylphenidate. Family Practice Notebook. URL accessed on 2012-08-07.. ↑ Education/Training » Clinical Resources. Illinois DocAssist website. University of Illinois at Chicago. URL accessed on 2012-07-26.. ↑ Apo‑Methylphenidate SR product monograph. (PDF) Apotex Inc. URL accessed on 2012-07-26. If the monograph link doesn't work, visit Health Canada's Drug Product Database query form one time, then click the monograph link again. ↑ New product: Sandoz Methylphenidate SR 20 mg. Sandoz Canada Inc. URL accessed on 2012-07-26.. ↑ Concerta for Kids with ADHD. (2003-04-01). Retrieved on 2011-04-30. ↑ Concerta (Methylphenidate Extended-Release Tablets) Drug Information: User Reviews, Side Effects, Drug Interactions and Dosage at RxList. Retrieved on 2011-04-30. ↑ Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, Novartis ↑ Metadate CD. Retrieved on 2011-04-30. ↑ Full Prescribing Information for Concerta. (215 KiB) ↑ Generic Concerta ↑ Cite error: Invalid tag; no text was provided for refs named pmid17949504 ↑ Cite error: Invalid tag; no text was provided for refs named DEA_Petition_Response ↑ Cite error: Invalid tag; no text was provided for refs named ↑ Cite error: Invalid tag; no text was provided for refs named ↑ Cite error: Invalid tag; no text was provided for refs named NYTShortage ↑ Cite error: Invalid tag; no text was provided for refs named NYTGoneWrong ↑ Cite error: Invalid tag; no text was provided for refs named JoanHamburg ↑ Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine ↑ Cite error: Invalid tag; no text was provided for refs named ↑ Cite error: Invalid tag; no text was provided for refs named Wilens ↑ Cite error: Invalid tag; no text was provided for refs named Barkley ↑ Cite error: Invalid tag; no text was provided for refs named ↑ Cite error: Invalid tag; no text was provided for refs named WeinbergBrumback ↑ Ouellette EM (1991). Legal issues in the treatment of children with attention deficit hyperactivity disorder. Journal of Child Neurology 6 Suppl: S68–75. ↑ FDA OKs Concerta for Adult ADHD, ↑ Ritalin for Adults. (2007-03-06). Retrieved on 2011-04-30. ↑ Attention Deficit Hyperactivity Disorder (ADHD) – Treatment – NHS Choices. (2010-05-19). Retrieved on 2011-04-30. ↑ Froimowitz M, Patrick KS, Cody V (1995). Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT. Pharmaceutical Research 12 (10): 1430–4. ↑ (2001). Approaches to the Preparation of Enantiomerically Pure (2R,2′R)-(+)-threo-Methylphenidate Hydrochloride. Adv. Synth. Catal 343 (5): 379–92. ↑ DOI:10.1021/jo982214t This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand ↑ Singh, Satendra (2000). Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Chem. Rev. 100 (3): 925–1024 (1008). External links Department of Energy 1998 September 29 press release on Ritalin at Brookhaven National Laboratory Online library of psychoactive plants, chemicals and related topics from A coalition of harm reduction advocates with resources and insightful help for those dealing with drug issues as well as those trying to provide help.] Ritalin addiction resource from Template:Drug use v·d·e Stimulants (N06B) Adamantanes Adaphenoxate • Adapromine • Amantadine • Bromantane • Chlodantane • Gludantane • Memantine • Midantane Adenosine antagonists 8-Chlorotheophylline • 8-Cyclopentyltheophylline • 8-Phenyltheophylline • Aminophylline • Caffeine • CGS-15943 • Dimethazan • Paraxanthine • SCH-58261 • Theobromine • Theophylline Alkylamines Cyclopentamine • Cypenamine • Cyprodenate • Heptaminol • Isometheptene • Methylhexaneamine • Octodrine • Propylhexedrine • Tuaminoheptane Arylcyclohexylamines Benocyclidine • Dieticyclidine • Esketamine • Eticyclidine • Gacyclidine • Ketamine • Phencyclamine • Phencyclidine • Rolicyclidine • Tenocyclidine • Tiletamine Benzazepines 6-Br-APB • SKF-77434 • SKF-81297 • SKF-82958 Cholinergics A-84543 • A-366,833 • ABT-202 • ABT-418 • AR-R17779 • Altinicline • Anabasine • Arecoline • Cotinine • Cytisine • Dianicline • Epibatidine • Epiboxidine • GTS-21 • Ispronicline • Nicotine • PHA-543,613 • PNU-120,596 • PNU-282,987 • Pozanicline • Rivanicline • Sazetidine A • SIB-1553A • SSR-180,711 • TC-1698 • TC-1827 • TC-2216 • TC-5619 • Tebanicline • UB-165 • Varenicline • WAY-317,538 Convulsants Anatoxin-a • Bicuculline • DMCM • Flurothyl • Gabazine • Pentetrazol • Picrotoxin • Strychnine • Thujone Eugeroics Adrafinil • Armodafinil • CRL-40941 • Modafinil Oxazolines 4-Methylaminorex • Aminorex • Clominorex • Cyclazodone • Fenozolone • Fluminorex • Pemoline • Thozalinone Phenethylamines 1-(4-Methylphenyl)-2-aminobutane • 1-Phenyl-2-(piperidin-1-yl)pentan-3-one • 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane • 2-Fluoroamphetamine • 2-Fluoromethamphetamine • 2-OH-PEA • 2-Phenyl-3-aminobutane • 2-Phenyl-3-methylaminobutane • 2,3-MDA • 3-Fluoroamphetamine • 3-Fluoroethamphetamine • 3-Fluoromethcathinone • 3-Methoxyamphetamine • 3-Methylamphetamine • 3,4-DMMC • 4-BMC • 4-Ethylamphetamine • 4-FA • 4-FMA • 4-MA • 4-MMA • 4-MTA • 6-FNE • Alfetamine • α-Ethylphenethylamine • Amfecloral • Amfepentorex • Amfepramone • Amidephrine • Amphetamine (Dextroamphetamine, Levoamphetamine) • Amphetaminil • Arbutamine • β-Methylphenethylamine • β-Phenylmethamphetamine • Benfluorex • Benzedrone • Benzphetamine • BDB (J) • BOH (Hydroxy-J) • BPAP • Buphedrone • Bupropion (Amfebutamone) • Butylone • Cathine • Cathinone • Chlorphentermine • Cinnamedrine • Clenbuterol • Clobenzorex • Cloforex • Clortermine • D-Deprenyl • Denopamine • Dimethoxyamphetamine • Dimethylamphetamine • Dimethylcathinone (Dimethylpropion, Metamfepramone) • Dobutamine • DOPA (Dextrodopa, Levodopa) • Dopamine • Dopexamine • Droxidopa • EBDB (Ethyl-J) • Ephedrine • Epinephrine (Adrenaline) • Epinine (Deoxyepinephrine) • Etafedrine • Ethcathinone (Ethylpropion) • Ethylamphetamine (Etilamfetamine) • Ethylnorepinephrine (Butanefrine) • Ethylone • Etilefrine • Famprofazone • Fenbutrazate • Fencamine • Fenethylline • Fenfluramine (Dexfenfluramine) • Fenmetramide • Fenproporex • Flephedrone • Fludorex • Furfenorex • Gepefrine • HMMA • Hordenine • Ibopamine • IMP • Indanylamphetamine • Isoetarine • Isoethcathinone • Isoprenaline (Isoproterenol) • L-Deprenyl (Selegiline) • Lefetamine • Lisdexamfetamine • Lophophine (Homomyristicylamine) • Manifaxine • MBDB (Methyl-J; "Eden") • MDA (Tenamfetamine) • MDBU • MDEA ("Eve") • MDMA ("Ecstasy", "Adam") • MDMPEA (Homarylamine) • MDOH • MDPR • MDPEA (Homopiperonylamine) • Mefenorex • Mephedrone • Mephentermine • Metanephrine • Metaraminol • Methamphetamine (Desoxyephedrine, Methedrine; Dextromethamphetamine, Levomethamphetamine) • Methoxamine • Methoxyphenamine • MMA • Methcathinone (Methylpropion) • Methedrone • Methoxyphenamine • Methylone • MMDA • MMDMA • MMMA • Morazone • N-Benzyl-1-phenethylamine • N,N-Dimethylphenethylamine • Naphthylamphetamine • Nisoxetine • Norepinephrine (Noradrenaline) • Norfenefrine • Norfenfluramine • Normetanephrine • Octopamine • Orciprenaline • Ortetamine • Oxilofrine • Paredrine (Norpholedrine, Oxamphetamine, Mycadrine) • PBA • PCA • PHA • Pargyline • Pentorex (Phenpentermine) • Pentylone • Phendimetrazine • Phenmetrazine • Phenpromethamine • Phentermine • Phenylalanine • Phenylephrine (Neosynephrine) • Phenylpropanolamine • Pholedrine • PIA • PMA • PMEA • PMMA • PPAP • Prenylamine • Propylamphetamine • Pseudoephedrine • Radafaxine • Ropinirole • Salbutamol (Albuterol; Levosalbutamol) • Sibutramine • Synephrine (Oxedrine) • Theodrenaline • Tiflorex (Flutiorex) • Tranylcypromine • Tyramine • Tyrosine • Xamoterol • Xylopropamine • Zylofuramine Piperazines 2C-B-BZP • BZP • CM156 • DBL-583 • GBR-12783 • GBR-12935 • GBR-13069 • GBR-13098 • GBR-13119 • MeOPP • MBZP • Vanoxerine Piperidines 1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine • 1-(3,4-Dichlorophenyl)-1-(piperidin-2-yl)butane • 2-Benzylpiperidine • 2-Methyl-3-phenylpiperidine • 3,4-Dichloromethylphenidate • 4-Benzylpiperidine • 4-Methylmethylphenidate • Desoxypipradrol • Difemetorex • Diphenylpyraline • Ethylphenidate • Methylnaphthidate • Methylphenidate (Dexmethylphenidate) • N-Methyl-3β-propyl-4β-(4-chlorophenyl)piperidine • Nocaine • Phacetoperane • Pipradrol • SCH-5472 Pyrrolidines 2-Diphenylmethylpyrrolidine • α-PPP • α-PBP • α-PVP • Diphenylprolinol • MDPPP • MDPBP • MDPV • MPBP • MPHP • MPPP • MOPPP • Naphyrone • PEP • Prolintane • Pyrovalerone Tropanes 3-CPMT • 3'-Chloro-3α-(diphenylmethoxy)tropane • 3-Pseudotropyl-4-fluorobenzoate • 4'-Fluorococaine • AHN-1055 • Altropane (IACFT) • Brasofensine • CFT (WIN 35,428) • β-CIT (RTI-55) • Cocaethylene • Cocaine • Dichloropane (RTI-111) • Difluoropine • FE-β-CPPIT • FP-β-CPPIT • Ioflupane (123I) • Norcocaine • PIT • PTT • RTI-31 • RTI-32 • RTI-51 • RTI-105 • RTI-112 • RTI-113 • RTI-117 • RTI-120 • RTI-121 (IPCIT) • RTI-126 • RTI-150 • RTI-154 • RTI-171 • RTI-177 • RTI-183 • RTI-193 • RTI-194 • RTI-199 • RTI-202 • RTI-204 • RTI-229 • RTI-241 • RTI-336 • RTI-354 • RTI-371 • RTI-386 • Salicylmethylecgonine • Tesofensine • Troparil (β-CPT, WIN 35,065-2) • Tropoxane • WF-23 • WF-33 • WF-60 Others 1-(Thiophen-2-yl)-2-aminopropane • 2-Amino-1,2-dihydronaphthalene • 2-Aminoindane • 2-Aminotetralin • 2-MDP • 2-Phenylcyclohexylamine • 2-Phenyl-3,6-dimethylmorpholine • 3-Benzhydrylmorpholine • 3,3-Diphenylcyclobutanamine • 5-(2-Aminopropyl)indole • 5-Iodo-2-aminoindane • AL-1095 • Amfonelic acid • Amineptine • Amiphenazole • Atipamezole • Atomoxetine (Tomoxetine) • Bemegride • Benzydamine • BTQ • BTS 74,398 • Carphedon • Ciclazindol • Cilobamine • Clofenciclan • Cropropamide • Crotetamide • Cypenamine • D-161 • Diclofensine • Dimethocaine • Efaroxan • Etamivan • EXP-561 • Fencamfamine • Fenpentadiol • Feprosidnine • G-130 • Gamfexine • Gilutensin • GSK1360707F • GYKI-52895 • Hexacyclonate • Idazoxan • Indanorex • Indatraline • JNJ-7925476 • JZ-IV-10 • Lazabemide • Leptacline • Levopropylhexedrine • Lomevactone • LR-5182 • Mazindol • Meclofenoxate • Medifoxamine • Mefexamide • Mesocarb • Methastyridone • Methiopropamine • N-Methyl-3-phenylnorbornan-2-amine • Nefopam • Nikethamide • Nomifensine • O-2172 • Oxaprotiline • Phthalimidopropiophenone • PNU-99,194 • Propylhexedrine • PRC200-SS • Rasagiline • Rauwolscine • Rubidium chloride • Setazindol • Tametraline • Tandamine • Trazium • UH-232 • Yohimbine See also Sympathomimetic amines Template:Antihyperkinetics v·d·e Adrenergics [. v]·[. d]·[. e] Receptor ligands α1 Agonists: 5-FNE • 6-FNE • Amidephrine • Anisodamine • Anisodine • Cirazoline • Dipivefrine • Dopamine • Ephedrine • Epinephrine (Adrenaline) • Etilefrine • Ethylnorepinephrine • Indanidine • Levonordefrin • Metaraminol • Methoxamine • Methyldopa • Midodrine • Naphazoline • Norepinephrine (Noradrenaline) • Octopamine • Oxymetazoline • Phenylephrine • Phenylpropanolamine • Pseudoephedrine • Synephrine • Tetrahydrozoline Antagonists: Abanoquil • Adimolol • Ajmalicine • Alfuzosin • Amosulalol • Arotinolol • Atiprosin • Benoxathian • Buflomedil • Bunazosin • Carvedilol • CI-926 • Corynanthine • Dapiprazole • DL-017 • Domesticine • Doxazosin • Eugenodilol • Fenspiride • GYKI-12,743 • GYKI-16,084 • Indoramin • Ketanserin • L-765,314 • Labetalol • Mephendioxan • Metazosin • Monatepil • Moxisylyte (Thymoxamine) • Naftopidil • Nantenine • Neldazosin • Nicergoline • Niguldipine • Pelanserin • Phendioxan • Phenoxybenzamine • Phentolamine • Piperoxan • Prazosin • Quinazosin • Ritanserin • RS-97,078 • SGB-1,534 • Silodosin • SL-89.0591 • Spiperone • Talipexole • Tamsulosin • Terazosin • Tibalosin • Tiodazosin • Tipentosin • Tolazoline • Trimazosin • Upidosin • Urapidil • Zolertine * Note that many TCAs, TeCAs, antipsychotics, ergolines, and some piperazines like buspirone, trazodone, nefazodone, etoperidone, and mepiprazole all antagonize α1-adrenergic receptors as well, which contributes to their side effects such as orthostatic hypotension.  α2 Agonists: (R)-3-Nitrobiphenyline • 4-NEMD • 6-FNE • Amitraz • Apraclonidine • Brimonidine • Cannabivarin • Clonidine • Detomidine • Dexmedetomidine • Dihydroergotamine • Dipivefrine • Dopamine • Ephedrine • Ergotamine • Epinephrine (Adrenaline) • Esproquin • Etilefrine • Ethylnorepinephrine • Guanabenz • Guanfacine • Guanoxabenz • Levonordefrin • Lofexidine • Medetomidine • Methyldopa • Mivazerol • Naphazoline • Norepinephrine (Noradrenaline) • Phenylpropanolamine • Piperoxan • Pseudoephedrine • Rilmenidine • Romifidine • Talipexole • Tetrahydrozoline • Tizanidine • Tolonidine • Urapidil • Xylazine • Xylometazoline Antagonists: 1-PP • Adimolol • Aptazapine • Atipamezole • BRL-44408 • Buflomedil • Cirazoline • Efaroxan • Esmirtazapine • Fenmetozole • Fluparoxan • GYKI-12,743 • GYKI-16,084 • Idazoxan • Mianserin • Mirtazapine • MK-912 • NAN-190 • Olanzapine • Phentolamine • Phenoxybenzamine • Piperoxan • Piribedil • Rauwolscine • Rotigotine • SB-269,970 • Setiptiline • Spiroxatrine • Sunepitron • Tolazoline • Yohimbine * Note that many atypical antipsychotics and azapirones like buspirone and gepirone (via metabolite 1-PP) antagonize α2-adrenergic receptors as well.  β Agonists: 2-FNE • 5-FNE • Amibegron • Arbutamine • Arformoterol • Arotinolol • BAAM • Bambuterol • Befunolol • Bitolterol • Broxaterol • Buphenine • Carbuterol • Cimaterol • Clenbuterol • Denopamine • Deterenol • Dipivefrine • Dobutamine • Dopamine • Dopexamine • Ephedrine • Epinephrine (Adrenaline) • Etafedrine • Etilefrine • Ethylnorepinephrine • Fenoterol • Formoterol • Hexoprenaline • Higenamine • Indacaterol • Isoetarine • Isoprenaline (Isoproterenol) • Isoxsuprine • Labetalol • Levonordefrin • Levosalbutamol • Mabuterol • Methoxyphenamine • Methyldopa • N-Isopropyloctopamine • Norepinephrine (Noradrenaline) • Orciprenaline • Oxyfedrine • Phenylpropanolamine • Pirbuterol • Prenalterol • Ractopamine • Procaterol • Pseudoephedrine • Reproterol • Rimiterol • Ritodrine • Salbutamol (Albuterol) • Salmeterol • Solabegron • Terbutaline • Tretoquinol • Tulobuterol • Xamoterol • Zilpaterol • Zinterol Antagonists: Acebutolol • Adaprolol • Adimolol • Afurolol • Alprenolol • Alprenoxime • Amosulalol • Ancarolol • Arnolol • Arotinolol • Atenolol • Befunolol • Betaxolol • Bevantolol • Bisoprolol • Bopindolol • Bormetolol • Bornaprolol • Brefonalol • Bucindolol • Bucumolol • Bufetolol • Buftiralol • Bufuralol • Bunitrolol • Bunolol • Bupranolol • Burocrolol • Butaxamine • Butidrine • Butofilolol • Capsinolol • Carazolol • Carpindolol • Carteolol • Carvedilol • Celiprolol • Cetamolol • Cicloprolol • Cinamolol • Cloranolol • Cyanopindolol • Dalbraminol • Dexpropranolol • Diacetolol • Dichloroisoprenaline • Dihydroalprenolol • Dilevalol • Diprafenone • Draquinolol • Dropranolol • Ecastolol • Epanolol • Ericolol • Ersentilide • Esatenolol • Esmolol • Esprolol • Eugenodilol • Exaprolol • Falintolol • Flestolol • Flusoxolol • Hydroxycarteolol • Hydroxytertatolol • ICI-118,551 • Idropranolol • Indenolol • Indopanolol • Iodocyanopindolol • Iprocrolol • Isoxaprolol • Isamoltane • Labetalol • Landiolol • Levobetaxolol • Levobunolol • Levocicloprolol • Levomoprolol • Medroxalol • Mepindolol • Metalol • Metipranolol • Metoprolol • Moprolol • Nadolol • Nadoxolol • Nafetolol • Nebivolol • Neraminol • Nifenalol • Nipradilol • Oberadilol • Oxprenolol • Pacrinolol • Pafenolol • Pamatolol • Pargolol • Parodilol • Penbutolol • Penirolol • PhQA-33 • Pindolol • Pirepolol • Practolol • Primidolol • Procinolol • Pronethalol • Propafenone • Propranolol • Ridazolol • Ronactolol • Soquinolol • Sotalol • Spirendolol • SR 59230A • Sulfinalol • TA-2005 • Talinolol • Tazolol • Teoprolol • Tertatolol • Terthianolol • Tienoxolol • Tilisolol • Timolol • Tiprenolol • Tolamolol • Toliprolol • Tribendilol • Trigevolol • Xibenolol • Xipranolol [. v]·[. d]·[. e] Reuptake inhibitors NET Selective norepinephrine reuptake inhibitors: Amedalin • Atomoxetine (Tomoxetine) • Ciclazindol • Daledalin • Esreboxetine • Lortalamine • Mazindol • Nisoxetine • Reboxetine • Talopram • Talsupram • Tandamine • Viloxazine; Norepinephrine-dopamine reuptake inhibitors: Amineptine • Bupropion (Amfebutamone) • Fencamine • Fencamfamine • Lefetamine • Levophacetoperane • LR-5182 • Manifaxine • Methylphenidate • Nomifensine • O-2172 • Radafaxine; Serotonin-norepinephrine reuptake inhibitors: Bicifadine • Desvenlafaxine • Duloxetine • Eclanamine • Levomilnacipran • Milnacipran • Sibutramine • Venlafaxine; Serotonin-norepinephrine-dopamine reuptake inhibitors: Brasofensine • Diclofensine • DOV-102,677 • DOV-21,947 • DOV-216,303 • JNJ-7925476 • JZ-IV-10 • Methylnaphthidate • Naphyrone • NS-2359 • PRC200-SS • SEP-225,289 • SEP-227,162 • Tesofensine; Tricyclic antidepressants: Amitriptyline • Butriptyline • Cianopramine • Clomipramine • Desipramine • Dosulepin • Doxepin • Imipramine • Lofepramine • melitracen • Nortriptyline • Protriptyline • Trimipramine; Tetracyclic antidepressants: Amoxapine • Maprotiline • Mianserin • Oxaprotiline • Setiptiline; Others: Cocaine • CP-39,332 • EXP-561 • Fezolamine • Ginkgo biloba • Nefazodone • Nefopam • Pridefrine • Tapentadol • Tramadol • Ziprasidone VMAT Ibogaine • Reserpine • Tetrabenazine [. v]·[. d]·[. e] Releasing agents Morpholines: Fenbutrazate • Morazone • Phendimetrazine • Phenmetrazine; Oxazolines: 4-Methylaminorex • Aminorex • Clominorex • Cyclazodone • Fenozolone • Fluminorex • Pemoline • Thozalinone; Phenethylamines (also amphetamines, cathinones, phentermines, etc): 2-OH-PEA • 4-CAB • 4-FA • 4-FMA • 4-MA • 4-MMA • Alfetamine • Amfecloral • Amfepentorex • Amfepramone • Amphetamine (Dextroamphetamine, Levoamphetamine) • Amphetaminil • β-Me-PEA • BDB • Benzphetamine • BOH • Buphedrone • Butylone • Cathine • Cathinone • Clobenzorex • Clortermine • D-Deprenyl • Dimethylamphetamine • Dimethylcathinone (Dimethylpropion, metamfepramone) • DMA • DMMA • EBDB • Ephedrine • Ethcathinone • Ethylamphetamine • Ethylone • Famprofazone • Fenethylline • Fenproporex • Flephedrone • Fludorex • Furfenorex • Hordenine • IAP • IMP • L-Deprenyl (Selegiline) • Lisdexamfetamine • Lophophine • MBDB • MDA (Tenamfetamine) • MDEA • MDMA • MDMPEA • MDOH • MDPEA • Mefenorex • Mephedrone • Mephentermine • Methamphetamine (Dextromethamphetamine, Levomethamphetamine) • Methcathinone • Methedrone • Methylone • NAP • Ortetamine • Paredrine • pBA • pCA • Pentorex (Phenpentermine) • Phenethylamine • Pholedrine • Phenpromethamine • Phentermine • Phenylpropanolamine • pIA • Prenylamine • Propylamphetamine • Pseudoephedrine • Tiflorex • Tyramine • Xylopropamine • Zylofuramine; Piperazines: 2C-B-BZP • BZP • MBZP • mCPP • MDBZP • MeOPP • pFPP; Others: 2-Amino-1,2-dihydronaphthalene • 2-Aminoindane • 2-Aminotetralin • 2-Benzylpiperidine • 4-Benzylpiperidine • 5-IAI • Clofenciclan • Cyclopentamine • Cypenamine • Cyprodenate • Feprosidnine • Gilutensin • Heptaminol • Hexacyclonate • Indanorex • Isometheptene • Methylhexanamine • Octodrine • Phthalimidopropiophenone • Propylhexedrine (Levopropylhexedrine) • Tuaminoheptane [. v]·[. d]·[. e] Enzyme inhibitors Anabolism PAH 3,4-Dihydroxystyrene TH 3-Iodotyrosine • Aquayamycin • Bulbocapnine • Metirosine • Oudenone AAAD Benserazide • Carbidopa • Genistein • Methyldopa DBH Bupicomide • Disulfiram • Dopastin • Fusaric acid • Nepicastat • Phenopicolinic acid • Tropolone PNMT CGS-19281A • SKF-64139 • SKF-7698 Catabolism MAO Nonselective: Benmoxin • Caroxazone • Echinopsidine • Furazolidone • Hydralazine • Indantadol • Iproclozide • Iproniazid • Isocarboxazid • Isoniazid • Linezolid • Mebanazine • Metfendrazine • Nialamide • Octamoxin • Paraxazone • Phenelzine • Pheniprazine • Phenoxypropazine • Pivalylbenzhydrazine • Procarbazine • Safrazine • Tranylcypromine; MAO-A selective: Amiflamine • Bazinaprine • Befloxatone • Befol • Brofaromine • Cimoxatone • Clorgiline • Esuprone • Harmala alkaloids (Harmine, Harmaline, Tetrahydroharmine, Harman, Norharman, etc) • Methylene Blue • Metralindole • Minaprine • Moclobemide • Pirlindole • Sercloremine • Tetrindole • Toloxatone • Tyrima; MAO-B selective: D-Deprenyl • Selegiline (L-Deprenyl) • Ladostigil • Lazabemide • Milacemide • Mofegiline • Pargyline • Rasagiline * Note that MAO-B inhibitors also influence norepinephrine/epinephrine levels since they inhibit the breakdown of their precursor dopamine.  COMT Entacapone • Tolcapone [. v]·[. d]·[. e] Others Precursors L-Phenylalanine → L-Tyrosine → L-DOPA (Levodopa) → Dopamine • L-DOPS (Droxidopa) Cofactors Ferrous Iron (Fe2+) • S-Adenosyl-L-Methionine • Vitamin B3 (Niacin, Nicotinamide → NADPH) • Vitamin B6 (Pyridoxine, Pyridoxamine, Pyridoxal → Pyridoxal Phosphate) • Vitamin B9 (Folic acid → Tetrahydrofolic acid) • Vitamin C (Ascorbic acid) • Zinc (Zn2+) Others Activity enhancers: BPAP • PPAP; Release blockers: Bethanidine • Bretylium • Guanadrel • Guanazodine • Guanclofine • Guanethidine • Guanoxan; Toxins: Oxidopamine (6-Hydroxydopamine) v·d·e Dopaminergics [. v]·[. d]·[. e] Receptor ligands Agonists Adamantanes: Amantadine • Memantine • Rimantadine; Aminotetralins: 7-OH-DPAT • 8-OH-PBZI • Rotigotine • UH-232; Benzazepines: 6-Br-APB • Fenoldopam • SKF-38,393 • SKF-77,434 • SKF-81,297 • SKF-82,958 • SKF-83,959; Ergolines: Bromocriptine • Cabergoline • Dihydroergocryptine • Lisuride • LSD • Pergolide; Dihydrexidine derivatives: 2-OH-NPA • A-86,929 • Ciladopa • Dihydrexidine • Dinapsoline • Dinoxyline • Doxanthrine; Others: A-68,930 • A-77,636 • A-412,997 • ABT-670 • ABT-724 • Aplindore • Apomorphine • Aripiprazole • Bifeprunox • BP-897 • CY-208,243 • Dizocilpine • Etilevodopa • Flibanserin • Ketamine • Melevodopa • Modafinil • Pardoprunox • Phencyclidine • PD-128,907 • PD-168,077 • PF-219,061 • Piribedil • Pramipexole • Propylnorapomorphine • Pukateine • Quinagolide • Quinelorane • Quinpirole • RDS-127 • Ro10-5824 • Ropinirole • Rotigotine • Roxindole • Salvinorin A • SKF-89,145 • Sumanirole • Terguride • Umespirone • WAY-100,635 Antagonists Typical antipsychotics: Acepromazine • Azaperone • Benperidol • Bromperidol • Clopenthixol • Chlorpromazine • Chlorprothixene • Droperidol • Flupentixol • Fluphenazine • Fluspirilene • Haloperidol • Loxapine • Mesoridazine • Methotrimeprazine • Nemonapride • Penfluridol • Perazine • Periciazine • Perphenazine • Pimozide • Prochlorperazine • Promazine • Sulforidazine • Sulpiride • Sultopride • Thioridazine • Thiothixene • Trifluoperazine • Triflupromazine • Trifluperidol • Zuclopenthixol; Atypical antipsychotics: Amisulpride • Asenapine • Blonanserin • Carpipramine • Clocapramine • Clozapine • Gevotroline • Iloperidone • Lurasidone • Melperone • Molindone • Mosapramine • Ocaperidone • Olanzapine • Paliperidone • Perospirone • Piquindone • Quetiapine • Remoxipride • Risperidone • Sertindole • Tiospirone • Ziprasidone • Zotepine; Antiemetics: AS-8112 • Alizapride • Bromopride • Clebopride • Domperidone • Metoclopramide • Thiethylperazine; Others: Amoxapine • Buspirone • Butaclamol • Ecopipam • EEDQ • Eticlopride • Fananserin • L-745,870 • Nafadotride • Nuciferine • PNU-99,194 • Raclopride • Sarizotan • SB-277,011-A • SCH-23,390 • SKF-83,566 • SKF-83,959 • Sonepiprazole • Spiperone • Spiroxatrine • Stepholidine • Tetrahydropalmatine • Tiapride • UH-232 • Yohimbine [. v]·[. d]·[. e] Reuptake inhibitors Plasmalemmal DAT inhibitors Piperazines: DBL-583 • GBR-12,935 • Nefazodone • Vanoxerine; Piperidines: BTCP • Desoxypipradrol • Dextromethylphenidate • Difemetorex • Ethylphenidate • Methylnaphthidate • Methylphenidate • Phencyclidine • Pipradrol; Pyrrolidines: Diphenylprolinol • Methylenedioxypyrovalerone (MDPV) • Naphyrone • Prolintane • Pyrovalerone; Tropanes: β-CPPIT • Altropane • Brasofensine • CFT • Cocaine • Dichloropane • Difluoropine • FE-β-CPPIT • FP-β-CPPIT • Ioflupane (123I) • Iometopane • RTI-112 • RTI-113 • RTI-121 • RTI-126 • RTI-150 • RTI-177 • RTI-229 • RTI-336 • Tenocyclidine • Tesofensine • Troparil • Tropoxane • WF-11 • WF-23 • WF-31 • WF-33; Others: Adrafinil • Armodafinil • Amfonelic acid • Amineptine • Benzatropine (Benztropine) • Bromantane • BTQ • BTS-74,398 • Bupropion (Amfebutamone) • Ciclazindol • Diclofensine • Dimethocaine • Diphenylpyraline • Dizocilpine • DOV-102,677 • DOV-21,947 • DOV-216,303 • Etybenzatropine (Ethylbenztropine) • EXP-561 • Fencamine • Fencamfamine • Fezolamine • GYKI-52,895 • Indatraline • Ketamine • Lefetamine • Levophacetoperane • LR-5182 • Manifaxine • Mazindol • Medifoxamine • Mesocarb • Modafinil • Nefopam • Nomifensine • NS-2359 • O-2172 • Pridefrine • Propylamphetamine • Radafaxine • SEP-225,289 • SEP-227,162 • Sertraline • Sibutramine • Tametraline • Tripelennamine Vesicular VMAT inhibitors Deserpidine • Ibogaine • Reserpine • Tetrabenazine [. v]·[. d]·[. e] Releasing agents Morpholines: Fenbutrazate • Morazone • Phendimetrazine • Phenmetrazine; Oxazolines: 4-Methylaminorex (4-MAR, 4-MAX) • Aminorex • Clominorex • Cyclazodone • Fenozolone • Fluminorex • Pemoline • Thozalinone; Phenethylamines (also amphetamines, cathinones, phentermines, etc): 2-Hydroxyphenethylamine (2-OH-PEA) • 4-CAB • 4-Methylamphetamine (4-MA) • 4-Methylmethamphetamine (4-MMA) • Alfetamine • Amfecloral • Amfepentorex • Amfepramone • Amphetamine (Dextroamphetamine, Levoamphetamine) • Amphetaminil • β-Methylphenethylamine (β-Me-PEA) • Benzodioxolylbutanamine (BDB) • Benzodioxolylhydroxybutanamine (BOH) • Benzphetamine • Buphedrone • Butylone • Cathine • Cathinone • Clobenzorex • Clortermine • D-Deprenyl • Dimethoxyamphetamine (DMA) • Dimethoxymethamphetamine (DMMA) • Dimethylamphetamine • Dimethylcathinone (Dimethylpropion, metamfepramone) • Ethcathinone (Ethylpropion) • Ethylamphetamine • Ethylbenzodioxolylbutanamine (EBDB) • Ethylone • Famprofazone • Fenethylline • Fenproporex • Flephedrone • Fludorex • Furfenorex • Hordenine • Lophophine (Homomyristicylamine) • Mefenorex • Mephedrone • Methamphetamine (Desoxyephedrine, Methedrine; Dextromethamphetamine, Levomethamphetamine) • Methcathinone (Methylpropion) • Methedrone • Methoxymethylenedioxyamphetamine (MMDA) • Methoxymethylenedioxymethamphetamine (MMDMA) • Methylbenzodioxolylbutanamine (MBDB) • Methylenedioxyamphetamine (MDA, tenamfetamine) • Methylenedioxyethylamphetamine (MDEA) • Methylenedioxyhydroxyamphetamine (MDOH) • Methylenedioxymethamphetamine (MDMA) • Methylenedioxymethylphenethylamine (MDMPEA, homarylamine) • Methylenedioxyphenethylamine (MDPEA, homopiperonylamine) • Methylone • Ortetamine • Parabromoamphetamine (PBA) • Parachloroamphetamine (PCA) • Parafluoroamphetamine (PFA) • Parafluoromethamphetamine (PFMA) • Parahydroxyamphetamine (PHA) • Paraiodoamphetamine (PIA) • Paredrine (Norpholedrine, Oxamphetamine) • Phenethylamine (PEA) • Pholedrine • Phenpromethamine • Prenylamine • Propylamphetamine • Tiflorex (Flutiorex) • Tyramine (TRA) • Xylopropamine • Zylofuramine; Piperazines: 2,5-Dimethoxy-4-bromobenzylpiperazine (2C-B-BZP) • Benzylpiperazine (BZP) • Methoxyphenylpiperazine (MeOPP, paraperazine) • Methylbenzylpiperazine (MBZP) • Methylenedioxybenzylpiperazine (MDBZP, piperonylpiperazine); Others: 2-Amino-1,2-dihydronaphthalene (2-ADN) • 2-Aminoindane (2-AI) • 2-Aminotetralin (2-AT) • 4-Benzylpiperidine (4-BP) • 5-IAI • Clofenciclan • Cyclopentamine • Cypenamine • Cyprodenate • Feprosidnine • Gilutensin • Heptaminol • Hexacyclonate • Indanylaminopropane (IAP) • Indanorex • Isometheptene • Methylhexanamine • Naphthylaminopropane (NAP) • Octodrine • Phthalimidopropiophenone • Propylhexedrine (Levopropylhexedrine) • Tuaminoheptane (Tuamine) [. v]·[. d]·[. e] Enzyme inhibitors Anabolism PAH inhibitors 3,4-Dihydroxystyrene TH inhibitors 3-Iodotyrosine • Aquayamycin • Bulbocapnine • Metirosine • Oudenone AAAD / DDC inhibitors Benserazide • Carbidopa • Genistein • Methyldopa Catabolism MAO inhibitors Nonselective: Benmoxin • Caroxazone • Echinopsidine • Furazolidone • Hydralazine • Indantadol • Iproclozide • Iproniazid • Isocarboxazid • Isoniazid • Linezolid • Mebanazine • Metfendrazine • Nialamide • Octamoxin • Paraxazone • Phenelzine • Pheniprazine • Phenoxypropazine • Pivalylbenzhydrazine • Procarbazine • Safrazine • Tranylcypromine; MAO-A selective: Amiflamine • Bazinaprine • Befloxatone • Befol • Brofaromine • Cimoxatone • Clorgiline • Esuprone • Harmala alkaloids (Harmine, Harmaline, Tetrahydroharmine, Harman, Norharman, etc) • Methylene Blue • Metralindole • Minaprine • Moclobemide • Pirlindole • Sercloremine • Tetrindole • Toloxatone • Tyrima; MAO-B selective: D-Deprenyl • L-Deprenyl (Selegiline) • Ladostigil • Lazabemide • Milacemide • Mofegiline • Pargyline • Rasagiline COMT inhibitors Entacapone • Tolcapone DBH inhibitors Bupicomide • Disulfiram • Dopastin • Fusaric acid • Nepicastat • Phenopicolinic acid • Tropolone [. v]·[. d]·[. e] Others Precursors L-Phenylalanine → L-Tyrosine → L-DOPA (Levodopa) Cofactors Ferrous Iron (Fe2+) • Tetrahydrobiopterin • Vitamin B3 (Niacin, Nicotinamide → NADPH) • Vitamin B6 (Pyridoxine, Pyridoxamine, Pyridoxal → Pyridoxal Phosphate) • Vitamin B9 (Folic acid → Tetrahydrofolic acid) • Vitamin C (Ascorbic acid) • Zinc (Zn2+) Others Activity Enhancers: Benzofuranylpropylaminopentane (BPAP) • Phenylpropylaminopentane (PPAP); Toxins: Oxidopamine (6-Hydroxydopamine) Template:Euphoriants This box: view • talk • edit Phenethylamines {2C-B} {2C-C} {2C-D} {2C-E} {2C-I} {2C-N} {2C-T-2} {2C-T-21} {2C-T-4} {2C-T-7} {2C-T-8} {3C-E} {4-FMP} {Bupropion} {Cathine} {Cathinone} {DESOXY} {Dextroamphetamine} {Methamphetamine} {Diethylcathinone} {Dimethylcathinone} {DOC} {DOB} {DOI} {DOM} {bk-MBDB} {Dopamine} {Br-DFLY} {Ephedrine} {Epinephrine} {Escaline} {Fenfluramine} {Levalbuterol} {Levmetamfetamine} {MBDB} {MDA} {MDMA} {bk-MDMA/MDMC/MDMCat/Methylone} {MDEA} (MDPV) {Mescaline} {Methcathinone} {Methylphenidate} {Norepinephrine} {Phentermine} {Salbutamol} {Tyramine} {Venlafaxine} This box: view • talk • edit Psychoanaleptics: psychostimulants, agents used for ADHD and nootropics (N06B) Centrally acting sympathomimetics Amphetamine - Dexamphetamine - Dextromethamphetamine - Methylphenidate - Pemoline - Fencamfamin - Modafinil - Fenozolone - Atomoxetine - Fenetylline Xanthine derivatives Caffeine - Propentofylline Other psychostimulants and nootropics Racetams (Piracetam, Oxiracetam, Aniracetam, Pramiracetam) - Meclofenoxate - Pyritinol - Deanol - Fipexide - Citicoline - Pirisudanol - Linopirdine - Nizofenone - Acetylcarnitine - Idebenone - Prolintane - Pipradrol - Adrafinil - Vinpocetine This page uses Creative Commons Licensed content from Wikipedia (view authors).

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