Dexmethylphenidate

Last updated

Dexmethylphenidate
Dexmethylphenidate structure.svg
Dextromethylphenidate-based-on-hydrochloride-xtal-1995-3D-balls.png
Clinical data
Trade names Focalin, Focalin XR, others
Other namesd-threo-methylphenidate (D-TMP)
AHFS/Drugs.com Monograph
MedlinePlus a603014
License data
Dependence
liability 		Physical: None[ medical citation needed ]; Psychological: High
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 11–52%
Protein binding 30%
Metabolism Liver
Elimination half-life 4 hours
Excretion Kidney
Identifiers
  • (R,R)-(+)-Methyl 2-phenyl-2-(2-piperidyl)acetate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C14H19NO2
Molar mass 233.311 g·mol−1
3D model (JSmol)
  • O=C([C@@H]([C@@H]1NCCCC1)C2=CC=CC=C2)OC

  • hydrochloride: Cl.[H][C@@](C(=O)OC)(C1=CC=CC=C1)[C@@]1([H])CCCCN1
  • InChI=1S/C14H19NO2/c1-17-14(16)13(11-7-3-2-4-8-11)12-9-5-6-10-15-12/h2-4,7-8,12-13,15H,5-6,9-10H2,1H3/t12-,13-/m1/s1 Yes check.svgY
  • Key:DUGOZIWVEXMGBE-CHWSQXEVSA-N Yes check.svgY

  • hydrochloride: InChI=1S/C14H19NO2.ClH/c1-17-14(16)13(11-7-3-2-4-8-11)12-9-5-6-10-15-12;/h2-4,7-8,12-13,15H,5-6,9-10H2,1H3;1H/t12-,13-;/m1./s1
  • Key:JUMYIBMBTDDLNG-OJERSXHUSA-N
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. [3] It is taken by mouth. [3] The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. [4] It is the more active enantiomer of methylphenidate. [3]

Contents

Common side effects include abdominal pain, loss of appetite, and fever. [3] Serious side effects may include psychosis, sudden cardiac death, mania, anaphylaxis, seizures, and dangerously prolonged erection. [3] Safety during pregnancy and breastfeeding is unclear. [5] Dexmethylphenidate is a central nervous system (CNS) stimulant. [6] [3] How it works in ADHD is unclear. [3]

Dexmethylphenidate was approved for medical use in the United States in 2001. [1] It is available as a generic medication. [3] In 2021, it was the 121st most commonly prescribed medication in the United States, with more than 4 million prescriptions. [7] [8]

Medical uses

Dexmethylphenidate is used as a treatment for ADHD, usually along with psychological, educational, behavioral or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behavior. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated. [6]

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo. [6] It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate. [6]

Contraindications

Methylphenidate is contraindicated for individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals. [9]

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. [10] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. [11] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen". [12]

Adverse effects

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate. [13]

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm. Rational harm assessment of drugs radar plot.svg
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. [15] Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure, and heart rate (typically mild), and tachycardia (rapid heart rate). [16] Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.[ contradictory ] [17] [18]

Results from a 2024 systematic review showed that methylphenidate significantly improves ADHD symptoms and broadband measures but can cause appetite suppression and other adverse events in children and adolescents. [19] Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3  cigarettes per day. [20]

There is some evidence of mild reductions in height with prolonged treatment in children. [21] This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years. [22] [23]

Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate. [24]

Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms. [25] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania. [26] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link. [21] Logorrhea is occasionally reported and visual hallucinations are very rarely reported. [17] Priapism is a very rare adverse event that can be potentially serious. [27]

U.S. Food and Drug Administration-commissioned studies in 2011 indicate that in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants. [28]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended. [29]

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low. [30]

The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children. [30] [lower-alpha 1]

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. [9] [31] A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse. [9] [31] [32] [lower-alpha 2] A methylphenidate overdose is rarely fatal with appropriate care. [32] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported. [33]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies. [32]

Packaging of a formulation of methylphenidate advises against crushing the tablets. It is placed under Schedule X of the Indian drug scheduling system. Schedule X medications typically hold abusable medications such as barbiturates or stimulants such as amphetamines. Add Wize Methylphenidate Warning.jpg
Packaging of a formulation of methylphenidate advises against crushing the tablets. It is placed under Schedule X of the Indian drug scheduling system. Schedule X medications typically hold abusable medications such as barbiturates or stimulants such as amphetamines.

Addiction and dependence

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs; [34] [35] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug. [35] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis. [36]

Biomolecular mechanisms

Further information: Addiction § Biomolecular mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain's reward system. At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system; consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction. [35]

Interactions

Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations. [37] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants. [38] [39] [40] [41]

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, [42] [43] not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible. [44] [43]

Coingestion of alcohol also increases the blood plasma levels of d-methylphenidate by up to 40%. [45]

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity. [46]

Mode of activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET), [47] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system. [48] Moreover, it is thought to "increase the release of these monoamines into the extraneuronal space." [2]

Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. Dexmethylphenidate (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate. [49] [50] In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product. [47] [51]

Compd [52] DAT (Ki)DA (IC50)NET (Ki)NE (IC50)
D-TMP1612320639
L-TMP22501600>10K980
DL-TMP1212078851

Pharmacology

Dexmethylphenidate has a 4–6 hour duration of effect. A long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability. [53] [54] It has also been demonstrated to reduce ADHD symptoms in both children [55] and adults. [56] d-MPH has a similar side-effect profile to MPH [13] and can be administered without regard to food intake. [57]

CTx-1301 is an experimental medication that is an extended-release formulation of dexmethylphenidate that has a half life more than an hour longer than extended-release dexmethylphenidate (d-MPH-ER). It is under development for ADHD. [58] [59] [60] [61] [62]

Notes

  1. ↑ "Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children" "Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events." [30]
  2. ↑ The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. ... However, fatalities are rare with appropriate care. [32]

Related Research Articles

A psychiatric or psychotropic medication is a psychoactive drug taken to exert an effect on the chemical makeup of the brain and nervous system. Thus, these medications are used to treat mental illnesses. These medications are typically made of synthetic chemical compounds and are usually prescribed in psychiatric settings, potentially involuntarily during commitment. Since the mid-20th century, such medications have been leading treatments for a broad range of mental disorders and have decreased the need for long-term hospitalization, thereby lowering the cost of mental health care. The recidivism or rehospitalization of the mentally ill is at a high rate in many countries, and the reasons for the relapses are under research.

<span class="mw-page-title-main">Attention deficit hyperactivity disorder</span> Neurodevelopmental disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by executive dysfunction occasioning symptoms of inattention, hyperactivity, impulsivity and emotional dysregulation that are excessive and pervasive, impairing in multiple contexts, and developmentally-inappropriate.

<span class="mw-page-title-main">Stimulant</span> Drug that increases activity of central nervous system

Stimulants are a class of drugs that increase the activity of the brain. They are used for various purposes, such as enhancing alertness, attention, motivation, cognition, mood, and physical performance. Some of the most common stimulants are caffeine, nicotine, amphetamines, cocaine, methylphenidate, and modafinil.

<span class="mw-page-title-main">Methylphenidate</span> Central nervous system stimulant

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines, alleviating the executive functioning deficits of sustained attention, inhibition, working memory, reaction time and emotional self-regulation.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine (INN:dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Dextroamphetamine reduces the negative symptoms of schizophrenia, and has been shown to enhance the effects of auditory discrimination training. Prescribed dextroamphetamine has also been shown to reduce rates of hospitalisation in patients with schizophrenia, although repeated, elevated doses can provoke psychosis. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.

<span class="mw-page-title-main">Clonidine</span> Pharmaceutical drug

Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. The drug is often prescribed off-label for tics. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.

<span class="mw-page-title-main">Atomoxetine</span> Medication used to treat ADHD

Atomoxetine, sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome. It may be used alone or along with psychostimulants. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.

<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

Adult Attention Deficit Hyperactivity Disorder is the persistence of attention deficit hyperactivity disorder (ADHD) into adulthood. It is a neurodevelopmental disorder, meaning impairing symptoms must have been present in childhood, except for when ADHD occurs after traumatic brain injury. Specifically, multiple symptoms must be present before the age of 12, according to DSM-5 diagnostic criteria. The cutoff age of 12 is a change from the previous requirement of symptom onset, which was before the age of 7 in the DSM-IV. This was done to add flexibility in the diagnosis of adults. ADHD was previously thought to be a childhood disorder that improved with age, but recent research has disproved this. Approximately two-thirds of childhood cases of ADHD continue into adulthood, with varying degrees of symptom severity that change over time and continue to affect individuals with symptoms ranging from minor inconveniences to impairments in daily functioning.

<span class="mw-page-title-main">Pemoline</span> Stimulant, used in the treatment of ADHD

Pemoline, sold under the brand name Cylert among others, is a stimulant medication which has been used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. It has been discontinued in most countries due to rare but serious problems with liver toxicity. The medication was taken by mouth.

<span class="mw-page-title-main">Viloxazine</span> Medication used to treat ADHD

Viloxazine, sold under the brand name Qelbree among others, is a selective norepinephrine reuptake inhibitor medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form, latterly with comparable effectiveness to atomoxetine and methylphenidate.

<span class="mw-page-title-main">Guanfacine</span> Medication used for high blood pressure and ADHD

Guanfacine, sold under the brand name Tenex (immediate-release) and Intuniv (extended-release) among others, is an oral alpha-2a agonist medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure. Guanfacine is FDA-approved for monotherapy treatment of ADHD, as well as being used for augmentation of other treatments, such as stimulants. Guanfacine is also used off-label to treat tic disorders, anxiety disorders, and post-traumatic stress disorder (PTSD).

Attention deficit hyperactivity disorder predominantly inattentive, is one of the three presentations of attention deficit hyperactivity disorder (ADHD). In 1987–1994, there were no subtypes or presentations and thus it was not distinguished from hyperactive ADHD in the Diagnostic and Statistical Manual (DSM-III-R). In DSM-5, subtypes were discarded and reclassified as presentations of the same disorder that change over time.

<span class="mw-page-title-main">Attention deficit hyperactivity disorder controversies</span> Controversies surrounding the topic of ADHDs nature, diagnosis, and treatment

Despite the scientifically well-established nature of attention deficit hyperactivity disorder (ADHD), its diagnosis, and its treatment, each of these has been controversial since the 1970s. The controversies involve clinicians, teachers, policymakers, parents, and the media. Positions range from the view that ADHD is within the normal range of behavior to the hypothesis that ADHD is a genetic condition. Other areas of controversy include the use of stimulant medications in children, the method of diagnosis, and the possibility of overdiagnosis. In 2009, the National Institute for Health and Care Excellence, while acknowledging the controversy, stated that the current treatments and methods of diagnosis are based on the dominant view of the academic literature.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.

Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD. Approaches that have been evaluated in the management of ADHD symptoms include FDA-approved pharmacologic treatment and other pharmaceutical agents, psychological or behavioral approaches, combined pharmacological and behavioral approaches, cognitive training, neurofeedback, neurostimulation, physical exercise, nutrition and supplements, integrative medicine, parent support, and school interventions. Based on two 2024 systematic reviews of the literature, FDA-approved medications and to a lesser extent psychosocial interventions have been shown to improve core ADHD symptoms compared to control groups.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).

<span class="mw-page-title-main">Isopropylphenidate</span> Stimulant designer drugs

Isopropylphenidate is a piperidine based stimulant drug, closely related to methylphenidate, but with the methyl ester replaced by an isopropyl ester. It has similar effects to methylphenidate but with a longer duration of action, and was banned in the UK as a Temporary Class Drug from April 2015 following its unapproved sale as a designer drug.

<span class="mw-page-title-main">Serdexmethylphenidate/dexmethylphenidate</span> A combination of CNS Stimulants

Serdexmethylphenidate/dexmethylphenidate, sold under the brand name Azstarys, is a fixed-dose combination medication containing serdexmethylphenidate, a prodrug of dexmethylphenidate, and dexmethylphenidate, a d-threo enantiomer of racemic methylphenidate, which is used to treat attention deficit hyperactivity disorder (ADHD) in people aged six years and older.

References

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