Chemistry:Dexmethylphenidate

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. It is taken by mouth. The immediate-release formulation lasts up to five hours while the extended-release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate. Methylphenidate has been shown to be more effective than atomoxetine and superior in treating ADHD symptoms when compared.

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

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

Medical uses

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.

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

Contraindications

{{#section-h:Methylphenidate|Contraindications}}

Adverse effects

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate. {{#section-h:Methylphenidate|Adverse effects}}

Interactions

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.

{{#section-h:Methylphenidate|Interactions}}

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. It has also been demonstrated to reduce ADHD symptoms in both children and adults. d-MPH has a similar side-effect profile to MPH and can be administered without regard to food intake.

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.

Mechanism of action

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

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.

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.

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. In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product.

Compd	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