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Dexmethylphenidate
Dexmethylphenidate
Dexmethylphenidate
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Dexmethylphenidate
Clinical data
Trade namesFocalin, Focalin XR, others
Other namesd-threo-methylphenidate (D-TMP)
AHFS/Drugs.comMonograph
MedlinePlusa603014
License data
Dependence
liability		Physical: None
Psychological: Moderate[1]
Addiction
liability		Moderate
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability11–52%
Protein binding30%
MetabolismLiver
Elimination half-life4 hours
ExcretionKidney
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
FormulaC14H19NO2
Molar mass233.311 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 checkY
  • Key:DUGOZIWVEXMGBE-CHWSQXEVSA-N checkY

  • 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
 ☒NcheckY (what is this?)  (verify)

Dexmethylphenidate, sold under the brand name Focalin among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) in those over the age of five years.[4] It is taken by mouth.[4] The immediate-release formulation lasts up to five hours while the extended-release formulation lasts up to twelve hours.[5] It is the more active enantiomer of methylphenidate.[4] Methylphenidate has been shown to be more effective than atomoxetine and superior in treating ADHD symptoms when compared.[6]

Common side effects include abdominal pain, loss of appetite, and fever.[4] Serious side effects may include psychosis, sudden cardiac death, mania, anaphylaxis, seizures, and priapism.[4] Safety during pregnancy and breastfeeding is unclear.[7]

Dexmethylphenidate was approved for medical use in the United States in 2001.[2] It is available as a generic medication.[4] In 2023, it was the 127th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[8][9]

Medical uses

[edit]

Dexmethylphenidate is used as a treatment for attention deficit hyperactivity disorder (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.[10]

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[10] 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.[10]

Contraindications

[edit]
This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate is contraindicated for individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[11]

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks.[12] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.[13] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".[14]

Adverse effects

[edit]
Part of this section is transcluded from Methylphenidate. (edit | history)

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.[15]

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.[16]

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia.[17] Gastrointestinal adverse effects may include abdominal pain[18] 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).[19] Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.[contradictory][20][21] In some cases, tolerance might be an issue with stimulants like methylphenidate.[22]

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.[23] 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.[24]

There is some evidence of mild reductions in height with prolonged treatment in children.[25] 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.[26][27]

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.[28]

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.[29] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[30] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[25] Logorrhea is occasionally reported and visual hallucinations are very rarely reported.[20] Priapism is a very rare adverse event that can be potentially serious.[31]

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.[32]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[33]

A 2018 Cochrane review found the drug "may be associated with a number of serious adverse events as well as a large number of non‐serious adverse events in children and adolescents". It stated "it is not possible to accurately estimate the actual risk of adverse events" because the quality of evidence in the 260 studies assessed was "very low".[34][a]

Overdose

[edit]

The symptoms of a moderate acute overdose of 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.[35][36] A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse.[35][36][37][b] A methylphenidate overdose is rarely fatal with appropriate care.[37] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[38]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies.[37]

Addiction and dependence

[edit]

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs;[39][40] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used as a recreational drug.[40] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.[41]

Biomolecular mechanisms

[edit]
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.[40]

Interactions

[edit]
This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate (MPH) is widely described in the pharmacological literature as being metabolized primarily, and almost exclusively, by carboxylesterase 1 (CES1) into its inactive metabolite, ritalinic acid (RA). This oversimplification has shaped decades of teaching, clinical interpretation, and drug–drug interaction assumptions.

However, enzyme induction/inhibition data, alongside structural biochemistry of MPH and analogues, challenges the CES1 only framework. Evidence strongly indicates that CYP2B6, CYP2E1, and CYP3A4 play critical roles in the clearance and metabolic fate of Methylphendiate.

  1. CYP2B6 involvement
    • Induction (Carbamazepine) → significantly lowers MPH plasma levels.
    • Inhibition (Turmeric) → raises MPH levels and prolongs duration.
  1. CYP2E1 involvement
    • Responsible for α-hydroxylation of the ester side chain, leading to spontaneous breakdown into ritalinic acid.
    • Inhibition (Alcohol) → increases MPH levels.
  1. CYP3A4 involvement
    • In presence of ethanol, CYP3A4 catalyzes transesterification of MPH → ethylphenidate, an active metabolite.
    • Induction (Glucose) → increases flux through this pathway, altering levels and shortening duration.

The classical teaching that CES1 alone governs MPH metabolism is incomplete and misleading. A multi-enzyme model explains the real-world drug–drug interaction data:

  • CYP2B6 is the primary clearance enzyme.
  • CYP2E1 is responsible for ritalinic acid formation.
  • CYP3A4 mediates the clinically relevant ethylphenidate pathway in the presence of alcohol.

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.[11] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[42][43][44][45]

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[46][47] 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.[48][47]

Coingestion of alcohol also increases the blood plasma levels of d-methylphenidate by up to 40%.[49]

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.[50]

Pharmacology

[edit]
Main article: Methylphenidate § 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.[51][52] It has also been demonstrated to reduce ADHD symptoms in both children[53] and adults.[54] d-MPH has a similar side-effect profile to MPH[15] and can be administered without regard to food intake.[55]

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.[56][57][58][59][60]

Mechanism of action

[edit]

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET),[61] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.[62] Moreover, it is thought to "increase the release of these monoamines into the extraneuronal space."[3]

Methylphenidate, by acting as a negative allosteric modulator of the DAT transporter, prevents dopamine molecules from being absorbed into DAT. This modulation makes DAT less efficient at coupling sodium and chloride gradients to drive inward dopamine transport.

Instead, DAT is shifted to the outward-facing state, making it harder to use the sodium gradient (positive charge that normally pulls dopamine inward) and the chloride gradient (negative charge that normally stabilizes the cycle).

In this outward conformation, dopamine is “pulled” from the cytosol into the synapse while reuptake is blocked.

By keeping DAT outward-facing, sodium coupling is disrupted, chloride coupling is decreased, and inward turnover destabilized. This biases DAT toward outward release, allowing dopamine to leak out without fully coupling to ions. As a result, dopamine is no longer tightly gated by sodium binding, and the firing rate of dopamine from DAT increases.

Methylphenidate increases extracellular dopamine not only by competitively inhibiting reuptake at the dopamine transporter (DAT), but also by modulating DAT conformation through non-substrate-mediated mechanisms. Specifically, methylphenidate acts as a negative allosteric modulator (NAM) at the presynaptic Dopamine Transporter, stabilizing the transporter in its outward-facing conformation. This shift alters the electrochemical gradient and transporter kinetics in a way that promotes dopamine efflux from the presynaptic cytosol into the synaptic cleft even though methylphenidate is not a DAT substrate. This presynaptic Dopamine Transporter Negative allosteric modulation driven efflux amplifies phasic dopamine release and uniquely increases phasic firing rate. This of course in contrast to amphetamines, which reverse DAT via substrate competition and concurrently reduce the dopamine transporter firing rate. Notably, methylphenidate has been shown in studies to induce up to a 500% increase in dopamine release, comparable in magnitude to methamphetamine, though via a non-vesicular, transporter-mediated mechanism. Its 2–3-fold higher DAT binding affinity compared to cocaine may contribute to its more potent and sustained dopaminergic effect.[63]

This is identical in process to how cocaine leads to an increase in dopamine firing rate and dopamine release into the synapse. However because methylphenidate binds to the DAT transporter with 2-3 fold higher affinity than cocaine this leads to methylphenidate being more powerful as a DAT negative allosteric modulator. Producing a robust dopamine release of 500% equivalent to methamphetamine.[64]

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.[65][66] In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product.[61][67]

Compd[68] DAT (Ki) DA (IC50) NET (Ki) (IC50)
D-TMP 161 23 206 39
L-TMP 2250 1600 >10K 980
DL-TMP 121 20 788 51

Notes

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Dexmethylphenidate

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Dexmethylphenidate is a (CNS) stimulant medication that serves as the pharmacologically active d-threo of racemic , primarily prescribed to treat (ADHD) in children aged 6 years and older and adults. It is available under brand names such as Focalin (immediate-release tablets) and Focalin XR (extended-release capsules), as well as generic versions of dexmethylphenidate hydrochloride tablets and extended-release capsules, which provide options for twice-daily or once-daily dosing to manage symptoms like inattention, hyperactivity, and as part of a comprehensive treatment plan. Dexmethylphenidate exerts its therapeutic effects by selectively blocking the of norepinephrine and into presynaptic neurons, thereby increasing the release of these neurotransmitters into the extraneuronal space and enhancing their activity in the CNS. This mechanism is thought to improve focus and reduce ADHD symptoms, though the exact in ADHD remains not fully understood. As a Schedule II controlled substance under the , it carries a high potential for abuse, misuse, and dependence, necessitating careful monitoring during use. The immediate-release form of dexmethylphenidate was first approved by the U.S. (FDA) on November 13, 2001, for ADHD treatment, with the extended-release approved on May 26, 2005, to offer prolonged symptom control. Dosage typically begins low—such as 5 mg once daily for children new to stimulants—and is titrated weekly based on response, with maximum recommended doses of 30 mg/day for and 40 mg/day for adults. Capsules may be swallowed whole or opened and sprinkled on soft food like for those who have difficulty swallowing. Common side effects include decreased appetite, , , dry mouth, and anxiety, while serious risks encompass cardiovascular events, psychiatric symptoms such as hallucinations, growth suppression in children, and . Contraindications include known to or its components and concurrent or use within 14 days of inhibitors (MAOIs), with caution advised in patients with , including advanced , or severe . Patients should be screened for heart disease and prior to initiation, with regular monitoring of , , and growth in pediatric users.

Clinical Use

Indications

Dexmethylphenidate is indicated for the treatment of (ADHD) in patients aged 6 years and older as part of a comprehensive treatment program. Its efficacy in this primary indication is supported by multiple placebo-controlled clinical trials demonstrating significant improvements in core ADHD symptoms, including inattention, hyperactivity, and , as measured by standardized scales such as the Conners ADHD/DSM-IV Scales and the ADHD Rating Scale-IV. In pediatric populations (ages 6-17), flexible dosing (5-30 mg/day) over 7 weeks resulted in notable reductions in teacher-rated symptoms, while fixed dosing (20-40 mg/day) over 5 weeks showed superiority over placebo in adults (ages 18-60). The extended-release formulation of dexmethylphenidate (dexmethylphenidate XR) provides a faster onset of action and superior early symptom control compared to osmotic-release oral system (OROS) methylphenidate in children aged 6-12 with ADHD. In a randomized, double-blind, crossover laboratory classroom study, dexmethylphenidate XR (30 mg) demonstrated significant improvements in Swanson, Kotkin, Agler, Minkin, and Pelham (SKAMP) combined scores at 0.5 hours post-dose (p=0.044) and from 1-6 hours (p<0.05), outperforming OROS methylphenidate (36 mg), which showed delayed initial effects but extended coverage up to 12 hours. This pharmacokinetic advantage stems from dexmethylphenidate being the pharmacologically active d-isomer of racemic methylphenidate, allowing for lower effective doses and quicker therapeutic onset. A 2023 meta-analysis of stimulant dosing in adult ADHD indicated modest additional symptom reductions with higher doses, including those applicable to dexmethylphenidate formulations, though benefits were tempered by increased adverse event risks. Off-label uses of dexmethylphenidate include narcolepsy and treatment-resistant depression, though it lacks FDA approval for these indications and evidence is limited compared to its established role in ADHD. For narcolepsy, while methylphenidate is used off-label as a second-line therapy for excessive daytime sleepiness, specific data for dexmethylphenidate are sparse, with no large-scale trials supporting its routine application. In treatment-resistant depression, adjunctive use of stimulants like dexmethylphenidate may offer modest benefits for fatigue and apathy, but randomized evidence is primarily derived from methylphenidate studies rather than dexmethylphenidate-specific trials. Dexmethylphenidate is often employed adjunctively with non-pharmacological interventions, such as behavioral therapy, psychological counseling, and educational support, to optimize outcomes in ADHD management. This multimodal approach enhances long-term symptom control and functional improvements beyond medication alone.

Dosage and Administration

Dexmethylphenidate is available in immediate-release (IR) tablet formulations of 2.5 mg, 5 mg, and 10 mg, which provide symptom control for approximately 4 to 6 hours. The extended-release (XR) capsule formulation, approved by the FDA in 2005, is available in strengths of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg, offering up to 12 hours of duration. For pediatric patients aged 6 to 17 years with attention deficit hyperactivity disorder (ADHD), the recommended starting dose is 2.5 mg of IR tablets twice daily, at least 4 hours apart, or 5 mg of XR capsules once daily in the morning. For patients switching from racemic methylphenidate, the starting dose should be approximately half the total daily dose of racemic methylphenidate. Dosage should be titrated in increments of 2.5 mg to 5 mg weekly based on clinical response and tolerability, with a maximum daily dose of 20 mg for IR and 30 mg for XR. In adults with ADHD, treatment typically begins at 10 mg of XR capsules once daily or 2.5 mg of IR tablets twice daily, with titration in 10 mg weekly increments for XR or 2.5 mg to 5 mg for IR, up to a maximum of 40 mg daily for XR or 20 mg for IR. For patients switching from racemic methylphenidate, the starting dose should be approximately half the total daily dose of racemic methylphenidate. The overall maximum recommended daily dose across formulations is generally not to exceed 40 mg in adults. Dexmethylphenidate may be taken with or without food to accommodate individual preferences. XR capsules should be swallowed whole or, if swallowing is difficult, the entire contents may be sprinkled onto a small amount of applesauce and consumed immediately without chewing; the mixture should not be stored. To minimize the risk of insomnia, dosing should occur in the morning for XR and morning and early afternoon for IR, avoiding late-day administration. Ongoing monitoring is essential, including regular reassessment of efficacy and safety every 3 to 6 months, with evaluation of growth parameters in children and cardiovascular metrics in all patients. Treatment should be discontinued if there is no clinical improvement after one month at an optimized dose or if intolerable adverse effects emerge.

Contraindications and Precautions

Absolute Contraindications

Dexmethylphenidate is absolutely contraindicated in patients with known hypersensitivity to or other components of the formulation, as this may precipitate severe allergic reactions such as or . The medication is also contraindicated in individuals receiving concurrent treatment with (MAOIs), or within 14 days following discontinuation of an MAOI, due to the risk of and other severe interactions.

Use in Special Populations

Dexmethylphenidate is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in pediatric patients aged 6 years and older, with a recommended starting dose of 5 mg once daily for extended-release formulations, titrated in 5 mg increments weekly up to a maximum of 30 mg/day based on clinical response and tolerability. Use in children under 6 years is not recommended due to higher plasma exposure and increased incidence of adverse reactions, such as weight loss, observed in this age group. Long-term stimulant treatment, including dexmethylphenidate, has been associated with modest growth suppression in children, with longitudinal studies indicating an average reduction in height velocity of approximately 1 cm per year during the first three years of therapy; regular monitoring of height and weight is essential, and treatment interruption may be considered if significant suppression occurs. In patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems, use of dexmethylphenidate should be avoided due to the risk of sudden death and other cardiovascular events. For individuals with moderate to severe hypertension or hyperthyroidism, use with caution as the medication may exacerbate these conditions through increases in blood pressure and heart rate; monitor cardiovascular status closely. Patients with glaucoma should be evaluated for risk of acute angle closure or increased intraocular pressure; monitor closely if used, weighing benefits against risks. In those with motor tics, a diagnosis of Tourette's syndrome, or family history thereof, assess risk before initiation and monitor for exacerbation; discontinue if symptoms worsen. For patients with severe anxiety, tension, agitation, or psychosis, screen for underlying conditions like bipolar disorder prior to use and monitor for worsening or new-onset symptoms, as stimulants may aggravate psychiatric issues. In individuals with a history of substance abuse, assess the risk of misuse before prescribing and monitor closely for signs of abuse, dependence, and overdose throughout treatment. In geriatric patients, dexmethylphenidate has not been systematically studied, and its use is generally approached with caution due to potential increased sensitivity to cardiovascular effects, such as hypertension and tachycardia. When prescribed off-label for conditions like ADHD or treatment-resistant depression in older adults, dosing should begin at the lowest effective level, such as 2.5 mg twice daily, with careful titration and monitoring for adverse events; avoidance is preferable if alternative therapies are available. Data on dexmethylphenidate use during pregnancy are limited, with animal reproduction studies showing no evidence of teratogenicity at doses up to 7 times the maximum recommended human dose, though relevant human studies are ongoing. Available human data, including a 2024 registry-based study and meta-analysis of ADHD medications including methylphenidate derivatives like dexmethylphenidate, found no significant increase in major congenital malformations or miscarriage risk compared to unexposed pregnancies, suggesting a low malformation risk. The National Pregnancy Registry for ADHD Medications monitors outcomes and reports no identified risk of major birth defects to date. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. During lactation, dexmethylphenidate is expected to be excreted into breast milk in small amounts, similar to methylphenidate (0.16%-0.7% of maternal dose), with no reported adverse effects in breastfed infants; however, monitoring for infant agitation, insomnia, or reduced appetite is advised, and alternative treatments should be considered to minimize exposure. No dose adjustments are required for dexmethylphenidate in patients with mild to moderate renal impairment, as renal clearance is not a primary elimination pathway. In severe hepatic impairment, close monitoring is recommended due to potential reduced metabolism via carboxylesterase 1 (CES1), the primary hepatic enzyme responsible for dexmethylphenidate hydrolysis, which may lead to increased drug exposure. Pharmacogenomic data specific to dexmethylphenidate are limited, with no established ethnic variations in metabolism; however, CES1 genetic variants may influence exposure, as this enzyme accounts for the majority of dexmethylphenidate biotransformation in the liver.

Adverse Effects and Risks

Common Adverse Effects

Common adverse effects of dexmethylphenidate, primarily observed in clinical trials for attention-deficit/hyperactivity disorder (ADHD) in pediatric patients, are generally mild and transient, occurring at rates higher than placebo (typically ≥5% and at least twice the placebo rate). These effects are derived from pivotal placebo-controlled studies supporting the 2001 approval of the immediate-release formulation and subsequent trials for the extended-release version. Gastrointestinal effects include abdominal pain, reported in 15% of pediatric patients (versus 6% placebo), decreased appetite in up to 30% (versus 9% placebo), and nausea in 9% (versus 1% placebo). Decreased appetite often contributes to weight loss, with pediatric patients on extended-release dexmethylphenidate showing an average deficit of approximately 2.7 kg in expected weight gain over three years of consistent use, though short-term studies indicate about 0.5 kg loss in the first seven weeks compared to placebo gain. Central nervous system effects encompass headache, affecting 25% of children (versus lower placebo rates), insomnia in 12-17% depending on dose (up to 17% at 30 mg/day versus 5% placebo), and anxiety in 6% (versus 2% placebo). These symptoms are dose-related and more pronounced in flexible-dose trials. Other common effects include fever (5% versus 1% placebo) and dry mouth (5-20%, more common in adults). Management strategies focus on dose reduction or adjustment in timing—such as administering earlier in the day to mitigate insomnia—or supportive measures like ensuring hydration for headache and dry mouth, and monitoring nutrition to address appetite suppression and weight loss; if effects persist, discontinuation may be considered.

Serious Adverse Effects

Dexmethylphenidate has been associated with serious cardiovascular risks, including sudden death in patients with underlying structural heart abnormalities or cardiomyopathy. Cases of priapism, characterized by prolonged and painful erections lasting more than 4 hours, have been reported with methylphenidate products including dexmethylphenidate, though such events are rare and require immediate medical intervention to prevent permanent damage. Psychiatric adverse effects can include the onset of new psychotic or manic symptoms, such as hallucinations or mania, occurring in approximately 0.1% of treated patients; discontinuation is recommended if these emerge. In individuals predisposed to seizures, dexmethylphenidate may lower the seizure threshold, with studies indicating a modestly elevated risk, particularly in the initial 30 days of treatment. Long-term use of dexmethylphenidate in children has been associated with growth suppression, including a mean height deficit of approximately 2 cm and weight deficit of 2.7 kg over 3 years in clinical studies. A 2021 meta-analysis of 18 studies reported a small but significant reduction in height z-score (SMD -0.27). Regular growth monitoring is recommended. Other serious effects include hypersensitivity reactions such as anaphylaxis or angioedema, which are contraindications for use, and rare instances of severe liver injury ranging from transaminase elevations to hepatic failure reported with methylphenidate-class drugs. Peripheral vasculopathy manifesting as Raynaud's phenomenon, with potential for digital ulceration, has also been observed in post-marketing reports. To mitigate cardiac risks, the FDA added warnings to labels of ADHD stimulants like dexmethylphenidate in 2006 following investigations into sudden death and other events; baseline ECG screening is recommended for at-risk patients with cardiac history.

Overdose Management

Overdose of dexmethylphenidate, a central nervous system stimulant, manifests through sympathomimetic toxicity, including agitation, hallucinations, hyperthermia, tachycardia, hypertension, and seizures; in severe cases, it can progress to coma or cardiovascular collapse. These symptoms arise from excessive dopaminergic and noradrenergic stimulation, with cardiovascular effects such as tachyarrhythmias or hypotension potentially exacerbating the presentation. The toxicity threshold for dexmethylphenidate is not precisely defined in humans, but animal studies indicate an oral LD50 of approximately 350 mg/kg in rats, suggesting high acute toxicity potential. Human case reports of related methylphenidate overdoses demonstrate survival after ingestions of 100–500 mg, though dexmethylphenidate's higher potency (as the active d-enantiomer) may lower effective thresholds to roughly half those doses. Management of dexmethylphenidate overdose focuses on supportive care, as no specific antidote exists. Initial decontamination may involve activated charcoal if ingestion occurred within 1–2 hours and the patient is alert without contraindications, but gastric lavage is rarely indicated beyond the first hour. Benzodiazepines are recommended for agitation, seizures, or dystonia, while intravenous fluids address dehydration and hypotension; beta-blockers or vasodilators may be used cautiously for severe hypertension or tachycardia under monitoring. Hyperthermia requires aggressive cooling measures, and advanced cardiovascular support follows ACLS protocols if collapse occurs. Hemodialysis is ineffective due to the drug's large volume of distribution and rapid metabolism. Consultation with a poison control center (e.g., 1-800-222-1222 in the US) is essential for tailored guidance. Poison control data indicate that most dexmethylphenidate and related overdoses resolve with observation and supportive measures, with moderate effects in about 11% of cases and major toxicity in under 1%; fatalities are rare and often involve polysubstance abuse. Recent analyses of stimulant overdoses emphasize early intervention to prevent complications, aligning with American Academy of Clinical Toxicology guidelines adapted for this agent.

Dependence and Tolerance

Dexmethylphenidate is classified as a Schedule II controlled substance under the due to its high potential for abuse and the risk of psychological dependence. At supratherapeutic doses, it can induce euphoria by enhancing release in reward pathways through blockade of the , which reinforces misuse behaviors such as snorting or intravenous administration for recreational effects. Among individuals prescribed for ADHD, including dexmethylphenidate, misuse rates range from 2.1% to 14.3%, with higher prevalence among those with a history of . Tolerance to the therapeutic effects of dexmethylphenidate develops in a subset of patients, often manifesting as a partial or complete loss of symptom control after months to years of continuous use. Early tolerance may occur within days to weeks in approximately 25% of cases, while late tolerance affects up to 66% of patients beyond two years, frequently necessitating dose adjustments or medication holidays to restore efficacy. Cross-tolerance with amphetamines is well-documented, as both compounds share overlapping mechanisms on dopamine systems, potentially limiting the benefits of switching between stimulant classes. Withdrawal from dexmethylphenidate, particularly after chronic or abusive use, typically involves an acute phase lasting 1–2 weeks, characterized by fatigue, depression, hypersomnia, increased appetite, and psychomotor changes. These symptoms arise from the rebound downregulation of dopamine pathways following prolonged transporter blockade and can unmask underlying ADHD symptoms or exacerbate mood disturbances. Management involves gradual tapering under medical supervision to minimize severity, with no FDA-approved pharmacotherapies specifically for stimulant withdrawal. Key risk factors for dependence include a personal or family history of substance abuse, as these individuals exhibit heightened vulnerability to the reinforcing effects of stimulants. Diversion remains a concern, with nonmedical use of prescription stimulants reported among approximately 5% of high school students in recent national surveys, often sourced from peers with legitimate prescriptions.

Drug Interactions

Metabolic Interactions

Dexmethylphenidate undergoes primary metabolism through de-esterification by carboxylesterase 1 (CES1) in the liver and erythrocytes, converting it to the inactive metabolite d-ritalinic acid. This process accounts for the majority of its clearance, with approximately 90% of the dose excreted in urine primarily as ritalinic acid. Minor oxidative metabolism occurs via cytochrome P450 enzymes, including small contributions from and , though these pathways play a limited role overall. Alcohol acts as a CES1 inhibitor when coadministered with dexmethylphenidate, leading to increased plasma exposure of the parent drug through competitive transesterification to ethylphenidate, a metabolite that further impairs CES1 activity. In healthy volunteers, ethanol increased the maximum plasma concentration (Cmax) of dexmethylphenidate by 27% and the partial area under the curve (AUC) from 4 to 8 hours by 20%. This interaction occurs independently of formulation effects and primarily affects second-peak exposure due to delayed absorption. Inducers of hepatic enzymes, such as carbamazepine, can accelerate dexmethylphenidate clearance by enhancing CES1 expression or activity, potentially reducing its efficacy and requiring dose adjustments. Although rifampin and phenytoin are potent inducers of CYP3A4 and CYP2C enzymes, their impact on dexmethylphenidate is likely modest given the predominance of CES1-mediated metabolism. As a CES1 substrate, dexmethylphenidate can competitively inhibit the metabolism of coadministered drugs reliant on the same enzyme, such as oseltamivir, a prodrug activated by CES1 to its active carboxylate form. This competition may elevate oseltamivir prodrug levels while reducing active metabolite concentrations, potentially diminishing its antiviral efficacy. Pharmacogenetic variations in CES1 significantly influence dexmethylphenidate exposure. The loss-of-function variant G143E (rs71647871) reduces enzyme activity, resulting in approximately 1.5-fold higher AUC of d-methylphenidate compared to wild-type carriers, classifying affected individuals as poor metabolizers with prolonged drug exposure. Similarly, homozygous duplication of CES1 (four gene copies) is associated with a 61% increase in d-methylphenidate AUC, possibly due to linked regulatory mutations affecting expression. These variants underscore the need for therapeutic drug monitoring in genetically susceptible patients to optimize dosing and minimize toxicity risks.

Clinical Interactions

Dexmethylphenidate, when coadministered with certain antidepressants, can lead to clinically significant outcomes affecting patient safety and efficacy. Concomitant use with selective serotonin reuptake inhibitors (SSRIs), such as sertraline or escitalopram, may increase blood levels and effects of the SSRI, potentially posing a risk of serotonin syndrome, a condition characterized by symptoms including agitation, hallucinations, fever, and autonomic instability, though evidence for this risk is limited. However, studies indicate that combining methylphenidate (and by extension its active enantiomer dexmethylphenidate) with SSRIs, including escitalopram, is generally safe and may be beneficial for treating comorbid ADHD and depression, with no significant increase in adverse events and potential reductions in risks such as headaches and tremors. Close monitoring is recommended due to possible interactions. Similarly, use with tricyclic antidepressants (TCAs), such as amitriptyline, may result in additive pharmacodynamic effects on the central nervous system or cardiovascular system, potentially leading to side effects like cardiac arrhythmias or anticholinergic toxicity; no significant pharmacokinetic interaction is expected. Interactions with antihypertensives can compromise blood pressure control. Dexmethylphenidate reduces the efficacy of guanethidine by inhibiting its uptake into sympathetic nerve terminals, thereby diminishing its antihypertensive action and potentially leading to inadequate blood pressure management. When combined with beta-blockers, such as propranolol, dexmethylphenidate's sympathomimetic effects may counteract blood pressure lowering, necessitating close monitoring of blood pressure to adjust therapy as needed. Regarding anticonvulsants, dexmethylphenidate may lower the seizure threshold, increasing the risk of seizures particularly in patients with a history of epilepsy or concurrent anticonvulsant use. Co-administration with caffeine can produce additive central nervous system stimulation, resulting in enhanced side effects such as jitteriness, insomnia, tachycardia, and elevated blood pressure. Dexmethylphenidate is contraindicated with monoamine oxidase inhibitors (MAOIs) due to the risk of hypertensive crisis, as detailed in the absolute contraindications section.

Pharmacology

Pharmacodynamics

Dexmethylphenidate is the pharmacologically active d-threo enantiomer of and functions primarily as a reuptake inhibitor of dopamine and norepinephrine by blocking their respective transporters in the central nervous system. It exhibits high affinity for the dopamine transporter (DAT; Ki = 34 nM) and moderate affinity for the norepinephrine transporter (NET; Ki = 339 nM), leading to increased extracellular concentrations of these catecholamines in key brain regions such as the prefrontal cortex. Microdialysis studies in rats demonstrate that therapeutic doses of methylphenidate substantially elevate extracellular dopamine and norepinephrine levels in the prefrontal cortex, without substantially affecting subcortical regions at low doses that enhance cognition. The d-threo enantiomer is responsible for the therapeutic effects, being approximately 10-fold more potent than the l-threo enantiomer in inhibiting DAT and NET, as evidenced by binding and uptake inhibition assays. Dexmethylphenidate shows only weak affinity for the serotonin transporter (SERT; Ki ≈ 100 μM), minimizing serotonergic effects, and does not act as a direct agonist at dopamine or norepinephrine receptors. In the context of attention-deficit/hyperactivity disorder (ADHD), dexmethylphenidate enhances catecholamine signaling within frontal-striatal circuits, thereby improving executive functions such as attention, working memory, and impulse control through optimized prefrontal cortical activity. Its potential for abuse is linked to robust DAT inhibition in the nucleus accumbens, which elevates dopamine in this reward pathway and promotes reinforcing effects similar to other psychostimulants.

Pharmacokinetics

Dexmethylphenidate is readily absorbed after oral administration, with approximately 90% of the dose absorbed from the gastrointestinal tract, though its mean absolute oral bioavailability is 22-25% owing to extensive first-pass hepatic metabolism. For the immediate-release (IR) formulation, plasma concentrations increase rapidly, achieving a maximum (Tmax) of approximately 1 to 1.5 hours in the fasted state. The extended-release (XR) formulation exhibits a bimodal absorption profile, with initial and secondary peaks at about 1.5 hours (range: 1-4 hours) and 6.5 hours (range: 4.5-7 hours), respectively, providing a delayed release to extend therapeutic duration. The volume of distribution for dexmethylphenidate is approximately 2.65 ± 1.11 L/kg, indicating moderate distribution into body tissues, and it efficiently crosses the blood-brain barrier to exert central effects. is low, ranging from 12-15%. Metabolism of dexmethylphenidate occurs primarily via hydrolysis by (CES1) in the liver and erythrocytes, converting it to the inactive d-ritalinic acid (d-α-phenyl-piperidine acetic acid), with minimal interconversion to the l-threo . The mean terminal elimination is about 2.2 hours for the IR formulation and approximately 3 hours for XR in adults (2-3 hours in pediatric patients), resulting in a clearance of 0.40 ± 0.12 L/hr/kg. The XR formulation extends the effective duration beyond the IR due to its release mechanism. Excretion is predominantly renal, with about 90% of the dose recovered in primarily as (accounting for ~80% of the administered dose) and less than 0.5% excreted unchanged as parent compound. Pharmacokinetic variability includes differences, with area under the curve (AUC) 25-35% higher and maximum concentration (Cmax) ~45% higher in females compared to males; pediatric patients (ages 6-12) show plasma concentrations roughly twice those of adults on a mg/kg basis due to differences in body size and clearance. Food effects are formulation-dependent: a high-fat delays Tmax to ~2.9 hours for IR without significantly altering Cmax or AUC, while for XR, food may slow early onset but does not reduce overall exposure. Steady-state concentrations are typically achieved within 3-5 days of repeated dosing given the short .

Chemistry and Formulation

Chemical Properties

Dexmethylphenidate hydrochloride is a chiral molecule with the IUPAC name (2R,2'R)-(α-phenyl-2-piperidineacetic acid) methyl ester hydrochloride. Its molecular formula is C14H19NO2·HCl, and it has a molecular weight of 269.77 g/mol. The compound features two chiral centers: one at the α-carbon of the acetic acid moiety and the other at the 2-position of the piperidine ring. As the dextrorotatory threo of , dexmethylphenidate exhibits optical activity due to its specific (2R,2'R) configuration, which is responsible for its pharmacological potency compared to the inactive l-enantiomer. This enantiomeric purity allows dexmethylphenidate to achieve equivalent therapeutic effects at approximately half the dose of racemic . Physically, dexmethylphenidate appears as a white to off-white crystalline powder. It is freely soluble in water and , soluble in alcohol, and slightly soluble in and acetone. The pKa value is 8.9, reflecting its basic nature as a derivative. The compound remains stable when stored at (20–25°C), with excursions permitted to 15–30°C. Dexmethylphenidate is typically synthesized through enantiomeric resolution of racemic using derivatives, such as dibenzoyl-D-, in an organic solvent to isolate the desired (2R,2'R) .

Available Formulations

Dexmethylphenidate is commercially available under the brand name Focalin as immediate-release tablets in strengths of 2.5 mg, 5 mg, and 10 mg dexmethylphenidate hydrochloride. The extended-release formulation, Focalin XR, is offered as capsules in strengths of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg . These capsules employ Spheroidal Oral Absorption (SODAS) technology, featuring microbeads that provide a bimodal release profile: half immediate-release beads and half enteric-coated, delayed-release beads. Another extended-release option is Azstarys, approved by the FDA in March 2021, which combines dexmethylphenidate hydrochloride with serdexmethylphenidate hydrochloride ( that converts to dexmethylphenidate) in capsules providing once-daily dosing. Available strengths include 26.1 mg serdexmethylphenidate/5.2 mg dexmethylphenidate, 39.2 mg/7.8 mg, and 52.3 mg/10.4 mg. The formulation uses immediate-release dexmethylphenidate for rapid onset and the for extended release over 13 hours. Generic equivalents of both immediate-release tablets and extended-release capsules have been available since , following FDA approval of the first generic versions. Due to its composition as the active d-isomer, dexmethylphenidate achieves similar to racemic at approximately half the total daily dose. Inactive ingredients in Focalin immediate-release tablets include lactose monohydrate, , , pregelatinized starch, and sodium starch glycolate, with strength-specific colorants such as FD&C Blue No. 1 aluminum lake in the 2.5 mg tablets. Focalin XR capsules contain ammonio copolymer, , copolymer, , sugar spheres, , , , and colorants including FD&C Blue No. 2 and yellow iron oxide. Formulations should be stored at controlled (20°C to 25°C; excursions permitted between 15°C and 30°C) in a tight , protected from and . The typical is 2 to 3 years from the date of manufacture when stored appropriately. In 2025, Cingulate Therapeutics' CTx-1301, a novel abuse-deterrent extended-release formulation of dexmethylphenidate using Precision Timed Release technology for once-daily dosing, completed phase III trials and had its accepted by the FDA in October, with a target action date of May 31, 2026.

History and Society

Development and Approval

Dexmethylphenidate, the pharmacologically active d-threo-enantiomer of racemic , was developed as a refined to enhance efficacy while potentially minimizing side effects associated with the less active l-enantiomer. Originally synthesized and advanced by Corporation in the , the compound was licensed to Pharmaceuticals for global commercialization under the brand name Focalin. Preclinical studies during this period established that dexmethylphenidate exhibits approximately twice the potency of racemic in inhibiting , supporting lower dosing requirements. Clinical development progressed through phases focused on pediatric ADHD populations. Two pivotal phase III, multicenter, double-blind, -controlled trials conducted from 1999 to 2001 enrolled a total of 687 children aged 6 to 12 years, demonstrating significant symptom reductions on the Connors ADHD Index compared to , with doses of 10, 15, and 20 mg daily. These trials confirmed comparable to equimolar doses of immediate-release racemic but with potentially improved tolerability profiles. The U.S. (FDA) approved the immediate-release formulation of dexmethylphenidate hydrochloride on November 13, 2001, for treating (ADHD) in children aged 6 years and older, marking it as the first single-enantiomer product. Building on this, the extended-release capsules (Focalin XR) received FDA approval on May 26, 2005, after pharmacokinetic studies showed to the immediate-release version and bimodal release characteristics enabling once-daily administration. Pediatric exclusivity, granted under the Best Pharmaceuticals for Children Act, extended market protections for both formulations by six months, delaying generic entry until mid-2007. Post-approval regulatory actions emphasized risk mitigation for misuse. In 2010, the FDA approved labeling updates for Focalin and Focalin XR to strengthen warnings on abuse potential, dependence, and cardiovascular risks, aligning with class-wide guidance. By 2023, dexmethylphenidate ranked as the 127th most prescribed medication , with approximately 4.8 million outpatient prescriptions dispensed. Ongoing development includes advanced extended-release formulations, such as CTx-1301, which is under FDA review following phase III trials evaluating its triple-bead release profile for improved onset and duration in pediatric and adult ADHD patients. In the United States, dexmethylphenidate is classified as a Schedule II controlled substance under the , a designation it has held since its approval as Focalin in , due to its high potential for abuse and dependence similar to other products. Prescribers must register with the (DEA) to handle Schedule II substances, and prescriptions require a valid , with no refills allowed without a new prescription. Internationally, dexmethylphenidate's status varies by jurisdiction. In , it falls under Schedule III of the , alongside other prescription stimulants like , permitting medical use with strict oversight but lower abuse potential classification than Schedule II. Within the , it is regulated as a psychotropic substance under the , available by prescription in all member states for ADHD treatment, though specific national controls (e.g., Anlage III in requiring special forms) apply. In , dexmethylphenidate is prohibited as part of broader restrictions on medications for ADHD, with import banned without special certification, reflecting stringent narcotics laws. Prescription of dexmethylphenidate in the is limited to treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years and older, typically initiated by qualified healthcare providers following comprehensive evaluation, though physicians may prescribe after specialist consultation in many cases. Some states mandate security-enhanced or official prescription forms for Schedule II drugs to prevent forgery, replacing older triplicate systems with or tamper-evident paper. Following DEA rule extensions in 2023 and beyond, prescribing of Schedule II substances like dexmethylphenidate is permitted without an initial in-person exam under certain conditions, including audio-video encounters and limited to established patients, with flexibilities extended through December 31, 2025, to ensure access while permanent rules are developed. Dexmethylphenidate is widely available in generic form in the and , with FDA approval of generics since facilitating lower costs, typically ranging from $50 to $200 per month depending on dosage and insurance coverage. In developing countries, access remains limited due to high out-of-pocket costs, regulatory barriers, and issues, often resulting in reliance on alternative ADHD treatments or unmet needs.

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