ADHD: how methylphenidate interacts with cognitive control networks and attention behaviors


For decades, doctors have treated kids with attention-deficit/hyperactivity disorder (ADHD) with methylphenidate, a stimulant drug sold as Ritalin and Concerta, making it one of the most widely prescribed medications aimed at the central nervous system.

One might expect that researchers would know how methylphenidate works in the brain by now, but little is known about the drug’s mechanism of action.

Now, a new study seeks to close this gap and understand how methylphenidate interacts with cognitive control networks and attentional behavior.

The new study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

What researchers do know is that individuals with ADHD have lower dopamine signaling activity than neurotypical individuals in the interconnected brain networks that control attention and goal-directed behaviors.

Specifically, methylphenidate is hypothesized to ameliorate ADHD symptoms by increasing dopamine levels in the nucleus accumbens (NAc), a hub for dopamine signaling.

In the new study, researchers led by Yoshifumi Mizuno, MD, Ph.D., Weidong Cai, Ph.D., and Vinod Menon, Ph.D., used brain imaging to explore the effects of methylphenidate on the NAc and a so-called triple network system that plays a key role in behaviors that require adaptive control of attention.

The three networks include the salience, frontoparietal, and default mode networks. Aberrant activity was detected in the NAc and in multiple brain networks in children with ADHD, suggesting that dysregulation in the system may underlie ADHD symptoms, and that correcting the dysfunction might alleviate those symptoms.

“Our findings demonstrate in two independent cohorts that methylphenidate changes spontaneous neural activity in reward and cognitive control systems in children with ADHD. Medication-induced changes in cognitive control networks result in more stable sustained attention.

“Our findings reveal a novel brain mechanism underlying methylphenidate treatment in ADHD and inform biomarker development for evaluating treatment outcomes,” noted Dr. Menon, Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine.

The researchers used functional magnetic resonance imaging (fMRI) to measure the effects of methylphenidate on spontaneous brain activity in 27 children with ADHD and 49 typically developing controls. Children with ADHD were scanned during two different visits one to six weeks apart – once while receiving methylphenidate and once while receiving a placebo. (Typically developing children did not receive medication or placebo.)

Outside the scanner, children with ADHD also performed a standardized task to assess sustained attention. Additionally, the researchers tested the replicability of methylphenidate’s effects on spontaneous brain activity in a second independent cohort.

Not surprisingly, children performed better on the attention tasks when they were medicated. And as the researchers hypothesized, they also saw greater spontaneous neural activity in the NAc and the salience and default mode networks when methylphenidate was administered.

Children with ADHD who displayed enhanced changes in brain activity patterns in the default mode network with medication performed better on the attention tasks with medication.

Findings were replicated across two independent cohorts, providing further evidence that methylphenidate may alleviate ADHD symptoms by its actions on the NAc and the triple network cognitive system.

Cameron Carter, MD, editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, said of the study, “The findings, which used the widely available technique of resting-state functional MRI, confirm the positive effects of methylphenidate on attention in children with ADHD and reveal the likely mechanism of action, through improved coordinated brain network activity and a likely key role for enhanced dopamine effects in the NAc region of the brain.”

The work advances researchers’ understanding of how ADHD affects cognitive control networks in the brain and how methylphenidate interacts with these networks to shift behavior. The findings could guide future work using brain imaging as a clinically useful biomarker of response to treatments.


Methylphenidate is FDA-approved for treating attention deficit hyperactivity disorder (ADHD) in children and adults and as a second-line treatment for narcolepsy in adults.[1][2] 

Children diagnosed with ADHD should be at least six years of age or older before being started on this medication. The treatment of both ADHD and narcolepsy have significantly better outcomes when used concurrently with nonpharmacologic therapies (i.e., social skills training in ADHD or sleep hygiene measures in narcolepsy). 

Off-label uses of methylphenidate include treatment for fatigue in patients with cancer, refractory depression in the geriatric population, apathy in Alzheimer disease, and enhancing cognitive performance (e.g., memory).[3][4][5][6][7][8]

Since it can be abused as a cognitive enhancer, it is a federally controlled Schedule II substance. The efficacy of methylphenidate for its off-label uses varies from limited to moderate. Most of these relatively newer uses are still being studied and implemented into clinical practice.

Mechanism of Action

Methylphenidate blocks the reuptake of two neurotransmitters, norepinephrine (NE) and dopamine, in presynaptic neurons. More specifically, it inhibits the transporters of these neurotransmitters, increasing the concentration of dopamine and NE in the synaptic cleft.[9] 

This creates its classic stimulant effect within the central nervous system (CNS), mainly in the prefrontal cortex. It chemically derives from phenethylamine and benzylpiperazine. It undergoes metabolism by the liver to ritalinic acid through a process called de-esterification via carboxylesterase CES1A1.

Compared to other medications (i.e., amphetamines) that are phenethylamine derivatives, methylphenidate appears to increase the firing rate of neurons.[10] It is also a weak agonist at the 5HT1A receptor, which is an additional mechanism that contributes to the increased levels of dopamine.[11] 

With the increase in dopamine levels, methylphenidate can provide neuroprotection in certain conditions like Parkinson disease, which involves loss of dopaminergic neurons and methamphetamine abuse.[12] This effect occurs not only through its direct inhibition of the dopamine transporter but also via indirect regulation of the vesicular monoamine transporter 2.

The combined interactions methylphenidate has on both of these transporters reduce the amount of dopamine that accumulates within the cytoplasm in patients with these conditions, thereby preventing the formation of reactive oxygen species that would otherwise be dangerously toxic to the brain. 


The therapeutic dosages for ADHD or narcolepsy that physicians prescribe are not harmful enough to activate the reward system within the CNS, known as the nucleus accumbens. However, excessively higher dosages taken by those who intentionally abuse the drug lead to an overexpression of deltaFosB, a transcriptional activator, in specific neurons within the striatum. This accumulation of deltaFosB in the nucleus accumbens activates a series of signaling cascades that further triggers the addiction.[13]


  • Absorption: Slow but extensive; relative bioavailability for extended-release tablets 105% in children and 101% in adults (verses immediate-release tablets); the absolute oral bioavailability for extended-release capsules in children was 22% and 5% for d-methylphenidate and l-methylphenidate, respectively. 
  • Time of peak plasma concentration: 1.9 hours for immediate-release tablets and 4.7 hours for extended-release tablets
  • Food effects: Increase total exposure and peak plasma concentration; reduce the time for peak plasma concentration for extended-release tablets.
  • Alcohol effect: 98% of the drug from extended-release 40 mg capsule dosage form was released in an alcohol concentration of 40% in an in-vitro study.
  • Distribution: Volume of distribution was 2.65 and 1.80 L/kg for d- methylphenidate and l- methylphenidate, respectively.
  • Plasma Protein Binding: 10% to 33%
  • Metabolism: It is primarily metabolized by de-esterification to ritalinic acid, which is pharmacologically inactive.
  • Excretion: A majority of the drug (78% to 97%) is excreted in the urine, while small amounts are excreted in feces.


For medical purposes, methylphenidate is mainly given orally or, less commonly, as a transdermal patch. Multiple oral formulations are available that categorize according to how quickly the drug is released: immediate (IR), extended (XR or ER), and sustained. Two of the more unique formulations of methylphenidate are its ER sphenoidal oral drug absorption system that has a bimodal release and the osmotic (controlled) release delivery system.

There are chewable tablets (either IR or ER) for children and an IR solution. Doses should not exceed 72 mg, the maximum dose of the ER tablet. If using the transdermal patch, the patient must be aware of placing the patch on the opposite hip each time to achieve its full effect. Those who misuse methylphenidate for recreational purposes prefer to use the intravenous (IV) or the intranasal route. Assess the risk of abuse before prescribing methylphenidate in any form.

Available Dosage Forms and Strengths 

  • Attention deficit disorder (ADD) in adults and pediatric patients (6 years and older) and for narcolepsy
    • Chewable tablets: 2.5 mg, 5 mg, and 10 mg
    • Immediate-release tablets: 5 mg, 10 mg, and 20 mg
  • Attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients (6 years and older) and for narcolepsy
    • Immediate-release tablets: 5 mg, 10 mg, and 20 mg
    • Extended-release tablets: 10 mg, 20 mg, 18 mg, 27 mg, 36mg, 54 mg, and 72 mg
    • Extended-release tablets (24 hours): 18 mg, 27 mg, 36mg, and 54 mg
    • Extended-release capsules: 10 mg, 20 mg, 30 mg, and 40 mg
    • Extended-release capsules CD: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg
    • Solution: 5 mg/ 5 ml and 10 mg / 5 ml in 500 ml bottle
    • ADHD in adults and pediatric patients (6 years and older) as well as for narcolepsy
  • Attention deficit hyperactivity disorder (ADHD) in pediatric patients (age 6 to 17 years)
    • Orally disintegrating tablets: 8.6 mg, 13.7 mg, and 25.9 mg
    • Patch: 10 mg, 15 mg, 20 mg, and 30 mg nominal dose over 9 hours

 Specific Patients Population 

  • Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment.
  • Patient with Renal Impairment: There is no dose adjustment guidance in the manufacturer label for patients with renal impairment. However, most of the drug and its metabolites are excreted in the urine. 
  • Pregnant Women: It is considered as pregnancy category C medicine. Many researchers studied methylphenidate during pregnancy to treat ADHD and narcolepsy, However, data is conflicting so use the medication with caution.[14][15][16][17]
  • Breastfeeding Women: It is recommended to monitor and keep relative infant dose below 10% while using methylphenidate therapy in nursing mothers as the drug is present in breast milk.[18][19]
  • Pediatric Patients: There are multiple dosage forms and strengths available for pediatric patients ages ranging from 6 years to 17 years.
  • Geriatric Patients: There is no specific dose adjustment guidance available.

Adverse Effects

Insomnia and nervousness are the most commonly reported adverse effects in patients using methylphenidate.[20]

Growth retardation (decreased height, weight, and bone marrow density) is observed when taken long-term in children.[21]

Other frequent side effects mainly involve the CNS (dizziness, headache, tics, restlessness/akathisia), gastrointestinal (nausea/vomiting, dry mouth, decreased appetite, weight loss, abdominal pain), and cardiovascular systems (tachycardia, and palpitations).

Dermatologically, patients can complain of excessive sweating and ulceration of their digits.

Some patients may even develop blurry vision or decreased libido. While it rarely occurs, priapism is a medical emergency that requires immediate attention.[20] 

Patients are more prone to become easily agitated, irritable, or depressed and go through mood swings/lability.

While many common side effects can be relieved by adjusting the dosage or avoiding an afternoon or evening dose, some require treatment emergently to prevent complications.

It is important to note that there have been reported cases of sudden death in both children and adults with a pre-existing structural cardiac abnormality.[22] Stroke and myocardial infarction also have been observed in adults. Due to the risk of such fatal side effects, it is advisable to avoid methylphenidate in patients with a structural cardiac abnormality, cardiomyopathy, or arrhythmias.[23]

Drug Interactions: Methylphenidate can inhibit the metabolism of warfarin, phenytoin, tricyclic antidepressants, or SSRIs and can increase plasma concentration.


Patients must not use methylphenidate if they are currently on monoamine oxidase inhibitors (MAOIs). There should be a minimum of at least 14 days after discontinuation of MAOIs before methylphenidate can be considered a safe treatment option to begin due to the risk of hypertensive crisis.

Medical conditions that are not compatible with methylphenidate include glaucoma, severe hypertension, motor tics, Tourette syndrome, or a family history of Tourette syndrome.

If a patient is noticeably anxious, tense, or agitated, then seek alternative treatment options. However, it can be given cautiously in patients with a history of bipolar disorder or psychosis as long as clinicians are wary of mania or psychotic episodes induced by the medication.[12]

Any patient who develops a hypersensitive reaction to methylphenidate or an individual component of a formulation should have the medication immediately discontinued and switch to another pharmacologic agent.

Children under the age of six should not be prescribed this medication as there are limited studies to prove its safety or benefit, and it could cause learning impairments.


Since it has the potential risk of abuse, monitor patients for signs of dependence and or abuse while on therapy.

A complete blood count with differential should be obtained periodically for those on methylphenidate.

The main vitals to note at each visit are blood pressure and heart rate, especially in patients with underlying hypertension, heart failure, a recent MI, or ventricular arrhythmia, as slight elevations can occur with methylphenidate use. In addition, if a patient complains of cardiac symptoms, such as chest pain, that worsens with exertion or has a near-syncope episode, then a full cardiac workup should be performed.

In children, it is essential to evaluate their growth curve for a stable progression in height, and weight since methylphenidate has demonstrated growth suppression when used daily, long-term. The medication should either be readjusted or discontinued if children are not in a healthy percentile on their growth curve.[21]

Clinicians should screen for symptoms of depression, agitation, aggressiveness, new-onset or pre-existing psychosis or mania, and suicidality as these can be worsened when initially starting methylphenidate. Physicians should also monitor for signs of intravenous abuse as frank psychotic episodes can develop.

On physical exam, look for peripheral vasculitis (digital ulceration). 

Controversial evidence exists regarding the potential for methylphenidate to affect seizure threshold. If seizures develop while being treated with methylphenidate, the prescribing clinician should immediately stop the drug.[24][25]

In adults, patients should limit their alcohol use while taking methylphenidate as its stimulant action can mask the actual sedative effect caused by alcohol intoxication, possibly inducing severe respiratory depression.

Additionally, a patient who is concurrently on warfarin, phenytoin, tricyclic antidepressants, or SSRIs should have their drug levels monitored and adjust doses as needed to achieve a therapeutic effect.


The first step in a medication overdose is to immediately contact a poison control center for the appropriate management steps. Doses that exceed 60 mg of the IR (immediate-release) formulation or 120 mg of the ER (extended-release) formulation can be considered toxic. If the overdosed quantity is unknown, look for signs and symptoms such as tremors, hyperreflexia, convulsions, euphoria, confusion, hallucinations, delirium, flushing, and fever, in addition to the common adverse effects mentioned above. Supportive care with supplemental oxygen, IV fluids and external cooling methods is the mainstay of treatment. Multiple studies have shown that benzodiazepines are an option, especially if dystonia, agitation, or convulsions are present.[20]

Enhancing Healthcare Team Outcomes

It is essential to gather a thorough history from the patient (or patient’s legal guardian) regarding their past medical history, current medications, and social history (obtain a developmental history if the patient is a child). An interprofessional healthcare team consisting of the patient’s primary care provider, psychiatrist, nurse practitioners, physician assistants, social workers, therapists, school teachers, and pharmacists should oversee the patient case. Communication between each member of the healthcare team is crucial as medication combined with non-pharmacologic treatment measures provide the most long-term success. Evaluation of side effects requires close monitoring at each visit. If the patient is a child, it is crucial to give patient’s legal guardian education regarding the medication and its side effects. This interprofessional approach will optimize therapeutic results while limiting adverse events. [Level 5]


Studies have shown that medication alone is not as effective as when methylphenidate is combined with non-pharmacologic treatment measures. Patients with ADHD managed on both medication, and non-pharmacologic treatments have been shown to have higher self-esteem and social functioning skills versus those untreated. Long-term beneficial effects have been shown in adults with ADHD who continue to take methylphenidate. Further long-term studies are still in progress.[26][27]

reference link :

Original Research: Open access.
Methylphenidate enhances spontaneous fluctuations in reward and cognitive control networks in children with attention-deficit/hyperactivity disorder” by Yoshifumi Mizuno et al. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging


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